GENE-39911; No. of pages: 14; 4C: Gene xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

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Ha Zhu a, Cong-Cong Hou a, Ling-Feng Luo a, Yan-Jun Hu b,⁎, Wan-Xi Yang a,⁎⁎ a

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Article history: Received 30 March 2014 Received in revised form 24 July 2014 Accepted 24 August 2014 Available online xxxx

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Keywords: Decidualization Endometrium Implantation Endometrial stromal cells (ESCs) Decidualized stromal cells (DSCs)

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The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China

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Decidualization of endometrium, which is characterized by endometrial stromal cell (ESC) decidualization, vascular reconstruction, immune cell recruitment, and plentiful molecule production, is a crucial step for uterus to become receptive for embryo. When implantation takes place, ESCs surround and directly interact with embryo. Decidualized stromal cells (DSCs) are of great importance in endometrial decidualization, having a broad function in regulating immune activity and vascular remodeling of uterus. DSCs are shown to have a higher metabolic level and looser cytoskeleton than ESCs. What's the origin of ESCs and how ESCs successfully transform into DSCs had puzzled scientists in the last decades. Breakthrough had been achieved recently, and many studies had elucidated some of the characters and functions of DSCs. However, several questions still remain unclear. This paper reviews current understanding of where ESCs come from and how ESCs differentiate into DSCs, summarizes some characters and functions of DSCs, analyzes current studies and their limitations and points out research areas that need further investigation. © 2014 Published by Elsevier B.V.

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Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions

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Abbreviations: A, androstenedione; Adipod, adiponectin; AdipoR, adiponectin receptor; AJs, adherens junctions; a-SMAs, alpha smooth-muscle actins; 17b-HSD type 2, 17bhydroxysteroid dehydrogenase type 2; BMP2, bone morphogenetic protein2; CDKs, cyclindependent kinases; C/EBPβ, CCAAT enhancer-binding protein beta; CFUs, colony-forming units; ChM-I, chondromodulin-I; CKIs, cyclin-dependent kinase inhibitors; DCs, dendritic cells; DEDD, death effector domain-containing protein; DII4, Delta-like ligand 4; Dkk1, Dickkopf 1; dNK cells, decidual natural killer cells; DSCs, decidualized stromal cells; E2, estradiol; ECM, extracellular matrix; EGF, epidermal growth factor; EMP, endometrial main population; ERα, estradiol receptorα; ERβ, estradiol receptorβ; ERK, extracellular signal-regulated kinase; ESCs, endometrial stromal cells; ESP, endometrial side population; FADD, FASassociated death domain; FAK, focal adhesion kinase; FGFs, fibroblast growth factors; FOXO1A, forkhead boxO1A; FSH, follicle stimulating hormone; Fzds, seven-transmembrane frizzled receptors; GLUTs, facilitative glucose transporters; HCG, human chorionic gonadotropin; HIF, hypoxia-induced factor; HOXA10, homeoboxA10; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL, interleukin; LH, luteinizing hormone; LNs, lymph nodes; LPA, lysophosphatidic acid; LRP5/6, low density lipoprotein receptorrelated protein5/6; Ltf, lactotransferrin; MLC, myosin light chain; MLCK, MLC kinase; MMPs, matrix metalloproteinases; MSCs, mesenchymal stem cells; Muc1, mucin1; P4, progesterone; PCOS, polycystic ovarian syndrome; PDCs, primary decidual cells; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PDZ, primary decidual zone; PKA, protein kinase A; PPARs, peroxisome proliferator-activated receptors; PR, progesterone receptor; PRKAAI/AMPK, adipoq-induced AMP-activated protein kinase; PRL, prolactin; RPL, recurrent pregnancy loss; rRNA, ribosomal RNA; SDCs, secondary decidual cells; SDZ, secondary decidual zone; SFRP4, secreted frizzle-related protein4; TF, tissue factor; TGFβ, tumor growth factor-β; TNFβ, tumor necrosis factor-β; TIMPs, tissue inhibitor of metalloproteinases; uNK cells, uterus natural killer cells; VEGF, endothelial growth factor; Wnt, Wingless. ⁎ Corresponding author. ⁎⁎ Correspondence to: W.-X. Yang, The Sperm Laboratory, College of Life Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou 310058, China. E-mail addresses: [email protected] (Y.-J. Hu), [email protected] (W.-X. Yang).

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1. Introduction

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Implantation is a crucial part for successful pregnancy. During implantation, a semi-allogeneic embryo needs to be accepted by maternal endometrium. It is a sophisticated process that requires an elaborate bidirectional communication between embryo and uterus. Implantation contains four steps. The first step is initiation of dialogues between free-floating blastocyst and receptive endometrium, followed by apposition when trophoblast cells adhere to receptive endometrial luminal epithelium through interaction with pinpodes which are micro-protrusions on epithelial surface. Then a stable attachment is achieved when blastocyst adheres to endometrial basal lamina and stromal extracellular matrix (ECM). Finally, invasion comes up. The embryo penetrates through the luminal epithelium into stroma and gradually establishes a vascular relationship with the mother (Singh et al., 2011). Process of implantation is restricted in a short period called “window of receptivity” or “window of implantation” (Dharmaraj et al., 2009; Salker et al., 2010). In human, it occurs 6–7 days after fertilization (in the mid-secretory phase), and lasts for about 4 days (van Mourik et al., 2009). In mice, implantation takes place 4–5 days after ovulation, and lasts for about 1 day (Dharmaraj et al., 2009; Quinn and Casper, 2009). Quality of embryos and receptivity of endometrium are two indispensible factors for successful implantation. Aberrant endometrial receptivity is reported to implicate in more than 50% of in-vitro fertilization implantation failures (Salamonsen et al., 2009). There are three phases of endometrium in pregnant animals: neutral to implanting blastocyst (pre-receptive), receptive and resistant (non-

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http://dx.doi.org/10.1016/j.gene.2014.08.047 0378-1119/© 2014 Published by Elsevier B.V.

Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

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After menstruation, human endometrial tissues are competent to accomplish regeneration within a few days and make endometrial thickness alter from 0.5–1 mm to 5–7 mm. This process of regeneration can also occur after parturition, extensive resection and in postmenopausal women taking estrogen replacement therapy (Dimitrov et al., 2008; Gargett et al., 2009). Researchers try hard to figure out where the endometrial stem cells lie and what are the unique characters. Small quantity and lack of reliable markers make the work a bit difficult. Yet some breakthroughs have been achieved (Gargett et al., 2008; Kyurkchiev et al., 2010). It is reported that endometrial epithelial cells and ESCs have different stem cells (Gargett et al., 2008). As far as stromal cells are concerned, two types of stromal colony-forming units (CFUs) are found: large (0.02% of endometrial stromal cells) and small (1.23% of the endometrium stromal cells) (Gargett et al., 2008; Schwab and Gargett, 2007). Both large and small stromal colonies express fibroblast markers. Some cells express α-SMAs, which is indicative of myofibroblast differentiation. A hypothesis arises that large CFUs originate in stem/progenitor cell possibly located at the base of glands in the basalis, while small CFUs are derived from more differentiated transit amplifying cells, likely located in functionalis layer. Small CFUs are responsible for extensive proliferation observed in proliferative stage (Gargett et al., 2008). Yet it still needs more evidence to prove this hypothesis. A sub-population of human ESCs, CD146+PDGFRβ+ stromal cells, with mesenchymal stem cell properties of CFU activity and multi-lineage (fat, muscle, cartilage and bone) differentiation have been isolated. These cells are mainly located at endometrial–myometrial junctions and peri-vascular sites (Gargett et al., 2008; Schwab and Gargett, 2007). Growth factors like epidermal growth factor (EGF), transforming growth factor α, platelet-derived growth factor BB, and basic fibroblast growth factor are required for stromal cells' CFU activity (Gargett et al., 2008). In addition to CFUs, endometrial side population (ESP) has been reported to be capable of proliferating and differentiating into various

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decidualized stromal cells (DSCs) exhibit a larger number of ribosomes, residual bodies, lysosomes, mitochondria and microfilaments and accumulate more glycogen and lipids in cytoplasm (Ma et al., 2011; Muto et al., 2011; Oliver et al., 1999). The genetic and proteomic profiles are also largely changed (Duncan et al., 2011; Muto et al., 2011; Paule et al., 2011; Tapia et al., 2011; Yap et al., 2011). Markers such as prolactin (PRL) (Richards et al., 1995; Telgmann and Gellersen, 1998), insulinlike growth factor binding protein (IGFBP) (Kim et al., 1999; Richards et al., 1995) and Dickkopf 1 (Dkk1) (Kocemba et al., 2012; Saleh et al., 2011), are greatly up-regulated. It is suggested that some changed genes are critical for ESC transformation into DSCs. DSCs also participate in ECM remodeling by secreting collagen IV, fibronectin, laminin and alpha smooth-muscle actins (a-SMAs) and so forth (Saleh et al., 2011). DSCs have an impact on the receptivity of endometrium and thus influencing the implantation and pregnancy. Implantation failure (Salamonsen et al., 2009), recurrent pregnancy loss (RPL) (Teklenburg et al., 2010), endometriosis (Yotova et al., 2011) and preeclampsia (Menkhorst et al., 2012) are proved to be related to impaired ESC decidualization. Like stromal cells in nervous system (Cooper et al., 2012) and thymus (Lei et al., 2011), stromal cells in endometrium take on appealing responsibility. Many investigators are attracted by the significant power of ESCs and kinds of research models are established. The tremendous alterations of ESCs during secretory phase involve numerous factors, signal networks, many of which are still unclear. So, it is necessary to write a review article about ESCs. In this review, we will focus on current knowledge about ESCs. Where do ESCs come from and how do they achieve transformation into DSCs? What are the main genes participating in this transformation? What are the characteristics of DSCs and how do DSCs interact with other components of endometrium to play part in implantation?

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receptive) (Das, 2009; Wilcox et al., 1999). Regulation of uterus is steroid hormone dependent. In humans, the fall in progesterone level does not induce regression of the endometrium but menstruation (Brosens and Gellersen, 2006). When women enter puberty, menstrual cycle starts. If oocyte is not fertilized, the functional endometrial layer will terminate in sloughing. Restoration commences in proliferative phase of the next cycle when circulating estradiol (E2) level rises. E2 promotes proliferation of both epithelial cells and stromal cells. After ovulation, endometrium enters into secretory phase, namely luteal phase. Progesterone (P4) level goes up, causing mitosis to be blocked and differentiation of E2-primed cells initiated. On the one hand, in luteal phase, glandular epithelial cells secrete implantation-promoting products into uterine lumen, so that luminal epithelial cells attain receptivity to blastocyst attachment (Lockwood et al., 2009a; Saleh et al., 2011). Several morphological changes of luminal epithelial cells, like types of surface protrusions, had been detected (Bartosch et al., 2011; Demir et al., 2002; Nikas, 2000). On the other hand, decidualization of endometrium starts, which is characterized by vascular leakage, angiogenesis and other vascular alterations (Bany and Hamilton, 2011; Li et al., 2011; Lockwood et al., 2009a), recruitment of immune cells (Salamonsen et al., 2009; Zhang et al., 2011), production of important molecules for implantation and embryo development (Singh et al., 2011), and decidualization of endometrial stromal cells (ESCs) (Singh et al., 2011). Morphologically, decidualized endometrium is distinctly different from non-decidualized endometrium. The superficial spiral arteries dilate and micro-vessel density is higher. Natural killer cells are recruited to the vicinity of spiral arteries. ESCs transform from spindleshaped cells into epithelioid cells and form a wide contact with vessels and immunocytes (Kara et al., 2007; Wewer et al., 1985). A few studies had revealed some morphological changes about decidualization on basis of ultrastructural images (Kajihara et al., 2014; Kara et al., 2007; Wewer et al., 1985). Decidualization widely happens in animals. In human, endometrial decidualization is not dependent on implanting conceptus. While in mice, it starts after implantation (Ramathal et al., 2010; Saleh et al., 2011; van Mourik et al., 2009). Although luminal endometrial epithelium is the primary barrier in implantation process, endometrial decidualization is of essential significance for pregnancy since it protects and nurtures embryo thus promoting embryo survival and development (Salamonsen et al., 2009). Interestingly, even though the outset of decidualization is independent of conceptus, the maintenance of decidualization is embryo-dependent (Saleh et al., 2011). ESCs are a key component of endometrium. When implantation takes place, ESCs surround the embryo and then establish a wide and direct interaction with the embryo (Castro-Rendón et al., 2006). ESCs produce numerous factors to mediate the activity of vascular endothelial cells (Hess et al., 2007; Niklaus et al., 2003), immune cells (Hess et al., 2007), and epithelial cells (Nallasamy et al., 2012; Osteen et al., 1994). Also, ESCs play a role in embryo recognition and selection (Salker et al., 2010). Decidualization of ESCs is a necessary process for ESCs to perform their duty. ESCs undergo proliferation and differentiation during decidualization and finally become decidual cells (Franco et al., 2011). This alteration is also E2 and P4 relevant and starts since midsecretory phase (Franco et al., 2011; Salker et al., 2010). Decidualization of stromal cells starts in the vicinity of terminal spiral arteries and under the glands around day 23 of a 28-day cycle and then spreads throughout the luteal phase and gestational endometrium (Gellersen et al., 2010; Lockwood et al., 2009a). After the invasion of trophoblasts, sequential decidual reactions result in the formation of two distinct zones: densely packed primary decidual zone (PDZ) proximal to the implanting embryo and broad secondary decidual zone (SDZ) in the distal peripheral which encircles PDZ (Luan et al., 2011; Miura et al., 2011). PDZ is avascular and composed of mature decidual cells. SDZ is rich in vessels and made up of immature mitotic decidual cells (Das, 2009; Miura et al., 2011). Typically, during differentiation, ESCs transform from spindleshaped form into enlarged, polygonal or round, polyploidy, epithelioid style (Ma et al., 2011; Pabona et al., 2010; Saleh et al., 2011). Besides,

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P4 and E2 are two critical steroid hormones contributing to endometrial alteration. Hormone regulation of the cycle of ESCs in mice has been drawn. On days 1 and 2 (day 1 = vaginal plug), pre-ovulatory ovarian

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E2 directs uterine epithelial cell proliferation. On day 3, when E2 expression is low, P4 from newly formed corpora lutea initiates stromal cell proliferation, which is further stimulated by pre-implantation E2 secretion on day 4. By contrast, epithelial cells cease to proliferate and become differentiated on this day. On day 4, the P4-primed uterus becomes receptive when complemented with pre-implantation ovarian E2 secretion (Das, 2009; Gargett et al., 2008; Nephew et al., 2000). Then uterus enters into the non-receptive state on day 5. During day 5 afternoon and day 6 morning, stromal cells which immediately surround the implanting blastocyst, stop proliferating and undergo differentiation into decidual cells, forming PDZ. By day 6, stromal cells next to PDZ continue to proliferate and differentiate into polyploidy decidual cells forming SDZ around PDZ. SDZ is fully developed by day 7, while PDZ degenerates progressively up to day 8. After day 8, the placental and embryonic growth slowly replaces the SDZ (Das, 2009; Nephew et al., 2000). However, hormone regulation of ESC proliferation and differentiation in human is not yet as so accurately determined as mice, due to ethical and moral reasons. We merely vaguely know that E2 stimulates ESC proliferation during proliferative phase, and then after ovulation, P4 and E2 co-regulate the proliferation and differentiation of ESCs. From midsecretory phase, differentiation of ESCs predominates over proliferation (Ramathal et al., 2010). When P4 withdraws, the inter-cellular junctions break and ESCs shed off. ESCs are the last cell type to shed off and epithelial cells first (Gaide Chevronnay et al., 2009; Gargett et al., 2008). Whether there is fluctuation of the two steroid hormones like mice is unknown. One of the important ways that E2 and P4 regulate the ESC cell cycle is via ERs and progesterone receptors (PRs) (Ramathal et al., 2010). There are two types of ERs, ERα and ERβ. Amusingly, though they are highly homologous and both ligand-activated regulatory proteins that act as homo- or hetero-dimmers on specific target genes (Nephew et al., 2000), they derive from separate genes and possess different ligand binding affinities (Lecce et al., 2001; Maliqueo et al., 2004). ERα and ERβ are both expressed in the stromal cells and the expression of ERα is much stronger than ERβ during the menstruation cycle, except at days 24–26 in the late-secretory phase when ERα becomes undetected. The highest level of ERβ is observed in the late-secretory phase and the expression of ERβ is low during menstrual cycle in other phases (Lecce et al., 2001). Whereas ERα is well known for its role in proliferation and differentiation, ERβ also has great functions. ERβ can partially replace ERα in the absence of ERα. Decidualization is normal in ERα−/− mice, but abnormal in ERβ−/− mice (Vallejo et al., 2005). P4 mainly functions via two isoforms of PR, PRA and PRB. Like ERα and ERβ, PRA and PRB have different functions. PRA regulates uterine development and reproductive function, while PRB is essential for mammary gland development. PRA–PRB heterodimer is the main co-expression pattern of PR dimmers in human. When P4 increases, PRA decreases and PRB becomes the predominant form of PRs (Scarpin et al., 2009). According to Vallejo et al. (2005) experiment in ERα −/− UIII cell model, progestin can bind to cytoplasmic PRB which has formed PRΒ–ERβ complex, thus activating ERβ in the absence of E2 and resulting in activation of Src/Ras/Erk and PI3K/Atk cascades, promoting the proliferation of stromal cells. ERβ can contribute to non-genomic way in addition to classical transcription way (Vallejo et al., 2005). Several studies have focused on P4 regulation of ERs (Okulicz et al., 1993; Okulicz and Balsamo, 1993). Four typical days are tested, day 13 (peak of E2), day 14 (declining E2 and rising P4), day 17 (basal E2 and rising P4) and day 21 (basal E2 and peak P4). ERs are present in stromal fibroblasts on day 13. On day 14 few distinct changes come about. On day 17, ERs decrease and the ER expression on day 21 is similar to day 17. The state of proliferation is consistent with the concentration of ERs (Okulicz et al., 1993). P4 reduces the function of E2 via down-regulation of ERs. E2 can upregulate PRs and ERα expression in stromal cells (Nephew et al., 2000; Okulicz and Balsamo, 1993). As discussed above, E2 promotes stromal cell growth and primes the uterus for P4 action, and P4 promotes differentiation of stromal

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types of endometrial cells, including stromal cells, endothelial cells and glandular epithelial cells. ESP, constituting approximately 2% of human endometrial cells, exhibits preferential expression of several endothelial cell markers, estradiol receptorβ (ERβ) for instance. In contrast, endometrial main population (EMP) cells mainly express estradiol receptorα (ERα) (Masuda et al., 2010). ESP is supposed to be localized near vascular endothelial cells and is implicated with angiogenesis. The proportion of ESP is largest right after menstruation and small in late secretory phase. Given this phenomenon, a hypothesis was put forward. ESP functions via asymmetrical cell division, and the total number of ESP cells may be almost unchanged. The increasing number of non-SP cells, EMP and endometrial replicative population cells, accounts for the dropping ratio of ESP. ESP is found in both basalis layer and functionalis layer. It is interesting that EMP cells are also found to be able to differentiate into stromal cells. But EMP cells can't differentiate into endothelial cells and glandular epithelial cells and EMP cells are mainly localized in the functionalis layer (Masuda et al., 2010). In this context, we can easily found great similarity between CFUs and ESP. They both localize near vessels in both basalis layer and functionalis layer and have rare number. More and more scientists suggest that they belong to bone marrow-derived human mesenchymal stem cells (MSCs) (Gargett et al., 2009). Treating bone-marrow derived MSCs with E2, P4, bone morphogenetic protein2 (BMP2) and activators of the protein kinase A (PKA) pathway, leads to cell shape alteration and decidual marker expression (Aghajanova et al., 2010). This confirms the close relationship between stromal cells and MSCs. MSCs express estradiol receptor (ER in human and ESR in mouse), progesterone receptor (PR in human and PGR in mouse) as well as luteinizing hormone (LH) receptor and follicle stimulating hormone (FSH) receptor. ESR mRNA is greatly up-regulated in response to FSH (Schwab et al., 2008). Similarly, ESP expresses ERβ rather than ERα. Co-culture ESP cells with EMP cells can stimulate more proliferation of ESP cells than ESP cells cultured alone, suggesting an indirect function between E2 and ESP via EMP (Gargett et al., 2009; Masuda et al., 2010). This may result from participation of ERα. To find out more proof of MSC theory, several researchers have tested ESCs by three characteristics of MSCs, especially the surface markers like CD29+ (Dimitrov et al., 2008; Schwab and Gargett, 2007), CD44+ (Schwab and Gargett, 2007), CD73+ (Dimitrov et al., 2008; Schwab and Gargett, 2007), CD90+ (Dimitrov et al., 2008; Schwab and Gargett, 2007; Schwab et al., 2008), CD105+ (Masuda et al., 2010; Schwab and Gargett, 2007), CD146+ (Masuda et al., 2010; Schwab and Gargett, 2007; Schwab et al., 2008), PDGFRβ+ (Schwab and Gargett, 2007), CD31− (Schwab and Gargett, 2007), CD34− (Schwab and Gargett, 2007), CD45− (Schwab and Gargett, 2007), and Stro-1− (Schwab and Gargett, 2007; Schwab et al., 2008). Schwab et al. (2008) confirm that Stro-1− and CD133 don't enrich for endometrial stromal CFUs, while CD90 + and CD146+ are potential markers for CFUs (Schwab et al., 2008). Recently, some researchers have identified CD29+CD73+CD90+ stromal cells as candidate endometrial stem/ progenitor cells (Dimitrov et al., 2008). It is still a hot and important area to draw a picture of stromal stem cells and find unique markers since some diseases like endometriosis are associated with stromal stem cells (Gargett et al., 2008). Many riddles remain to be solved. Why are there different kinds of ESC stem cells in endometrium? Is the function of CFUs and ESP redundancy or complementary? Would EMP cells be more differentiated cells rooted from ESP, somewhat like the relation of hematopoietic stem cell and oriented progenitors cells? If not, what's the relationship between EMP and ESP?

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3.2.1. Three Transcription Factors Necessary for Proliferation and Differentiation

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3.2.1.1. C/EBPβ (CCAAT Enhancer-Binding Protein Beta). C/EBPβ is a transcription factor that belongs to basic zipper (bZIP) protein family. The C/EBP family members regulate transcription of target genes by binding to a conserved ATTCGG/CCAAT box, a nucleotide sequence motif residing in the promoter regions (Bagchi et al., 2006). C/EBPβ involves multiple biological functions including cell proliferation, differentiation, inflammation, apoptosis and metabolism (Wang et al., 2010). In human, C/EBPβ is expressed in glandular and stromal cells during menstrual cycle. The nuclear C/EBPβ expression begins to increase on about cycle day 20 (mid-secretory phase), becomes extremely distinct in latesecretory phase and continues for the remainder of the cycle (Plante et al., 2009). E2 and P4 can induce the expression of C/EBPβ via ER and PR separately (Bagchi et al., 2006; Mantena et al., 2006; Wang et al., 2010). C/EBPβ is a mediator of the cAMP-dependent endometrial stromal decidualization. C/EBPβ can induce the expression of IGFBP, PRL in stromal cells by altering the histone acetylation status of their promoters (Tamura et al., 2014). The fact that C/EBPβ-null mouse stromal cells lose proliferative response to steroid hormones P4 and E2, and then fail to differentiate confirms the importance of C/EBPβ in regulating both proliferation and differentiation (Wang et al., 2010). Interestingly, Bagchi et al. (2006) have indicated that insufficient proliferation will lead to failed differentiation in mice (Bagchi et al., 2006). If so, differentiation may rely on proliferation. What's the mechanism underlying it?

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3.2.1.2. HOXA10 (Homeobox A10). HOXA10 is a transcription factor that belongs to the homeobox gene family. HOXA10 comprises a 61 amino acid residue polypeptide encoding a helix–turn–helix DNA-binding domain (Das, 2010; Lu et al., 2008). HOXA10 plays a role in uterine receptivity, implantation and decidualization. Like C/EBPβ, HOXA10 is expressed during menstruation and is increased during mid-secretory phase in humans (Das, 2010). However, HOXA10 is a bit downregulated in differentiated stromal cells. Expression of PRL and IGFBP can be induced by HOXA10 (Kim and Fazleabas, 2004; Lynch et al., 2009). HOXA10 null cells have a decreased rate of proliferation; however apoptosis process is not influenced (Lu et al., 2008). HOXA10 in stromal cells is primarily controlled by P4 and E2 (Das, 2010). The current graph of how HOXA10 regulates proliferation is that HOXA10 can stabilize cyclinD3 and cyclinB/CDC2 (CDK1). During differentiation, HOXA10 helps the pole alteration from CDK4 to CDK6. In HOXA10 null cells, more cells are blocked in G2/M phase and fewer cells in G0/G1 phase (Lu et al., 2008). HOXA10 can also suppress the expression of p57 (CDKN1C). Interestingly, p21 is repressed in HOXA10 null cells after deciduogenic stimulation (Das, 2009; Lu et al., 2008) (Table 1). This function is opposed to that of C/EBPβ. Some researchers suggest that though the total level of HOXA10 rises in mid-secretory phase in endometrium, the HOXA10 level in ESCs decreases. Thus p57 and p21 are upregulated, which may help ESCs exit proliferation (Qian et al., 2005) (Fig. 1). On the other hand, HOXA10/p/CAF/PTEN signaling is found in uterine decidualization. But the significance of this signaling remains unclear. p/CAF is a histone acetyltransferase interacting with other regulators like p300/CBP (Lu et al., 2008). PTEN is a tumor suppressor gene and inhibitor of PI3K/PKB signaling (Gellersen and Brosens, 2003).

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3.2.1.3. FOXO1A (Forkhead Box O1A). FOXO1A is a transcription factor that belongs to the FOXO sub-family of Fork-head/winged helix family. It has a common helix–turn–helix DNA-binding domain of up to 110 amino acids. FOXO1A involves in multiple cellular functions like proliferation, apoptosis and differentiation (Lam et al., 2012; Takano et al., 2007; Uhlenhaut and Treier, 2011). Like C/EBPβ, FOXO1A is expressed during menstruation and increased during mid-secretory phase in human. FOXO1A can also increase the expression of PRL and IGFBP (Kim and Fazleabas, 2004; Lynch et al., 2009). FOXO1A is mainly regulated by P4 and cAMP. During decidualization, cAMP induces the nuclear accumulation of FOXO1A. The transcriptional output is tightly regulated by P4. In response to P4 signaling, stromal cells accumulate inactive FOXO1A in the cytoplasm through SGK1 and Skp1/cul1/F-box pathways. As a result, decidual cells have a pool of inactive FOXO1A in cytoplasm and FOXO1A in nuclear as well. Withdraw of P4 causes

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Development of tissues requires coordinative regulation of exiting cell proliferative cycle and entering into differentiation. It is amazing that ESCs, which can be considered as differentiated cells from stem cells, still have cell cycles to proliferate somewhat like cancer cells, to exhibit unique morphological and functional differentiation. There must be precise unique cell cycle controls. Sanjoy K Das' review (2009) has shown different expressions of cyclins, cylin-dependent kinases (CDKs) and CDK inhibitors (CKIs) during the proliferation, differentiation and terminal differentiation (polyploidy) (Das, 2009). Three cyclins (D1, D2, D3), accumulating in late G1 phase, react with CDK4 or CDK6 and boost the formation of holoenzymes that facilitate the cell entry into S phase. When ESCs accomplish terminal differentiation, cyclin D3 can also express during S phase. CyclinB/CDK1 (or CDC2A) complex promotes G2-M phase transition (Das, 2009). p21, p27 and p57 belong to CIP/KIP family, which is a kind of CKIs (Qian et al., 2005). Many mediators can influence the expression of cyclins, CDKs and CKIs, thus regulating proliferation and differentiation of ESCs. Here we will discuss several mediators important for cell cycle control of ESCs.

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More in-depth researches are in need. The current graph of the C/EBPβ regulation of proliferation is that C/EBPβ maintains the expression levels of CDC25C and thus keeping the activity of CDK1 by dephosphorylation of Thr14/Tyr15 sites against the function of Wee1 and Myt1 kinases. In this way, C/EBPβ strengthens the function of cyclinB/CDK1, enables cells enter into mitotic phase and promotes proliferation. Moreover, C/EBPβ can bind to the promoter of p53 and suppress its transcription. p53 is a cell cycle repressor capable of arresting cell cycle at G1 to S and G2 to M checkpoints. Intriguingly, only the p53 expressed during G2/M phase is suppressed. C/EBPβ can also repress the expression of p21 (transcriptional target of p53) and p27 (interference of G1/S and G2/M cyclins) (Wang et al., 2010) (Table 1, Fig. 1). In addition, PRs are demonstrated to be competent in associating with two C/EBPβ isoforms, LAP and LIP and the functional consequences of this interaction are dependent on the relative ratios of PRs and C/EBPβ. C-Jun transactivation of AP-1 implicates in this interplay (Gellersen and Brosens, 2003). It is reasonable to say that C/EBPβ may be a candidate way of P4 to regulate stromal cell proliferation. To authors' knowledge, how C/EBPβ specially contributes to the cyclins changes during differentiation is still unclear. Since C/EBPβ is conserved and functions extensively, more depth research is necessary and of great significance.

T

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cells. The balance of ERs and PRs can be a vital mediator of complex crosstalk between E2 and P4. Network of signal ways associated with pregnancy is downstream or regulators of E2 and P4, like BMP7 (Kodama et al., 2010), Wnt/β catenin (Rider et al., 2006), FOXOA1 (Brosens and Gellersen, 2006), C/EBPβ and HOXA10 (Ramathal et al., 2010). Both E2 and P4 are regulated by HCG and LH (Chambers et al., 2011; Fujiwara, 2009; Robker et al., 2009). Besides E2 and P4, there are other hormones participating in ESC cycle regulation, androstenedione (A) included (Maliqueo et al., 2004). A can promote proliferation and inhibit apoptosis of ESCs through androstenedione receptor (Maliqueo et al., 2004). Besides, A is crucial for the morphological changes of ESCs and can enhance the expression of PRL and EGF receptor (Kajihara et al., 2014; Maliqueo et al., 2004). Yet, no significant modifications are found in the expression of ERα, ERβ, and BLC-2, Bax of ESCs when treated with A. Hyperandrogenemia can result in polycystic ovary syndrome (PCOS) (Maliqueo et al., 2004). It is believed there is a crosstalk among A, E2 and P4 (Siiteri, 1978). This is a field acquiring further research.

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382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 Q13 397 398 399 400 401

404 405 406 407 408 409 410 Q14 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 Q15

432 433 434 435 Q16 436 437 438 Q17 439 440 441 442 443 444

H. Zhu et al. / Gene xxx (2014) xxx–xxx t1:1 t1:2

5

Table 1 Factors and proteins involved in regulating transformation of ESCs to DSCs. Name

Type

Functions

Stages

Ref.

t1:4 t1:5

Transcription factors C/EBPβ CCAAT enhancer-binding protein beta

Member of basic zipper (bZIP) protein family

Proliferation Differentiation

Wang et al. (2010), Bagchi et al. (2006)

t1:6

HOXA10

Homeobox A10

Member of the homeobox gene family

Proliferation Differentiation Polyploidization

Lu et al. (2008), Das (2009)

t1:7

FOXO1A

Forkhead box O1A

Member of the FOXO sub-family of Fork-head/winged helix family

Stabilizes CyclinB/CDK1 Suppresses p53, p21, p27 Alters CyclinD3/CDK4 to cyclinD3/CDK6 Stabilizes CyclinB/CDK1, cyclinD3 Induces p21 Suppresses p57 Induces p57 Suppresses cyclinB/CDK1

Differentiation Polyploidization

Lam et al. (2012), Takano et al. (2007), Uhlenhaut and Treier (2011)

t1:8 t1:9 t1:10

Proteins Dkk1

Dickkopf-1

Secreted glycoprotein

Suppresses Wnt/β-catenin

t1:11 Q2

Wnt

Wingless

Secreted glycoprotein

Induces cyclin D1 and c-myc

t1:12

DEDD

Death effector domaincontaining protein

Member of death effector domaincontaining protein family

t1:13 Q3

SFRP4

Secreted frizzle-related protein4

Member of secreted frizzle-related protein family

Blocks cyclinB/CDK1 stabilizes CyclinD3/CDK4 CyclinD3/CDK6 Suppresses Wnt/β-catenin

455

O

R O

P

T

C

454

3.2.1.4. Dkk1 (Dickkopf-1) and Wnt (Wingless) Important for Proper Proliferation and Differentiation. Wnt signaling pathway, a crucial and

E

452 453

re-accumulation of nuclear FOXO1A and leads to stromal cell apoptosis and endometrium shedding (Lam et al., 2012). The deep mechanism under this process is a mystery. The graph of FOXO1A regulating stromal cell proliferation is that FOXO1A induces the expression of p57, repress several important genes for S and G2/M phases, including cyclinB/ CDC2 (Lam et al., 2012). So the rising amount of FOXO1A in stromal cells during differentiation may be important for transformation from proliferation to differentiation (Table 1, Fig. 1). It is reported that FOXO1A interplays with C/EBPβ (Kajihara et al., 2013).

conserved pathway which is active from drosophila to human, consists of noncanonical form and canonical form (Sonderegger et al., 2010). Wnts, secreted glycoproteins, regulate cellular processes such as proliferation and differentiation (Carmon and Loose, 2008; Sonderegger et al., 2010). There are currently 19 known mammalian Wnts and 10 seventransmembrane frizzled receptors (Fzds). Wnt4 and Wnt7b are strongly increased in stromal cells around the implantation embryo. Their expression is much higher in implantation sites than non-implantation sites. Cross-talk between E2 and P4 with Wnts is identified (Sonderegger et al., 2010). β-Catenin is a central downstream in canonical Wnt signaling (Peng et al., 2008; Sonderegger et al., 2010). Progesterone initiates Wnt signaling in the ESCs by GSK-3B down-regulation and β-catenin

R

450 451

Carmon and Loose (2008)

R

448 449

Proliferation

N C O

446 447

Differentiation Polyploidization

Wang et al. (2000), Sonderegger et al. (2010), Macdonald et al. (2011) Rider et al. (2006), Carmon and Loose (2008), Wang et al. (2000), Sonderegger et al. (2010) Miyazaki and Arai (2007), Mori et al. (2011)

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Differentiation Polyploidization Proliferation Differentiation Polyploidization

D

Q1

E

Full name

F

t1:3

Fig. 1. Control of the cell cycle of ESCs during proliferation, differentiation and polyploidization (terminal differentiation). G1/S and G2/M are two critical checkpoints of cell cycle. CyclinD3/ CDK4 or CDK6 is critical for G1/S, and cyclinB/CDK1 is important for G2/M. p57, p27, p53, and p21 are negative regulators of G1/S and G2/M phase. ESCs have unique cell cycle control to accomplish proliferation, differentiation and polyploidization transformation. During proliferation, HOXA10 stabilizes cyclinD3/CDK4, inhibits p57.Wnt/β-catenin signaling stabilizes cyclinD1 and SFRP4 regulates Wnt/β-catenin signaling to avoid tumor. C/EBPβ only inhibit the expression of p27, p53 and p21 in G2/M, rather than G1/S. C/EBPβ can suppress p21, while HOXA10 exhibits opposed function. C/EBP β and HOXA10 stabilize cyclinB/CDK1. To transform from proliferation to differentiation, FOXO1A is upregulated and promotes the expression of p57. Dkk1 succeeds SFRP4 strongly inhibiting the expression of Wnt/β-catenin. Besides CDK6 expression is upregulated and CDK4 expression decreased under the modulation of HOXA10. DEDD can stabilize cyclin D3. Whether DEDD participate in the CDK4/CDK6 alteration is unclear. The level of HOXA10 decreases, as a result p57 increase. When entering into terminal differentiation (polyploidization), DEDD disables cyclinB/CDK1 and blocks the G2/M checkpoint, thus the cell stops getting into M phase and commencing polyploidization. CDK6 totally replaces CDK4 and cyclinD3/CDK6 begins to strongly express in S phase. This figure is just part of the ESC cell cycle controls, there must be a more complexed alteration and regulatory network.

Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

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4.1. Cytoskeleton Reorganization

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Differentiation of stromal cells into decidual cells involves complex cytoskeleton reorganization. Both intracellular cytoskeleton rearrangement and ECM reorganization are necessary for successful decidualization. Intracellular transformation is in favor of the enlarged polygonal/round cell shape while ECM reorganization provides space and new signal contact for decidual cells to perform their duty. Down-regulation of α-action, disintegration of focal adhesion and change of myosin are related to intracellular change while matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are stars for extracellular reformation.

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4.1.1. Actin There are six mammalian isoforms of actins. While β- and γ-actins ubiquitously localize in all cells, α-SMAs are restricted in specific cell types, like smooth muscle cells, fibroblast and fibroblast-like decidual cells (Rønnov-Jessen and Petersen, 1996). α-SMAs are concentrated at the edge of decidual cells and more likely to show in an F-actin form (Ihnatovych et al., 2007; Maruyama et al., 1999). It is reported that α-SMAs in stromal cells are decreased during decidualization resulting in reinforcement of cellular motility (Ihnatovych et al., 2007, 2009; Rønnov-Jessen and Petersen, 1996). In the meantime, F-actin:G-actin ratio is decreased. Actin-binding protein cofilin which mainly co-localizes with G-actin, is implicated in this process. Translocation of active phosphorylated cofilin from the cytosol to the nucleus is found during decidualization. Inactive dephosphorylated cofilin can't bind to actins. Cofilin can depolymerize F-actin to G-actin. Serine–threonine-specific LIM kinases 1 and 2 (LIMK1 and LIMK2) and RHOA are two main independent pathways to phosphorylate the conserved N-terminal serine (Ser3) of confilin. cAMP is described to regulate the above two pathways via PKA. Interleukin 1β (IL1β) is also the upstream of RHOA (Ihnatovych et al., 2009). The relationship between cAMP and IL β is complex (Ihnatovych et al., 2007, 2009). The decrease of α-SMAs can partly account for the reduced rate of F-actin:G-actin. Yet how α-SMAs lessen is not clear. Maybe α-SMAs are swallowed by lysosomes. Moreover, interaction between actin and myosin, which is mainly regulated by the phosphorylation status of myosin light chain (MLC20), is vital for proper cytoskeletal organization. MLC kinase (MLCK), MLC phosphatase and RHOA kinase are three enzymes regulating MLC20. Yet only MLCK functions during decidualization are induced by AMP, E2 and P4. Inhibition of MLCK accelerates decidualization induced by cAMP (with E2 and P4), but hampers decidualization induced by IL-1β (with E2 and P4)

565

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4. Characteristic of Differentiated ESCs

R O

488 489

P

486 487

533

D

484 485

to DEDD+/DEDD+ cells. DEDD depressed cyclinB1/CDK1-mediated RNA polymerase I transcription repression. Yet DEDD is responsible for maintenance of rRNA rather than synthesis of rRNA (Miyazaki and Arai, 2007). On the other hand, DEDD forms a complex with cyclinD3 to stabilize the cyclinD3/CDK4 and cyclinD3/CDK6 complex during cell growth. DEDD may also be associated with mTOR/PI3K/Akt signaling way to maintain Akt protein level thus stabilizing cyclinD3, since addition of Akt can rescue polyploidization in DEDD−/DEDD− cells. Lack of DEDD will also result in reduced insulin level, which is important for energy metabolism (Mori et al., 2011) (Table 1, Fig. 1). Though polyploidization can be induced by multiple pathways, like apoptosis, immune system, mitochondrial function and tumors, the polyploidization of stromal cells is an elaborate regulatory system. Further studies reveal that polyploidy decidual cells are featured with lively mitochondrial activity and reduced mitochondrial activity results in suppression of polyploidy development of stromal cells. In contrast, tumor cells show no mitochondrial activity (Ma et al., 2011). Though some hepatic cells are bi-nucleus, few genic changes are found. And many gene expression related to polyploidization are changed in stromal cells. These genes have a hand in different biological signal pathways (Ma et al., 2011).

T

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R

476 477

R

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O

472 473 Q20

C

470 471 Q19

accumulation in cytoplasm (Rider et al., 2006). Then, Wnts bind with Fzd and form a complex with LRP5/6 (low density lipoprotein receptorrelated protein5/6) co-receptor, and many β-catenins are translocated to nucleus (Carmon and Loose, 2008; Peng et al., 2008). β-Catenin forms complex with TCF/LEF to activate stromal cell cycle entry by inducing Wnt target genes like cyclin D1 and c-myc (Carmon and Loose, 2008; Rider et al., 2006; Wang et al., 2000) (Table 1). Wnt/β-Catenin signaling is vital for proper proliferation. Aberrant regulation of Wnt/β-catenin signaling may cause carcinoma (Mohamed et al., 2005). Dkk1, a secreted glycoprotein, is a potent inhibitor of the Wnt/βcatenin signaling. Dkk1 protein expression is localized to glandular epithelial and stromal cells during proliferative, early- and mid-secrestory phases, whereas expression is confined to the stroma in late-secretory phase and first trimester decidua (Macdonald et al., 2011; Wang et al., 2000). Stromal cells can produce Dkk1, and the increasing amount of Dkk1 proteins (Wang et al., 2000) in mid-secretory phase are markers of decidualization (Duncan et al., 2011; Peng et al., 2008). Dkk1 mRNA peaks in mid-secretory phase and decreases in late-secretory phase (Wang et al., 2000). The expression of Dkk1 is P4-dependent but E2, cAMP independent (Saleh et al., 2011; Sonderegger et al., 2010). Dkk1 can be regulated by P4 directly or modulated indirectly via P4-mediated regulation of PROK1. Dkk1 inhibits canonical Wnt signaling by binding to Wnt receptors LRP5 and LRP6, and to Kremen1 and Kremen2, forming a trimolecular complex of Dkk1, LRP5/6 and Kremen. This interplay results in internalization of Wnt receptors (Macdonald et al., 2011; Sonderegger et al., 2010) (Table 1). Otherwise, p53 can induce Dkk1, so Dkk1 participates in tumor suppression as well (Wang et al., 2000). Macdonald et al. (2011) report that Wnt/β-catenin signaling is highly expressed during proliferative phase and then inhibited once decidualization starts (Macdonald et al., 2011). However, Mohamed et al. (2005) indicated that Wnt/β-catenin signaling is triggered by signals emanating from the embryo before implantation rather than decidualization (Mohamed et al., 2005). So we propose if embryo signals are added to Macdonald et al. (2011) experiment, Wnt/β-catenin signaling may not be inhibited during decidualization. Yet it has not been tested. We suggest that embryo signals and Dkk1 which is elevated during decidualization co-control the proper expression of Wnt/βcatenin signaling, and keep the stromal cell cycle work well. Besides Dkk1, SFRP4 (secreted frizzle-related protein4) is also an inhibitor of Wnt/β-catenin signaling. SFRP4 owning similar structure like Fzd, antagonizes Wnt action, thus regulating the expression rate of Wnt in proliferative phase (Carmon and Loose, 2008) (Table 1). SFRP4 is restricted to the endometrial stroma and mainly expressed in the proliferative phase, reaching its peak level in response to E2 (Carmon and Loose, 2008). It is believed that many other molecules are associated with Wnt/β-catenin signaling and forming a strong regulatory net. Though inhibiting Wnt/β-catenin signal pathway by Dkk1 is not yet powerful enough to make Wnt/β-catenin signal switch off, it may encourage stromal cell transformation from the state of proliferation to differentiation (Fig. 1).

N

469

3.2.1.5. DEDD (Death Effector Domain-Containing Protein) Is Essential for Polyploidization. DEDD, which can bind to FAS-associated death domain (FADD) or caspase-8/10 through DED domains (about eighty amino acid residues), belongs to DED-containing protein family. DEDD can induce apoptosis process in in vitro over-expression studies in mice (Miyazaki and Arai, 2007). DEDD implicates in decidual cell polyploidization and greatly increases in stromal cells during decidualization (Ma et al., 2011; Miyazaki and Arai, 2007; Mori et al., 2011; Paule et al., 2011; Tapia et al., 2011). DEDD protein is highly expressed at G2/M phase, while it is low in S phase and post-mitotic G1 phase, whose temporal distribution is similar to cyclinB1, according to Miyazaki and Arai's experiment (2007). DEDD can connect to cyclinB1 then block the activity of cyclinB1/CDK1 complex within the nucleus, thus permitting further cell growth prior to cell division. Both 28S and 18S ribosomal RNA (rRNA) are decreased by more than 50% in DEDD−/DEDD− compared

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6

Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552

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566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594

H. Zhu et al. / Gene xxx (2014) xxx–xxx

595 596 597 598

(Ihnatovych et al., 2007). This phenomenon confirms the complicacy of hormone regulation of decidualization and experimental models may count for the discrepancy. To the authors' knowledge, the actual alteration of myosin in human is still unclear.

599

4.1.2. Focal Adhesion Focal adhesions are sites of tight adhesion to the underlying ECM. Integrins which are important adhesion factors, are one of the structural 602 components of focal adhesion. It is suggested that alteration of ECM 603 components may activate decidualization-specific signaling cascades 604 through ECM/integrin interplay. c-Src and Fyn (members of Src family 605 tyrosine kinases), which are also included in the focal adhesion com606 plex, participate in integrin-mediated signal transduction. Aggregation 607 of integrins in focal adhesion sites induces focal adhesion kinase (FAK) 608 autophosphorylation, then recruits Src/Fyn through SH2 domains to 609 bind to FAK phosphorylate additional sites and activate FAK. Src/FAK or 610 Fyn/FAK complex activates paxillin and the downstream signal cascades 611 to mediate the actin-based cytoskeletal organization (Maruyama et al., 612 1999). However, the dissociation of FAK, paxillin and Src is found during 613 decidualization. In the multicellular nodules of decidual cells, no accu614 mulation of paxillin and FAK is found at borders of cells, or rather they 615 differ in cytosol (Maruyama et al., 1999). This may result from the de616 crease of F-actins. If there is a lack of proper ECM, the complex fails to 617 Q23 form.

629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657

658

4.2.1. GLUTs (Facilitative Glucose Transporters) The decidualization of ESCs needs great nutrients and energy support. Glucose metabolism is important for differentiation of endometrial functionalis layer into receptive decidua. It has been reported that reduced level of decidualization occurs in cells which are cultured in glucose concentration below 2.5 mM. Taking glucose into the cell is the first step of glucose utilization, mediated by either the sodium-coupled glucose transporters (SGLTs, now known as the SLC5 family) or the facilitative glucose transporters (GLUTs, now known as the SLC2 family). The latter are more widely applied by mammalian cells (Frolova and Moley, 2011). By far, human SLC2 protein family has been found to own 14 isoforms, GLUT1–12, the H+-coupled myo-inositol-transporter (HMIT, GLUT13), GLUT14. They are classified into three different subclasses and all have highly glycosylated membrane proteins owning an N-linked glycosylation site, though they have different tissue distributions (Augustin, 2010). SLC2A1, -3, -4, and -8 are present in both murine and human uteri. SLC2A1 (GLUT1) is the main GLUT responsible for glucose uptake into the ESCs (Frolova and Moley, 2011; Frolova et al., 2009). SCL2A3 that functions when glucose supply is limited in the early stages of implantation, is a potent transporter with a high affinity for glucose. SLC2A4, which localizes between cell membrane and cytoplasm, is able to translocate to plasma membrane from plasma on insulin stimuli. SLC2A4 is an insulin-regulated protein implicated with glucose take-up (Augustin, 2010; Frolova and Moley, 2011). Yet it is unclear whether insulin-like growth factor (IGF) which is also important for decidualization, has interaction with SLC2A4 or not. Like SLC2A3, SLC2A8 is also an efficient transporter with a high affinity for glucose. However, in contrast to SLC2A3, SLC2A8 is less specific. Frolova and Moley (2011) have suggested that SLC2A8 may locate in the endoplasmic reticulum and lysosome in the stromal cells to help glycosylate protein and degrade glycogen (Frolova and Moley, 2011). Intriguingly, though many GLUTs are present in stromal cells, GLUT1 is the only one that is up-regulated during decidualization, while GLUT4 and GLUT8 are not increased (Augustin, 2010). GLUT12, owning a similar function like GLUT8, is even decreased during human decidualization (Augustin, 2010; Frolova et al., 2009). When treating the stromal cells with P4, the expression of SCL2A1 is significantly promoted at the stromal plasma membrane in the implantation site. Given the increased total GLUT1 protein, there are increasing synthesis of GLUT1 protein and the newly synthesized GLUT1 are transported to the membrane to uptake more glucose. Besides, the expression of GLUT1 is decreased by E2 and can be increased by cAMP and medroxyprogesterone-17acetate without E2. The expression of GLUT1 was much lower in the inter-implantation site of stroma compared with implantation site. P4 induces the expression of GLUT1 through PR pathway which can be inhibited by antagonist, RU486 (Frolova et al., 2009). Though the amount of SCL2A8 doesn't increase during decidualization, SCL2A8 is likely to have greater function since active synthesis of proteins including GLUT1 sets out during decidualization. Furthermore, SCL2A8 can influence the function of endoplasmic reticulum and lysosome, which are both critical organelles. Maybe there are more reserved SCL2A8 proteins activated during decidualization, whereas the total number is constant. It needs further research. The stable expression of GLUT4 responsive to insulin proclaims homeostasis of human. The ability of GLUT4 to regulate glucose take-up independent of P4 and E2 implies another glucose take-up pathway, may be complementary for classical hormone pathway. The relationship between these GLUTs and the underlying mechanism needs deep investigation.

659 660

4.2.2. AdipoR1 and AdipoR2 (Adiponectin Receptors 1 and 2) Adiponectin (Adipod) is an adipocyte-derived hormone (244-amino acid protein) that can improve insulin sensitivity and mediate energy homeostasis (Blümer et al., 2008; Kim et al., 2011; Nawrocki et al., 2006). AdipoR1 and AdipoR2 are two receptors of Adipod. During

717 718

O

R O

P

D

E

T

C

627 628

E

626

R

624 625

R

622 623

N C O

620 621

4.1.3. MMPs (Matrix Metalloproteinases), TIMPs (Tissue Inhibitor of Metalloproteinase) MMPs are a family of proteolytic enzymes with more than 20 members, including collagenases (MMP-1, -8, and -13), stromelysins (MMP3, -7, and -10), and gelatinases (MMP-2 and -9). The main role of MMPs during decidualization is to degrade and reorganize the ECM. TIMPs regulate the function and substrate specificity of MMPs (Anumba et al., 2010; Huang, 2006; Williams et al., 2011). The traditional view is that MMPs are produced by conceptus while TIMPs are produced by decidual cells. Yet, both the production and secretion of MMP-2 and MMP-9 are detected in stromal cells, and they are increased during decidualization (Gellersen et al., 2010; Guo et al., 2011; Huang, 2006). Gelatinases, MMP-2 (72 kd) and MMP-9 (92 kd), have been shown to cleave collagen type IV, which is a component of ECM and a marker of basal lamina of vascular endothelial cells, into two fragments (Huang, 2006; Le et al., 2011). MMPs may help neoangiogenesis and vascular remodeling. MMP3, known as stomelysin-1, is present throughout pregnancy and also capable of breaking down ECM (Williams et al., 2011). Yet whether MMP3 is expressed in the stromal cells is unclear. Stromal cells produce TIMPs to regulate MMPs. TIMP-3 is significantly expressed by stromal cells in the area in the vicinity of implanting embryonic tissue. It is largely increased during decidualization, showing a critical role of TIMP-3 for differentiation. TIMP-3 has been proved to have an inhibitory function against MMP3, collagenase-1 and MMP-9. TIMP-1 and TIMP-2 can also bind with MMP3, collagenase-1 and MMP-9 and hamper their activity (Huang, 2006). Besides, TIMP-1 possesses adipokinetic effects while TIMP-2 induces angiogenesis. CD63 and integrin α3β1 are respectively the receptors of TIMP-1 and TIMP-2. It is reported that the level of TIMP2 is raised in women with RPL, while MMP-1, MMP-3, and MMP-9 remain unchanged (Anumba et al., 2010), which shows critical function of stromal cells for successful pregnancy. Both IL-1 and tumor necrosis factor-β (TNF-β) stimulate the secretion of MMPs by cultured stromal cells. It is suggested that tumor growth factor-β (TGFβ) can regulate MMP-9, TIMP-1, and TIMP-2 production of stromal cells. Relaxin-2, which belongs to TGFβ family, is attenuated in RPL (Anumba et al., 2010). Motility of stromal cells can be enhanced by activin A, which is also a member of TGF-β (Gellersen et al., 2010). Yet, how TGF-β contacts with MMPs and TIMPs remains unknown. We can propose that MMPs and TIMPs expressed by ESCs help make migration and differentiation of ESCs under control.

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4.2. Nutrient Metabolism

F

600 601

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Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

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4.3.2. Adherens Junctions (AJs) Besides different vascular distribution, the AJs between ESCs in PDZ and SDZ are reported to show discrepancy. In mice, β-catenin, a-catenin and E cadherin proteins are co-localized and strongly expressed in the membranes of PDZ cells. Nevertheless, there are much fewer AJ proteins found in SDZ cells. Unlike mice, hamsters show inverse expression style. No β-catenin, a-catenin and E cadherin are found in PDZ cells while these AJ proteins are detected in SDZ cells (Luan et al., 2011). Though the expression pattern of AJs may be species dependent, it can be suggested that some decidual cells behave like epithelial cells and restrict the invasion of embryo. Proper cytoskeleton changes are important for suitable control of implantation process. The AJ protein expression pattern in humans is still unclear.

O

5. Differentiated ESCs Regulate Immune Activity 5.1. NK Cells

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4.3. Different Characteristics of PDZ (Primary Decidual Zone) and SDZ (Secondary Decidual Zone)

759 760

4.3.1. ChM-I (Chondromodulin-I) It is interesting that the PDZ is avascular and impermeable to macromolecules, forming a barrier to protect the implanted embryo from harmful macromolecules, while SDZ is rich in vessels (Afshar et al., 2012). ChM-I is differently expressed in these two zones and can be a marker in some conditions. ChM-I is an anti-angiogenic glycoprotein that specially localizes at the avascular domains of mesenchymal tissues such as cartilage, cardiac valves and eye, where angiogenesis is strictly limited. ChM-I is found to inhibit the migration, proliferation and tube morphogenesis of cultured vascular endothelial cells. It is reported by Miura et al. (2011) that the differentiated mouse decidua is a novel site of ChM-I expression (Miura et al., 2011). ChM-I transcripts were localized to well-differentiated decidual cells in PDZ and were not detectable in SDZ which is home to immature mitotic decidual cells. Prior to the invasion of trophoblasts, PDZ is still vascularized. TIMP-3, an antagonist of MMP9 which is secreted by trophoblasts and stromal cells, is strongly expressed at the antimesometrial side of PDZ and ChM-I mesometrial side. When the trophoblasts are extensively detected along the margin of the implantation chamber at 7.5 days in mouse, ChM-I is expressed at the entire PDZ and PDZ becomes avascular. ChM-I can suppress the mobility of Rcho-1 trophoblast cells and vascular endothelial cells stimulated by IGF-1. Less lamellipodia formation of Rcho-1 trophoblast cell is found, and the invasion is inhibited (Miura et al., 2011). Yet the mechanism among ChM-I, IGF-1, and the cytoskeleton remains a puzzle. The receptors, ligands and underlying signal way are still vague to us.

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5.2. DCs (Dendritic Cells) and T Cells

839

DSCs can not only regulate dNK cells, but also modulate other immunocytes like DCs and T cells. ESCs help inhibit DC surveillance of the maternal/fetal interface by preventing DCs reaching the draining lymph nodes and thus preventing immunogenic T cell exposure to fetal/placental antigens and the rejection of the fetus. One theory is that DSCs alter the ECM environment by lowering the amounts of

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Immunocytes are considered to be another important stromal population in decidual endometrium. Proper pro-inflammatory environment promotes permissibility for embryo survival and development (Salker et al., 2012). There are rich interactions between differentiated ESCs and immunocytes and DSCs are capable of regulating immune activity. Decidual natural killer (dNK) cells are predominate immune cells in the post-ovulatory uterus which have the largest number (van den Heuvel et al., 2005a,b). The rapid increase of dNK cells in the uterus is thought due to not only proliferation of resident population but also the recruitment of progenitor cells from the circulation (van den Heuvel et al., 2005a,b). CD16−CD56+CD9+CD103+KIR+NK cells, which have more limited lytic ability and more active production ability of chemokines than other NK cells, are the typical and major type of dNK cells (Keskin et al., 2007; van den Heuvel et al., 2005b). In addition to vascular muscle layers of decidual arteries (25%) and endothelium (10%), 65% of dNK cells are associated with stromal cells (van den Heuvel et al., 2005a). The intimate location implies indispensable function of DSCs on dNK cells. Under the regulation of P4, DSCs can produce TGFβ1 that upregulates the expression of CD9, CD103, and KIR and downregulates CD16 (Keskin et al., 2007). Moreover, expression of IL15 by DSCs, which is the non-redundant chemokine signaling, can increase expression of CD56 bright NK cells and maintain terminal dNK cell differentiation (van den Heuvel et al., 2005b). All CD56+ populations express CXCR3 (binds CXCL9, CXCL10, CXCL11), CXCR4 (binds CXCL12) and dNK cells strongly express CCR1,2,5, CXCR3,4 and CXCR1. Attractively, during decidualization, P4 induces stromal cell production of CXCR3 ligands, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (ITAC). This phenotype contributes to NK cell accumulation in implantation sites (van den Heuvel et al., 2005a,b). The recruitment of NK cells is active during decidualization (Fig. 2). Bone marrow, thymus, neonatal liver and spleen are proved to be sources of uterus natural killer (uNK) cells and spleen is the most competent source (van den Heuvel et al., 2005b). More accurately, Vacca et al. (2011) suggest that NK cells originate from CD34+ hematopoietic precursors. When co-cultured with decidual stromal cells, CD34+ derived from peripheral blood and cord blood are able to different into dNK cells (Vacca et al., 2011). This confirms the specific role of DSCs on the differentiation and positioning of dNKs. Yet whether DSCs are associated with the dNK cells trafficking from peri-vessels is not known.

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implantation, AdipoR1 is widely localized in all decidual cells, while AdipoR2 show more strong distribution in the primary decidual cells 724 (PDCs) than in the secondary decidual cells (SDCs). AdipoR1 abrogates 725 Adipoq-induced AMP-activated protein kinase (PRKAAI/AMPK) activa726 tion, while AdipoR2 increases inflammation and oxidative stress and 727 decreases the activity of peroxisome proliferator-activated receptor 728 (PPAR) signaling. Many key glucoregulatory and lipogenic proteins, 729 such as GLUT4, lipoprotein lipase, adipocyte fatty acid transporter pro730 tein (Slc27A1), and fatty acyl-CoA synthase, are downstream of PPARγ 731 signal way. Nawrocki et al. (2006) have proved that PPARγ ligand 732 Q24 thiazolindinediones, an agonist of PPARγ signal way, improves glucose 733 tolerance (Nawrocki et al., 2006). Thus Adipod can increase glucose 734 take-up and fat oxidation when acts with AdipoR2 by inhibition of 735 PPARs signal pathway. More AdipoR2 in PDCs than SDCs may account 736 for the support of conceptus survival. Besides, this interaction can also 737 increase the activity of mitochondria (Nawrocki et al., 2006). AMPK 738 phosphorylation inhibits acetyl-CoA carboxylase (ACC), resulting in de739 creased tissue malonyl-CoA content. Malonyl-CoA can abolish the effect 740 of carnitine palmitoyl-transferase1, the rate-limiting enzyme for oxida741 tion. So Adipod can increase mitochondrial fatty acid oxidation by 742 activation of AMPK pathway (Kim et al., 2011). So AdipoR1 may be im743 portant for the balance of fatty acid metabolism. The expression of 744 Adipod is regulated by insulin and amino acid. Insulin stimulates the se745 cretion of adiponectin in a PI3K-dependent manner, while amino acids 746 serve as important components for Adipod synthesis. Amino acid747 dependent mTOR-mediated signaling only has a minor role in stimula748 tion of Adipod. Moreover, an acidic pH in Adipod vesicular and body 749 mass index is vital for secretion of Adipod (Blümer et al., 2008; Herse 750 et al., 2009). It is reported that women with preeclampsia and PCOS 751 have reduced plasma Adipod levels (Herse et al., 2009; Kim et al., 752 2011). Adipod, AdipoR1 and AdipoR2 may be regulatory sites of metab753 olism of decidualization and maintenance of pregnancy, thus they may 754 be a potential medicine site to cure PCOS and preeclampsia. The changes 755 of Adipod, AdipoR1 and AdipoR2 in quantity, distribution as well as the 756 hormone response during decidualization, need further evaluation.

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Fig. 2. Differentiated ESC regulation of endometrial immune activity. Differentiated ESCs (DSCs) produce CXCL9, CXCL10, and CXCL11, which are ligands of CXCR3. CXCR3 is highly expressed in dNK cells. By this way, DSCs recruit dNK and make dNK accumulate near DSCs. DSCs promote recruited dNK cell differentiation. DSCs upregulate CD56 expression in dNK cells via IL-15, and increase CD9, CD103, and KIR and decrease CD16 via TGFβ1. DSCs also maintain CD56+CD9+CD103+KIR+CD16−dNK cells. Differentiated dNK cells have limited lytic ability and great chemokine production ability. DSCs produce IL-8 to recruit neutrophils. DSCs prevent DCs getting into lymph node and presenting antigen to CD4+ T cells. That DSCs lower the amount of hyaluronan may be the underlying mechanism. HLA–DR promotes cytokine secretion of T cells. B7-HI and B7-DC will antagonize the function of HLA–DR. The balance of HLA–DR, B7-HI and B7-DC is significant for proper activity of T cells and the survival of implanted embryos.

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During decidualization, the maternal uterine vasculature undergoes great changes in condition of hypoxia. The remodeling of vessels is a very significant change for uterus to gain the ability of exchanging materials with the blastocyst, including nutrients, blood and wastes, which is indispensible for successful implantation. Superficial spiral arteries in the decidua exhibit most distinct physiological changes.

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hyaluronan. Hyaluronan can interplay with DCs through its cell-surface receptor CD44 and promote DC migration. DSCs make the ECM insufficient for DC migration. Yet to the authors' knowledge, the mentioned theory hasn't been proved (Collins et al., 2009). On the other hand, DSCs can directly regulate T cell, regardless of DCs. DSCs express B7-HI (programmed death ligand 1 (PD-L1) or CD274) and B7-DC (PD-L2 or CD273), which can interact with PD-1, generate an inhibitory signal and suppress activity of CD4+ T cells. The expression of B7-H1 and B7DC can be promoted by IFN-γ and TNF-α. HLA–DR can also be found in DSCs, which can be induced by IFN-γ. DSCs are able to raise cytokine production of CD4+ T cells. It is suggested that B7-HI and B7-DC function via inhibiting the downstream effect of HLA–DR interaction. The balance between the function of PD-ligands and HLA–DR is important for modest ability of T cells to interact with embryo and pathogens (Nagamatsu et al., 2009). Moreover, mast cells and macrophage cells are another essential immunocytes. E2 and P4 can regulate mast cell migration through upregulation of CCR4 and CCR5 (Hyer et al., 2011) (Fig. 2). However, the real mechanism underlying this and how stromal cells play a role in this process is an enigma.

They are transforming from high-resistance, low-flow vessels into large dilated vessels with increased blood flow at a reduced pressure (Whitley and Cartwright, 2010), losing their muscular coat and ability to vasoconstrict, showing venous markers such as EPH-B4 (Chandana et al., 2010; Zhang et al., 2011). The endometrial microvessel density is significantly higher (Li et al., 2011), implying occurrence of neoangiogenesis. Bany and Hamilton (2011) have proved an increased permeability of the blood vessels which are adjacent to the implanting blastocyst in the rodent endometrium. The extravasated macromolecules and fluids arise (Bany and Hamilton, 2011). There are many stromal cells localizing near vessels whose impact on vascular remodeling is great. Under the regulation of E2 and P4, stromal cells secret vascular endothelial growth factor (VEGF), tissue factor (TF) and IL-8, all of which participate in modulation of vascular reconstruction.

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VEGF, a powerful endothelial cell mitogen, is the primary mediator of angiogenesis through sprouting (Chandana et al., 2010; Fujita et al., 2010; Lockwood et al., 2009a). Notch is the receptor of VEGF and Delta-like ligand 4 (DII4) is the ligand of VEGF. In response to VEGF, a subset of endothelial cells, termed tip cells, extend filopodia and migrate actively. Then another subset of endothelial cells, termed stalk cells, form tubular structures. DII4 expresses in the tip cells while Notch expresses in the stalk cells, critical for this cell type specification (Chandana et al., 2010). VEGF is also involved in vascular permeability and proliferation. E2 can disrupt tight junctions between endothelial cells and increase vascular permeability and endothelial cell

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TF is a cell membrane-bound glycoprotein member of the class-2 cytokine receptor family, whose hydrophilic extracellular domain acts as a receptor for factor VII and its active form VIIa. TF–VIIa complex mediates the proteolytic cleavage of prothrombin to thrombin and promotes the formation of fibrin, thus inducing hemostasis. TF increases in DSCs during the luteal phase (Lockwood et al., 2009a). TF is regulated by P4 via PRs, epidermal growth factor (EGF) via EGFR and is not mediated by E2 alone (Lockwood et al., 2009a,b). TF–VIIa complex functions via protease activated receptor-2 (PAR-2), a kind of G protein-coupled receptors sensitive to trypsin and trypsin-like enzymes. Thrombin, downstream of TF–VIIa, serves as an autocrine/paracrine mediator that degrades these ECM by augmenting decidual cell expression of MMPs and IL8. In the meantime, thrombin enhances the expression of TF, showing a positive loop between thrombin and TF. The Sp transcription family on the TF gene promoter may be involved in this interaction, since there is an increasing rate of Sp1 to its Sp3 antagonist in progestinregulated decidual cells in vitro and in vivo. IL8 is known to recruit neutrophils which express several ECM degrading proteases (Lockwood et al., 2009b). Besides TF, IL8 can also be regulated by lysophosphatidic acid (LPA) via LPA receptor on DSCs and NF-Βκ pathway (Chen et al., 2008) (Fig. 3). The absence of P4 in normal menstrual cycle results in

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Stromal–epithelial interaction is crucial for coordinate function of endometrium. Stromal cells can interplay with epithelial cells via cell–cell contact, ECM interactions and soluble paracrine factors (Osteen et al., 1994). This interaction is under regulation of many steroid hormones, including E2, P4, testosterone, and androgens (Cunha et al., 2004). In response to P4, DSCs will secret water-soluble and heat-sensitive factors primarily via up-regulated PR. These factors can play a paracrine role to induce transcription mediated by the −200/−100 bp 5′-regulatory region of the 17b-hydroxysteroid dehydrogenase (HSD) type 2 promoter in epithelial cells. 17b-HSD type 2 has the ability to converse the potent E2 to inactive form, estrone E1, thus inhibiting E2-induced growth in epithelial cells and help epithelial differentiation. The above interaction of 17b-HSD type 2 is specific for endometrial epithelial cells (Yang et al., 2001). Recently novel related genes have been reported. Msx1 and Msx2 belong to mammalian Msx homeobox genes. Conditional ablation of either Msx1 or Msx2 shows modest impairment in embryo implantation, leading to sub-fertility of mutant mouse. In contrast, ablation of both Msx1 and Msx2 results in infertility of mutant mouse. There is a compensatory function between Msx1 and Msx2. Msx1 and Msx2 expressed in

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lack of TF and leads to bleeding and functional endometrial layer sloughing (Lockwood et al., 2009b). The balance among TF, angiogenesis factor and hormone is essential for proper implantation depth and hemorrhage avoidance. Overexpression of VEGF and reduced expression of angiogenin, which can stabilize vascular structures, followed by overstimulation of P4 induces endothelial vascular “leakiness” and perivascular ECM dissolution and culminates in bleeding. Although TF also increases, it can't stop the trend of hemorrhages. It is also the reason why long-term progestin-only contraception leads to abnormal uterine bleeding (Lockwood et al., 2009a). Vascular regulation can be associated with surge recovery, tumor therapy and successful pregnancy. Depth study about this is of critical significance and more efforts are still needed.

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proliferation. However, these functions of E2 are violated when VEGF is blocked (Aberdeen et al., 2008). And estrogen-induced uterine edema becomes unobvious (Rockwell et al., 2002). VEGF doesn't influence the survival of mature vessels (Fan et al., 2008). The expression of VEGF is regulated by P4, E2, hypoxia-induced factor (HIF), TGF-β, human chorionic gonadotropin (HCG) and so on (Aberdeen et al., 2008; Hyer et al., 2011; Lockwood et al., 2009a; Rockwell et al., 2002; Sidell et al., 2010) (Fig. 3). Extracellular signal-regulated kinase (ERK) and AKT-mTOR cascades are important for VEGF produced by trophoblast-derived cell line (Fujita et al., 2010), yet whether ERK and AKT-mTOR signal way have a big function in DSCs induced VEGF is still unknown.

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Fig. 3. Differentiated ESCs regulate vascular remodeling and epithelial differentiation. Under the regulation of P4, E2, HIF, TGFβ and HCG, DSCs produce VEGF. VEGF will increase the permeability of vessels and promote the angiogenesis through sprouting. Tip cells and stalk cells, which are subsets of endothelial cells, are activated by VEGF. Tip cells extend filopodia and migrate, while stalk cells form tubular structure. VEGF also enhance endothelial proliferation. P4 and EGF up-regulate the expression of TF. In the downstream of TF–VIIa complex, thrombin induces DSC to secret MMPs and IL-8. MMPs will disrupt the adhesions between endothelial cells. Thrombin helps the formation of fibrins. Fibrins will inhibit the vessels from hemorrhage. Msx1 and Msx2 are expressed in DSC, and block the expression of fibroblast growth factors (FGFs) via inhibiting Wnt/β-catenin pathway. FGFs will make epithelial cells keep proliferation and express mucin1 (Muc1) and lactotransferrin (Ltf), thus epithelial cells stay in a non-receptive state. In the meantime, DSCs produce water-soluble and heat-sensitive factors primarily in response to P4, and activate 17b-hydroxysteroid dehydrogenase (HSD) type 2 promoter in epithelial cells. HSD promoter transforms active E2 into inactive E1, stopping its effect on epithelial proliferation.

Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

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8. Conclusion and Prospect

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Failed implantation and low success rate of assisted reproductive technology have been troubling problems. While more criteria are being established for pre-implantation genetic diagnosis to select valid embryos (Ercelen et al., 2011; Knez et al., 2011; Lietman, 2011; López Moratalla et al., 2011), correcting defects in endometrial receptivity is another useful method. Gaining receptivity of endometrium depends on function and interaction of endometrial cells, including ESCs, immunocytes, vascular endothelial cells, epithelial cells and stem cells. With many researchers focusing on particular genes and proteins, the authors think that seeing in a view of particular cell will replenish the scheme of endometrium and help find out the different expressions and regulations of genes in different cell types. Analyses in a view of particular cells as well as total endometrial gene expression will make the scheme of receptivity gaining process more distinct. In this review, we find that there are at least two main kinds of stem cells of ESCs in endometrium, CFUs and ESP. The process of transformation from ESCs to DSCs includes proliferation, differentiation and polyploidization, all of which are regulated by E2 and P4. During transformation, the checkpoints of cell cycle are under control of many transcription factors and the expression pattern of cyclins, CDKs, and CKIs is changed. After transformation, DSCs have a higher metabolic level and looser cytoskeleton. DSCs have a function in regulating immune activity, vascular remodeling and epithelium differentiation (Fig. 4). ESCs perform duty mainly via secretion of cytokines, growth factors, chemokines and so on. Proper transformation is a key step for ESCs to perform duty. Testing this transformation in a view of cell cycle brings a deeper understanding of the function of studied genes. There are still many confusions in the change of cyclins, CDK and CKI expression, like alteration of CDK6/CDK4 ratio, later expression of cyclin D3 in S phase and later expression of cyclin A in G2/M. It is reasonable that some greatly changed gene expression during secretory phase in ESCs must have relation with cell cycle changes. Nowadays, transcriptome and proteome alterations are being widely checked. By far, we still can't rule out the possibility of post-transcriptional regulation (Estella

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We are indebted to all members of the Sperm Laboratory at Zhejiang University for their enlightening discussion. This project was supported in part by the National Natural Science Foundation of China (No. 41276151) and partially supported by the National Basic Research Program of China (973 Program, Grant number: 2012CB967902).

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References

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Aberdeen, G.W., Wiegand, S.J., Bonagura Jr., T.W., Pepe, G.J., Albrecht, E.D., 2008. Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in baboon endometrium. Endocrinology 149, 6076–6083. Afshar, Y., Jeong, J.W., Roqueiro, D., DeMayo, F., Lydon, J., Radtke, F., Radnor, R., Miele, L., Fazleabas, A., 2012. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 26, 282–294. Aghajanova, L., Horcajadas, J.A., Esteban, F.J., Giudice, L.C., 2010. The bone marrow-derived human mesenchymal stem cell: potential progenitor of the endometrial stromal fibroblast. Biol. Reprod. 82, 1076–1087. Anumba, D.O., El Gelany, S., Elliott, S.L., Li, T.C., 2010. Circulating levels of matrix proteases and their inhibitors in pregnant women with and without a history of recurrent pregnancy loss. Reprod. Biol. Endocrinol. 8, 62. Augustin, R., 2010. The protein family of glucose transport facilitators: it's not only about glucose after all. IUBMB Life 62, 315–333. Bagchi, M.K., Mantena, S.R., Kannan, A., Bagchi, I.C., 2006. Control of uterine cell proliferation and differentiation by C/EBPbeta: functional implications for establishment of early pregnancy. Cell Cycle 5, 922–925. Bany, B.M., Hamilton, G.S., 2011. Assessment of permeability barriers to macromolecules in the rodent endometrium at the onset of implantation. Methods Mol. Biol. 763, 83–94.

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et al., 2012). Maybe we can use the cell cycle model to figure out the compensatory or antagonism relationship between different proteins and explain some phenomena. Disruption of the cell cycle regulation of ESCs can serve as a contraceptive method and an alternative choice instead of hormonal therapy. Also, we can make right the cell cycle regulation to reduce infertility risk. Thin endometrium and endometrial hypo-proliferation are two dangerous factors of implantation failure. Knowledge about the stem cells of ESCs will benefit the persons who are suffering from thin endometrium and endometrial hypo-proliferation. More evidence about surface markers and regulatory factors is needed. In addition to stem cells, the elaborate process of how ESCs accomplish proliferation, differentiation and polyploidization should be another focus point. What makes ESCs proceed under control remains a mystery. Also we suggest that comparative analysis of ESCs with cancer cells is feasible, which will benefit cancer research. Besides, insufficient supply of nutrients to ESCs and aberrant expression of metabolic genes will disable ESCs. It is necessary to find out the specific metabolic genes essential for nutrients take-up, including glucose, amino acid and fatty acid. With a map of metabolic genes of ESCs, we can have more criteria to evaluate the state of endometrium. What's more, better in vitro cultivation conditions for ESCs should be found to better study ESCs.

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the stromal cells can block Wnt/β-catenin pathway and thus reducing secretion of fibroblast growth factors (FGFs). FGFs, also paracrine factors, can react with FGF receptors in epithelium and then activate ERK1/2 pathway. As a consequence, epithelial cells keep proliferating and express mucin1 (Muc1) and lactotransferrin (Ltf), staying in a non-receptive state. So the expression of Msx1 and Msx2 can promote epithelium transform from non-receptive state into a receptive state. During this transformation, the long microvilli on the epithelium turn flattened (Nallasamy et al., 2012) (Fig. 3). Another transcription factor Hand2 can also suppress the production of FGFs and inhibit epithelial proliferation at the time of implantation (Nallasamy et al., 2012). Yet the relationship between Msx1/2 and Hand2 need to be clarified.

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Fig. 4. The scheme of ESCs from stem cells to decidualized stromal cells (DSCs). ESCs originate from CFUs and ESP, which are two main kinds of stem cells in endometrium. CFUs and ESP are supposed to derive from mesenchymal stem cells. The process of transformation from ESCs to DSCs is composed of proliferation, differentiation and polyploidization (terminal differentiation), all of which are well regulated by E2 and P4. E2 is predominant in proliferation period, while P4 in differentiation section. During transformation, checkpoints of cell cycle are under fine control of many transcription factors, such as HOXA10, C/EBPβ, FOXO1A, Dkk1 and DEDD. Wnt/β-Catenin signal way is a star in this transformation. The expression pattern of cyclins, CDKs, and CKIs are key functional targets during the modulation. After transformation, ESC transform from a spindle-shaped form into an enlarged, polygonal or round, polyploidy style. DSCs own a higher metabolic level and looser cytoskeleton. DSCs possess a broad function in regulating immune activity, vascular remodeling and epithelium differentiation.

Please cite this article as: Zhu, H., et al., Endometrial stromal cells and decidualized stromal cells: Origins, transformation and functions, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.08.047

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Gellersen, B., Reimann, K., Samalecos, A., Aupers, S., Bamberger, A.M., 2010. Invasiveness of human endometrial stromal cells is promoted by decidualization and by trophoblast-derived signals. Hum. Reprod. 25, 862–873. Guo, Y., He, B., Xu, X., Wang, J., 2011. Comprehensive analysis of leukocytes, vascularization and matrix metalloproteinases in human menstrual xenograft model. PLoS One 6, e16840. Herse, F., Youpeng, Bai, Staff, A.C., Yong-Meid, J., Dechend, R., Rong, Zhou, 2009. Circulating and uteroplacental adipocytokine concentrations in preeclampsia. Reprod. Sci. 16, 584–590. Hess, A.P., Hamilton, A.E., Talbi, S., Dosiou, C., Nyegaard, M., Nayak, N., Genbecev-Krtolica, O., Mavrogianis, P., Ferrer, K., Kruessel, J., Fazleabas, A.T., Fisher, S.J., Giudice, L.C., 2007. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol. Reprod. 76, 102–117. Huang, H.Y., 2006. The cytokine network during embryo implantation. Chang Gung Med. J. 29, 25–36. Hyer, S.L., Pratt, B., Newbold, K., Hamer, C.L., 2011. Outcome of pregnancy after exposure to radioiodine in utero. Endocr. Pract. 17, 1–10. Ihnatovych, I., Hu, W., Martin, J.L., Fazleabas, A.T., de Lanerolle, P., Strakova, Z., 2007. Increased phosphorylation of myosin light chain prevents in vitro decidualization. Endocrinology 148, 3176–3184. Ihnatovych, I., Livak, M., Reed, J., de Lanerolle, P., Strakova, Z., 2009. Manipulating actin dynamics affects human in vitro decidualization. Biol. Reprod. 81, 222–230. Kajihara, T., Brosens, J.J., Ishihara, O., 2013. The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy. Med. Mol. Morphol. 46, 69. Kajihara, T., Tanaka, K., Oguro, T., Tochigi, H., Prechapanich, J., Uchino, S., Itakura, A., Sućurović, S., Murakami, K., Brosens, J.J., Ishihara, O., 2014. Androgens modulate the morphological characteristics of human endometrial stromal cells decidualized in vitro. Reprod. Sci. 21, 372–380. Kara, F., Cinar, O., Erdemli-Atabeni, E., Tavil-Sabuncuoglu, B., Can, A., 2007. Ultrastructural alterations in human decidua in miscarriages compared to normal pregnancy decidua. Acta Obstet. Gynecol. Scand. 86, 1079–1086. Keskin, D.B., Allan, D.S., Rybalov, B., Andzelm, M.M., Stern, J.N., Kopcow, H.D., Koopman, L. A., Strominger, J.L., 2007. TGF beta promotes conversion of CD16+ peripheral blood NK cells into CD 16-NK cells with similarities to decidual NK cells. Proc. Natl. Acad. Sci. U. S. A. 104, 3378–3383. Kim, J.J., Fazleabas, A.T., 2004. Uterine receptivity and implantation: regulation and action of insulin-like growth factor binding protein-1(IGFBP-1), HOXA10 and forkhead transcription factor-1(FOXO-1) in the baboon endometrium. Reprod. Biol. Endocrinol. 2, 34. Kim, J.J., Jaffe, R.C., Fazleabas, A.T., 1999. Insulin-like growth factor binding protein-1 expression in baboon endometrial stromal cells: regulation by filamentous actin and requirement for de novo protein synthesis. Endocrinology 140, 997–1004. Kim, S.T., Marquard, K., Stephens, S., Louden, E., Allsworth, J., Moley, K.H., 2011. Adiponectin and adiponectin receptors in the mouse preimplantation embryo and uterus. Hum. Reprod. 26, 82–95. Knez, K., Zorn, B., Tomazevic, T., Vrtacnik-Bokal, E., Virant-Klun, I., 2011. The IMSI procedure improves poor embryo development in the same infertile couples with poor semen quality: a comparative prospective randomized study. Reprod. Biol. Endocrinol. 9, 123. Kocemba, K.A., Groen, R.W., van Andel, H., Kersten, M.J., Mahtouk, K., Spaargaren, M., Pals, S.T., 2012. Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma. PLoS One 7, e30359. Kodama, A., Yoshino, O., Osuga, Y., Harada, M., Hasegawa, A., Hamasaki, K., Takamura, M., Koga, K., Hirota, Y., Hirata, T., Takemura, Y., Yano, T., Taketani, Y., 2010. Progesterone decreases bone morphogenetic protein (BMP) 7 expression and BMP inhibits decidualization and proliferation in endometrial stromal cells. Hum. Reprod. 25, 751–756. Kyurkchiev, S., Shterev, A., Dimitrov, R., 2010. Assessment of presence and characteristics of multipotent stromal cells in human endometrium and decidua. Reprod. Biomed. Online 20, 305–313. Lam, E.W., Shah, K., Brosens, J.J., 2012. The diversity of sex steroid action: the role of micro-RNAs and FOXO transcription factors in cycling endometrium and cancer. J. Endocrinol. 212, 13–25. Le, J.A., Wilson, H.M., Shehu, A., Mao, J., Devi, Y.S., Halperin, J., Aguilar, T., Seibold, A., Maizels, E., Gibori, G., 2011. Generation of mice expressing only the long form of the prolactin receptor reveals that both isoforms of the receptor are required for normal ovarian function. Biol. Reprod. 86, 86. Lecce, G., Meduri, G., Ancelin, M., Bergeron, C., Perrot-Applanat, M., 2001. Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells. J. Clin. Endocrinol. Metab. 86, 1379–1386. Lei, L., Zhang, Y., Yao, W., Kaplan, M.H., Zhou, B., 2011. Thymic stromal lymphopoietin interferes with airway tolerance by suppressing the generation of antigen-specific regulatory T cells. J. Immunol. 186, 2254–2261. Li, Q.H., Yu, M., Chen, L.N., Li, H., Luo, C., Chen, S.M., Quan, S., 2011. Endometrial microvessel density for assessing endometrial receptivity during the peri-implantation period. Nan Fang Yi Ke Da Xue Xue Bao 31, 1365–1368. Lietman, S.A., 2011. Preimplantation genetic diagnosis for hereditary endocrine disease. Endocr. Pract. 3, 28–32. Lockwood, C.J., Krikun, G., Hickey, M., Huang, S.J., Schatz, F., 2009a. Decidualized human endometrial stromal cells mediate hemostasis, angiogenesis, and abnormal uterine bleeding. Reprod. Sci. 16, 162–170. Lockwood, C.J., Paidas, M., Murk, W.K., Kayisli, U.A., Gopinath, A., Huang, S.J., Krikun, G., Schatz, F., 2009b. Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption. Thromb. Res. 124, 516–520.

N

C

O

R

R

E

C

T

Bartosch, C., Lopes, J.M., Beires, J., Sousa, M., 2011. Human endometrium ultrastructure during the implantation window: a new perspective of the epithelium cell types. Reprod. Sci. 18, 525–539. Blümer, R.M., van Roomen, C.P., Meijer, A.J., Houben-Weerts, J.H., Sauerwein, H.P., Dubbelhuis, P.F., 2008. Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes. Metabolism 57, 1655–1662. Brosens, J.J., Gellersen, B., 2006. Death or survival-progesterone-dependent cell fate decisions in the human endometrial stroma. J. Mol. Endocrinol. 36, 389–398. Carmon, K.S., Loose, D.S., 2008. Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol. Cancer Res. 6, 1017–1028. Castro-Rendón, W.A., Castro-Alvarez, J.F., Guzmán-Martinez, C., Bueno-Sanchez, J.C., 2006. Blastocyst–endometrium interaction: intertwining a cytokine network. Braz. J. Med. Biol. Res. 39, 1373–1385. Chambers, A.E., Nayini, K.P., Mills, W.E., Lockwood, G.M., Banerjee, S., 2011. Circulating LH/hCG receptor (LHCGR) may identify pre-treatment IVF patients at risk of OHSS and poor implantation. Reprod. Biol. Endocrinol. 9, 161. Chandana, E.P., Maeda, Y., Ueda, A., Kiyonari, H., Oshima, N., Yamamoto, M., Kondo, S., Oh, J., Takahashi, R., Yoshida, Y., Kawashima, S., Alexander, D.B., Kitayama, H., Takahashi, C., Tabata, Y., Matsuzaki, T., Noda, M., 2010. Involvement of the Reck tumor suppressor protein in maternal and embryonic vascular remodeling in mice. BMC Dev. Biol. 10, 84. Chen, S.U., Lee, H., Chang, D.Y., Chou, C.H., Chang, C.Y., Chao, K.H., Lin, C.W., Yang, Y.S., 2008. Lysophosphatidic acid interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta. Endocrinology 149, 5888–5896. Collins, M.K., Tay, C.S., Erlebacher, A., 2009. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J. Clin. Investig. 119, 2062–2073. Cooper, Z.D., Jones, J.D., Comer, S.D., 2012. Glial modulators: a noble pharmacological approach to altering the behavioral effects of abused substances. Expert Opin. Investig. Drugs 21, 169–178. Cunha, G.R., Cooke, P.S., Kurita, T., 2004. Role of stromal–epithelial interactions in hormonal responses. Arch. Histol. Cytol. 67, 417–434. Das, S.K., 2009. Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction 137, 889–899. Das, S.K., 2010. Regional development of uterine decidualization: molecular signaling by Hoxa-10. Mol. Reprod. Dev. 77, 387–396. Demir, R., Kayisli, U.A., Celik-Ozenci, C., Korgun, E.T., Demir-Weusten, A.Y., Arici, A., 2002. Structural differentiation of human uterine luminal and glandular epithelium during early pregnancy: an ultrastructural and immunohistochemical study. Placenta 23, 672–684. Dharmaraj, N., Gendler, S.J., Carson, D.D., 2009. Expression of human MUC1 during early pregnancy in the human MUC1 transgenic mouse model. Biol. Reprod. 81, 1182–1188. Dimitrov, R., Timeva, T., Kyurkchiev, D., Stamenova, M., Shterev, A., Kostova, P., Zlatkov, V., Kehayov, I., Kyurkchiev, S., 2008. Characterization of clonogenic stromal cells isolated from human endometrium. Reproduction 135, 551–558. Duncan, W.C., Shaw, J.L., Burgess, S., McDonald, S.E., Critchley, H.O., Horne, A.W., 2011. Ectopic pregnancy as a model to identify endometrial genes and signaling pathways important in decidualization and regulated by local trophoblast. PLoS One 6, e23595. Ercelen, N., Turtar, E., Gultomruk, M., Comert, H., Coskun, H., Mercan, R., Nuhoglu, A., 2011. Successful preimplantation genetic aneuploidy screening in Turkish patients. Genet. Mol. Res. 10, 4093–4103. Estella, C., Herrer, I., Moreno-Moya, J.M., Quinonero, A., Martinez, S., Pellicer, A., Simon, C., 2012. miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro. PLoS One 7, e41080. Fan, X., Krieg, S., Kuo, C.J., Wiegand, S.J., Rabinovitch, M., Druzin, M.L., Brenner, R.M., Giudice, L.C., Nayak, N.R., 2008. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB J. 22, 3571–3580. Franco, H.L., Dai, D., Lee, K.Y., Rubel, C.A., Roop, D., Boerboom, D., Jeong, J.W., Lydon, J.P., Bagchi, I.C., Bagchi, M.K., DeMayo, F.J., 2011. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J. 25, 1176–1187. Frolova, A.I., Moley, K.H., 2011. Glucose transporters in the uterus: an analysis of tissue distribution and proposed physiological roles. Reproduction 142, 211–220. Frolova, A., Flessner, L., Chi, M., Kim, S.T., Foyouzi-Yousefi, N., Moley, K.H., 2009. Facilitative glucose transporter type 1 is differentially regulated by progesterone and estrogen in murine and human endometrial stromal cells. Endocrinology 150, 1512–1520. Fujita, D., Tanabe, A., Sekijima, T., Soen, H., Narahara, K., Yamashita, Y., Terai, Y., Kamegai, H., Ohmichi, M., 2010. Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line. J. Endocrinol. 206, 131–140. Fujiwara, H., 2009. Do circulating blood cells contribute to maternal tissue remodeling and embryo-maternal cross-talk around the implantation period? Mol. Hum. Reprod. 15, 335–343. Gaide Chevronnay, H.P., Galant, C., Lemoine, P., Courtoy, P.J., Marbaix, E., Henriet, P., 2009. Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium. Endocrinology 150, 5094–5105. Gargett, C.E., Chan, R.W., Schwab, K.E., 2008. Hormone and growth factor signaling in endometrial renewal: role of stem/progenitor cells. Mol. Cell. Endocrinol. 288, 22–29. Gargett, C.E., Schwab, K.E., Zillwood, R.M., Nguyen, H.P., Wu, D., 2009. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol. Reprod. 80, 1136–1145. Gellersen, B., Brosens, J., 2003. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J. Endocrinol. 178, 357–372.

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Peng, S., Li, J., Miao, C., Jia, L., Hu, Z., Zhao, P., Li, J., Zhang, Y., Chen, Q., Duan, E., 2008. Dickkopf-1 secreted by decidual cells promotes trophoblast cell invasion during murine placentation. Reproduction 135, 367–375. Plante, B.J., Kannan, A., Bagchi, M.K., Yuan, L., Young, S.L., 2009. Cycle regulation of transcription factor C/EBP beta in human endometrium. Reprod. Biol. Endocrinol. 7, 15. Qian, K., Chen, H., Zhang, H.W., Li, Y.F., Jin, L., Zhu, G.J., 2005. Expression of p57 and homeobox A10 during decidualization of endometrial stromal cell in vitro. Sheng Li Xue Bao 57, 498–504. Quinn, C.E., Casper, R.F., 2009. Pinopodes: a questionable role in endometrial receptivity. Hum. Reprod. Update 15, 229–236. Ramathal, C.Y., Bagchi, I.C., Taylor, R.N., Bagchi, M.K., 2010. Endometrial decidualization: of mice and men. Semin. Reprod. Med. 28, 17–26. Richards, R.G., Brar, A.K., Frank, G.R., Hartman, S.M., Jikihara, H., 1995. Fibroblast cells from term human decidua closely resemble endometrial stromal cells: induction of prolactin and insulin-like growth factor binding protein-1 expression. Biol. Reprod. 52, 609–615. Rider, V., Isuzugawa, K., Twarog, M., Jones, S., Cameron, B., Imakawa, K., Fang, J., 2006. Progesterone initiates Wnt-beta-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells. J. Endocrinol. 191, 537–548. Robker, R.L., Akison, L.K., Russell, D.L., 2009. Control of oocyte release by progesterone receptor-regulated gene expression. Nucl. Recept. Signal. 7, e012. Rockwell, L.C., Pillai, S., Olson, C.E., Koos, R.D., 2002. Inhibition of vascular endothelial growth factor/vascular permeability factor action blocks estrogen-induced uterine edema and implantation in rodents. Biol. Reprod. 67, 1804–1810. Rønnov-Jessen, L., Petersen, O.W., 1996. A function for filamentous alpha-smooth muscle actin: retardation of motility in fibroblasts. J. Cell Biol. 134, 67–80. Salamonsen, L.A., Nie, G., Hannan, N.J., Dimitriadis, E., 2009. Society for Reproductive Biology Founders' Lecture 2009. Preparing fertile soil: the importance of endometrial receptivity. Reprod. Fertil. Dev. 21, 923–934. Saleh, L., Otti, G.R., Fiala, C., Pollheimer, J., Knöfler, M., 2011. Evaluation of human first trimester decidual and telomerase-transformed endometrial stromal cells as model systems of in vitro decidualization. Reprod. Biol. Endocrinol. 9, 155. Salker, M., Teklenburg, G., Molokhia, M., Lavery, S., Trew, G., Aojanepong, T., Mardon, H.J., Lokugamage, A.U., Rai, R., Landles, C., Roelen, B.A., Quenby, S., Kuijk, E.W., Kavelaars, A., Heijnen, C.J., Regan, L., Macklon, N.S., Brosens, J.J., 2010. Natural selection of human embryos: impaired decidualization of endometrium disables embryo–maternal interactions and causes recurrent pregnancy loss. PLoS One 5, e10287. Salker, M.S., Nautiyal, J., Steel, J.H., Webster, Z., Sucurovic, S., Nicou, M., Singh, Y., Lucas, E. S., Murakami, K., Chan, Y.W., James, S., Abdallah, Y., Christian, M., Croy, B.A., MulacJericevic, B., Quenby, S., Brosen, J.J., 2012. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss. PLoS One 7, e52252. Scarpin, K.M., Graham, J.D., Mote, P.A., Clarke, C.L., 2009. Progesterone action in human tissues: regulation by progesterone receptor(PR) isoform expression, nuclear positioning and coregulator expression. Nucl. Recept. Signal. 7, e009. Schwab, K.E., Gargett, C.E., 2007. Co-expression of perivascular cell marker isolates mesenchymal stem-like cells from human endometrium. Hum. Reprod. 22, 2903–2911. Schwab, K.E., Hutchinson, P., Gargett, C.E., 2008. Identification of surface markers for prospective isolation of human endometrial stromal colony-forming cells. Hum. Reprod. 23, 934–943. Sidell, N., Feng, Y., Hao, L., Wu, J., Yu, J., Kane, M.A., Napoli, J.L., Taylor, R.N., 2010. Retinoic acid is a cofactor for translational regulation of vascular endothelial growth factor in human endometrial stromal cells. Mol. Endocrinol. 24, 148–160. Siiteri, P.K., 1978. Steroid hormones and endometrial cancer. Cancer Res. 38, 4360–4366. Singh, M., Chaudhry, P., Asselin, E., 2011. Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors. J. Endocrinol. 210, 5–14. Sonderegger, S., Pollheimer, J., Knöfler, M., 2010. Wnt signaling in implantation, decidualisation and placental differentiation—review. Placenta 31, 839–847. Takano, M., Lu, Z., Goto, T., Fusi, L., Higham, J., Francis, J., Withey, A., Hardt, J., Cloke, B., Stavropoulou, A.V., Ishihara, O., Lam, E.W., Unterman, T.G., Brosens, J.J., Kim, J.J., 2007. Transcriptional cross talk between the forkhead transcription factor forkhead boxO1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Mol. Endocrinol. 21, 2334–2349. Tamura, I., Sato, S., Okada, M., Tanabe, M., Lee, L., Maekawa, R., Asada, H., Yamagata, Y., Tamura, H., Sugino, N., 2014. Importance of C/EBPb binding and histone acetylation status in the promoter regions for induction of IGFBP-1, PRL, and Mn-SOD by cAMP in human endometrial stromal cells. Endocrinology 155, 275–286. Tapia, A., Vilos, C., Marín, J.C., Croxatto, H.B., Devoto, L., 2011. Bioinformatic detection of E47, E2F1 and SREBP1 transcription factors as potential regulators of genes associated to acquisition of endometrial receptivity. Reprod. Biol. Endocrinol. 9, 14. Teklenburg, G., Salker, M., Heijnen, C., Macklon, N.S., Brosens, J.J., 2010. The molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol. Hum. Reprod. 16, 886–895. Telgmann, R., Gellersen, B., 1998. Marker genes of decidualization: activation of the decidual prolactin gene. Hum. Reprod. Update 4, 472–479. Uhlenhaut, N.H., Treier, M., 2011. Forkhead transcription factors in ovarian function. Reproduction 142, 489–495. Vacca, P., Vitale, C., Montaldo, E., Conte, R., Cantoni, C., Fulcheri, E., Darretta, V., Moretta, L., Mingari, M.C., 2011. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proc. Natl. Acad. Sci. U. S. A. 108, 2402–2407. Vallejo, G., Ballaré, C., Barañao, J.L., Beato, M., Saragüeta, P., 2005. Progestin activation of nongenomic pathways via cross talk of progesterone receptor with estrogen

E

T

López Moratalla, N., Lago Fernández Purón, M., Santiago, E., 2011. Select embryos: preimplantation genetic diagnosis. Cuad. Bioet. 22, 243–258. Lu, Z., Hardt, J., Kim, J.J., 2008. Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol. Hum. Reprod. 14, 357–366. Luan, L., Ding, T., Stinnett, A., Reese, J., Paria, B.C., 2011. Adherens junction proteins in the hamster uterus: their contributions to the success of implantation. Biol. Reprod. 85, 996–1004. Lynch, V.J., Brayer, K., Gellersen, B., Wagner, G.P., 2009. HoxA-11 and FOXO1A cooperate to regulate decidual prolactin expression: towards inferring the core transcriptional regulators of decidual genes. PLoS One 4, e6845. Ma, X., Gao, F., Rusie, A., Hemingway, J., Ostmann, A.B., Sroga, J.M., Jegga, A.G., Das, S.K., 2011. Decidual cell polyploidization necessitates mitochondrial activity. PLoS One 6, e26774. Macdonald, L.J., Sales, K.J., Grant, V., Brown, P., Jabbour, H.N., Catalano, R.D., 2011. Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium. Mol. Hum. Reprod. 17, 626–636. Maliqueo, M.A., Quezada, S., Clementi, M., Bacallao, K., Anido, M., Johnson, C., Vega, M., 2004. Potential action of androstenedione on the proliferation and apoptosis of stromal endometrial cells. Reprod. Biol. Endocrinol. 2, 81. Mantena, S.R., Kannan, A., Cheon, Y.P., Li, Q., Johnson, P.F., Bagchi, I.C., Bagchi, M.K., 2006. C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc. Natl. Acad. Sci. U. S. A. 103, 1870–1875. Maruyama, T., Yoshimura, Y., Sabe, H., 1999. Tyrosine phosphorylation and subcellular localization of focal adhesion proteins during in vitro decidualization of human endometrial stromal cells. Endocrinology 140, 5982–5990. Masuda, H., Matsuzaki, Y., Hiratsu, E., Ono, M., Nagashima, T., Kajitani, T., Arase, T., Oda, H., Uchida, H., Asada, H., Ito, M., Yoshimura, Y., Maruyama, T., Okano, H., 2010. Stem celllike properties of the endometrial side population: implication in endometrial regeneration. PLoS One 5, e10387. Menkhorst, E.M., Lane, N., Winship, A.L., Li, P., Yap, J., Meehan, K., Rainczuk, A., Stephens, A., Dimitriadis, E., 2012. Decidual-secreted factors alter invasive trophoblast membrane and secreted proteins implying a role for decidual cell regulation of placentation. PLoS One 7, e31418. Miura, S., Shukunami, C., Mitsui, K., Kondo, J., Hiraki, Y., 2011. Localization of chondromodulin-I at the feto-maternal interface and its inhibitory actions on trophoblast invasion in vitro. BMC Cell Biol. 12, 34. Miyazaki, T., Arai, S., 2007. Two distinct controls of mitotic CDK1/cyclin B1 activity requisite for cell growth prior to cell division. Cell Cycle 6, 1419–1425. Mohamed, O.A., Jonnaert, M., Labelle-Dumais, C., Kuroda, K., Clarke, H.J., Dufort, D., 2005. Uterine Wnt/beta-catenin signaling is required for implantation. Proc. Natl. Acad. Sci. U. S. A. 102, 8579–8584. Mori, M., Kitazume, M., Ose, R., Kurokawa, J., Koga, K., Osuga, Y., Arai, S., Miyazaki, T., 2011. Death effector domain-containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice. J. Clin. Investig. 121, 318–327. Muto, A., Yi, T., Harrison, K.D., Dávalos, A., Fancher, T.T., Ziegler, K.R., Feigel, A., Kondo, Y., Nishibe, T., Sessa, W.C., Dardik, A., 2011. Eph-B4 prevents venous adaptive remodeling in the adult arterial environment. J. Exp. Med. 208, 561–575. Nagamatsu, T., Schust, D.J., Sugimoto, J., Barrier, B.F., 2009. Human decidual stromal cells suppress cytokine secretion by allogenic CD4+ T cells via PD-1 ligand interactions. Hum. Reprod. 24, 3160–3171. Nallasamy, S., Li, Q., Bagchi, M.K., Bagchi, I.C., 2012. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium. PLoS Genet. 8, e1002500. Nawrocki, A.R., Rajala, M.W., Tomas, E., Pajvani, U.B., Saha, A.K., Trumbauer, M.E., Pang, Z., Chen, A.S., Ruderman, N.B., Chen, H., Rossetti, L., Scherer, P.E., 2006. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem. 281, 2654–2660. Nephew, K.P., Long, X., Osborne, E., Burke, K.A., Ahluwalia, A., Bigsby, R.M., 2000. Effect of estrogen receptor expression in rat uterine cell types. Biol. Reprod. 62, 168–177. Nikas, G., 2000. Endometrial receptivity: changes in cell-surface morphology. Semin. Reprod. Med. 18, 229–235. Niklaus, A.L., Aberdeen, G.W., Babischkin, J.S., Pepe, G.J., Albrecht, E.D., 2003. Effect of estrogen on vascular endothelial growth/permeability factor expression by glandular epithelial and stromal cells in the baboon endometrium. Biol. Reprod. 68, 1997–2004. Okulicz, W.C., Balsamo, M., 1993. A double immunofluorescent method for simultaneous analysis of progesterone-dependent changes in proliferation and the estrogen receptor in endometrium of rhesus monkeys. J. Reprod. Fertil. 99 (2), 545–549. Okulicz, W.C., Balsamo, M., Tast, J., 1993. Progesterone regulation of endometrial estrogen receptor and cell proliferation during the late proliferative and secretory phase in artificial menstrual cycles in the rhesus monkey. Biol. Reprod. 49, 24–32. Oliver, C., Montes, M.J., Galindo, J.A., Ruiz, C., Olivares, E.G., 1999. Human decidual stromal cells express alpha-smooth muscle actin and show ultrastructural similarities with myofibroblasts. Hum. Reprod. 14, 1599–1605. Osteen, K.G., Rodgers, W.H., Gaire, M., Hargrove, J.T., Gorstein, F., Matrisian, L.M., 1994. Stromal–epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc. Natl. Acad. Sci. U. S. A. 91, 10129–10133. Pabona, J.M., Zeng, Z., Simmen, F.A., Simmen, R.C., 2010. Functional differentiation of uterine stromal cells involves cross-regulation between bone morphogenetic protein 2 and Kruppel-like factor (KLF) family members KLF9 and KLF13. Endocrinology 151, 3396–3406. Paule, S., Meehan, K., Rainczuk, A., Stephens, A.N., Nie, G., 2011. Combination of hydrogel nanoparticles and proteomics to reveal secreted proteins associated with decidualization of human uterine stromal cells. Proteome Sci. 9, 50.

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Whitley, G.S., Cartwright, J.E., 2010. Cellular and molecular regulation of spiral artery remodeling: lessons from the cardiovascular field. Placenta 31, 465–474. Wilcox, A.J., Baird, D.D., Weinberg, C.R., 1999. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799. Williams, P.J., Bulmer, J.N., Innes, B.A., Broughton, Pipkin F., 2011. Possible roles for folic acid in the regulation of trophoblast invasion and placental development in normal early human pregnancy. Biol. Reprod. 84, 1148–1153. Yang, S., Fang, Z., Gurates, B., Tamura, M., Miller, J., Ferrer, K., Bulun, S.E., 2001. Stromal PRs mediate induction of 17beta-hydroxysteroid dehydrogenase type2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2. Mol. Endocrinol. 15, 2093–2105. Yap, J., Foo, C.F., Lee, M.Y., Stanton, P.G., Dimitriadis, E., 2011. Proteomic analysis identifies interleukin 11 regulated plasma membrane proteins in human endometrial epithelial cells in vitro. Reprod. Biol. Endocrinol. 9, 73. Yotova, I.Y., Quan, P., Leditznig, N., Beer, U., Wenzl, R., Tschugguel, W., 2011. Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signaling pathways in eutopic endometrial stromal cells of patients with endometriosis. Hum. Reprod. 26, 885–897. Zhang, J., Chen, Z., Smith, G.N., Croy, B.A., 2011. Natural killer cell-triggered vascular transformation: maternal care before birth? Cell. Mol. Immunol. 8, 1–11.

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C

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receptor beta induces proliferation of endometrial stromal cells. Mol. Endocrinol. 19, 3023–3037. van den Heuvel, M., Peralta, C., Bashar, S., Taylor, S., Horrocks, J., Croy, B.A., 2005a. Trafficking of peripheral blood CD56(bright) cells to the decidualizing uterus—new tricks for old dogmas? J. Reprod. Immunol. 67, 21–34. van den Heuvel, M.J., Chantakru, S., Xuemei, X., Evans, S.S., Tekpetey, F., Mote, P.A., Clarke, C.L., Croy, B.A., 2005b. Trafficking of circulating pro-NK cells to the decidualizing uterus: regulatory mechanisms in the mouse and human. Immunol. Investig. 34, 273–293. van Mourik, M.S., Macklon, N.S., Heijnen, C.J., 2009. Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J. Leukoc. Biol. 85, 4–19. Wang, J., Shou, J., Chen, X., 2000. Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Oncogene 19, 1843–1848. Wang, W., Li, Q., Bagchi, I.C., Bagchi, M.K., 2010. The CCAAT/enhancer binding protein beta is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization. Endocrinology 151, 3929–3940. Wewer, U.M., Faber, M., Liotta, L.A., Albrechtsen, R., 1985. Immunochemical and ultrastructural assessment of the nature of the pericellular basement membrane of human decidual cells. Lab. Investig. 53, 624–633.

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Endometrial stromal cells and decidualized stromal cells: origins, transformation and functions.

Decidualization of endometrium, which is characterized by endometrial stromal cell (ESC) decidualization, vascular reconstruction, immune cell recruit...
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