TISSUE-SPECIFIC STEM CELLS Concise Review: The Plasticity of Stem Cell Niches: A General Property Behind Tissue Homeostasis and Repair PATRICIA ROJAS–R´IOS, ACAIMO GONZA´LEZ–REYES* Key Words. Stem cell niche • Niche physiology • Tissue homeostasis • Tissue repairAging
Centro Andaluz de Biologıa del Desarrollo, CSIC/ Universidad Pablo de Olavide/JA, Carretera de Utrera km 1, Sevilla, Spain Correspondence: Acaimo Gonzalez-Reyes, Ph.D., Andalusian Centre for Developmental Biology (CABD), CSIC/UPO/JA, Ctra. de Utrera km 1, Seville, Spain. Telephone: 34-954-348672; Fax: 34954-349376; e-mail: [email protected] Received September 3, 2013; accepted for publication November 9, 2013; first published online in STEM CELLS EXPRESS December 19, 2013. C AlphaMed Press V
1066-5099/2014/$30.00/0 http://dx.doi.org/ 10.1002/stem.1621
ABSTRACT Stem cell activity is tightly regulated during development and in adult tissues through the combined action of local and systemic effectors. While stem cells and their microenvironments are capable of sustaining homeostasis in normal physiological circumstances, they also provide host tissues with a remarkable plasticity to respond to perturbations. Here, we review recent discoveries that shed light on the adaptive response of niches to systemic signals and aging, and on the ability of niches to modulate signaling upon local perturbations. These characteristics of stem cells and their niches give organs an essential advantage to deal with aging, injury or pathological conditions. STEM CELLS 2014;32:852–859
INTRODUCTION Stem cells are essential during development and in adulthood in most multicellular organisms, as they are responsible for the generation of tissue-specific cell types. Stem cells are uncommitted cells with the potential to form one, many, or all cell types present in an organism. They self-renew and, in adult animals, are able to adapt to changing physiological conditions, to respond to tissue damage and to replenish the host tissue. Adult stem cells are found in specific locations or niches that are ultimately responsible for the maintenance of stem cell populations, their controlled proliferation, and the differentiation of their progeny into multiple cellular lineages. Niches provide stem cells specific signals and physical support in the form of specialized cells and/or extracellular matrix (ECM) [1–4]. The ability of adult stem cell populations to drive adaptive growth under challenging physiological conditions and to sustain tissue homeostasis and repair has raised high expectations for the use of these cells in regenerative medicine. In the last decade, an increasing number of studies on stem cell behavior and the influence that niches exert in the control of stem cell proliferation, self-renewal, and differentiation have advanced our knowledge of the molecular mechanisms involved in stem cell biology [5]. However, multiple questions related to the proper functioning of stem cell niches and how they react to pathological conditions or to physiological variations remain to
Stem Cells 2014;32:852–859 www.StemCells.com
be answered. In this concise review, we will highlight recent advances in our understanding of the cellular mechanisms behind niche signaling and the plasticity of niches in response to external stimuli. The use of model systems, such as the fruit fly Drosophila melanogaster, the nematode Caenorhabdites elegans, or the mouse, has paved the road for a deeper understanding of the behavior of tissuespecific stem cell populations.
CELLULAR
AND INTERSTITIAL NICHE COMPONENTS
Niche components often include populations of support cells and/or ECM, which can be arranged to conform microenvironments of different complexity both in invertebrate and vertebrate organs. The so-called cellular niches contain support cells that could be either postmitotic, as in the germline stem cell (GSC) niche in C. elegans or in the Drosophila female [6–8], or retain proliferative capacity, as described for the perivascular stromal cells and the endothelial cells in the perivascular hematopoietic stem cell (HSC) niche in mice [9]. Niches lacking cellular components have also been reported. These a-cellular niches are defined by the absence of a dedicated set of support cells and by the presence of basement membrane, a specialized ECM found at the basal side of epithelial monolayers. A canonical example of an epithelial niche is that of the somatic follicle stem cells (FSCs) of the Drosophila ovary. Here, the maintenance and proliferation of FSCs are controlled by their C AlphaMed Press 2013 V
Rojas-Rıos, Gonzalez-Reyes integrin-mediated interaction with the basement membrane [10]. Interestingly, in addition to defining a novel niche organization, the FSC niche has also provided the basis to demonstrate that stem cell replacement can be mediated by stem cell interniche migration and by competition for niche occupancy [11]. Finally, more complex niches composed of both support cells and an interacting ECM can also be found in adult organs. The subventricular zone (SVZ) of the forebrain of postnatal rodents, home to neural progenitor cells closely associated with transit amplifying cells, young neurons, blood vessels, ependymal cells lining the ventricles, and the ECM, represents a clear example [12]. Niche activity depends on cell-cell and/or cell-matrix interactions, as shown in Drosophila, mouse, and human models. Thus, adhesion to the surrounding tissues is fundamental for stem cell retention, proliferation, and controlled differentiation in mammalian blood, neural, epidermal, muscular, spermatogonial, and prostate niches [13–15]. In the Drosophila ovary, adhesion to the ECM (via integrins) or to niche support cells (via cadherins) prevents the loss of FSCs and GSCs, respectively [10, 16–18]. Importantly, in addition to mediating adhesion, matrix-stem cell interactions also modulate signaling events. For instance, in muscle satellite cells in mice the binding of the ECM component Fibronectin to the satellite cell-expressed Syndecan-4 potentiates the ability of Wnt7a factor to stimulate satellite cell expansion [19]. Considering the essential role of satellite cells in muscle regeneration and the fact that Fibronectin is synthesized and secreted by the satellite stem cells themselves, these findings give another twist to the story and emphasize the importance of the stem cell-niche interactions in homeostasis and repair. Experiments in vitro have also identified a number of interactions between ECM components and cultured stem cells that regulate stem cell differentiation. Thus, fibronectin and vitronectin interact, respectively, with integrins a5 and aV, both present in human embryonic stem cells (ESCs), to promote definitive endoderm differentiation [20]. Similarly, the adhesiveness of nonhuman primate ESCs to various biological and nonbiological substrates and of human cord bloodderived neural stem cells (NSCs) to poly(L-lysine) or fibronectin determines their differentiation potential [21, 22]. Niche support cells and surrounding tissues have been reported to secrete factors that activate signaling in stem cells in vertebrate and invertebrate systems [23]. Whereas the large majority of the niche molecules described act at shortrange and affect the stem cell pool within the niche, recent reports have also placed the focus on long-range signaling as a means to regulate stem cell behavior and tissue response to environmental variations. In the mouse skin, cycling dermal bone morphogenetic protein (BMP) signaling controls stem cell activity during hair follicle regeneration, supporting a role for inter-organ signaling in stem cell homeostasis [24, 25]. Similarly, the intersection of opposing long-range gradients of Hedgehog (Hh) and Unpaired (Upd, a cytokine that acts as ligand of the Janus Kinase/Signal Transducer and Activator of Transcription, JAK/STAT, pathway) regulates Drosophila FSC behavior and numbers, indicating that epithelial niches can also be defined by long-range signaling [26]. These examples of the regulation of stem cell homeostasis by a macroenvironment create a new paradigm in which to elucidate niche function and they point to a higher level coordination of niche activity to ensure whole organ dynamics [27].
www.StemCells.com
853
While the above properties depict stem cell niches as entities able to self-regulate stem cell maintenance, proliferation, and differentiation, their activity is integrated in the overall homeostasis of organs and whole organisms. Thus, systemic signaling or pathological conditions influence the output of niche operation, as reviewed below.
AGING
OF
STEM CELLS
AND
THEIR NICHES
Aging is concomitant with altered tissue maintenance and repair. Because stem cell activity is key to maintaining tissue homeostasis and since tissue attrition correlates with decreased stem cell homing abilities, self-renewal, and cell repopulation capacity, stem cell aging lies beneath the aging of tissues [28, 29]. This is best exemplified in the study of parabiotic mice pairs in which a young and an old mice share the circulatory system. These heterochronic parabioses showed the existence of systemic factors present in younger mice that could rejuvenate aged progenitor cells and that these factors change with age, thus jeopardizing successful tissue regeneration in older animals [30]. The analysis of the SVZ niche in mice has also provided solid evidence of the transition into a quiescent state of aging adult NSCs. In this system, the contribution of the SVZ niche to the numbers of olfactory-bulb neuroblasts greatly diminishes with time. This decrease in SVZ-niche activity correlates with changes in the behavior of forebrain-derived adult NSCs, as middle-aged NSCs divide less frequently than young ones [31]. Aging is known to affect directly stem cells (intrinsic factors) and to provoke changes in their microenvironment (extrinsic factors). In either case, the modifications in the stem cells and their niches result in impaired niche activity. Examples of agedependent stem cell intrinsic factors can be found in the Drosophila germline niches and the blood system in mice. In Drosophila adults, the number of GSCs present in their niches decreases with age. The adhesion molecule Drosophila ECadherin is an essential protein required to attain stem cell maintenance within the niche. Since its amounts are reduced in aged male and female GSCs, loss of DE-Cadherin contributes to the stem cell loss observed in aged GSC niches [32, 33]. In the vertebrate blood system, HSCs show a diminished regenerative potential in serial transplantation assays upon aging, indicating a lessening in their intrinsic self-renewal properties. Aging HSCs are also characterized by a pronounced decrease in the production of lymphoid and erythroid lineages, whereas the myeloid lineage is maintained or even increased [28]. While recent data indicate that environmental (external) factors partially underlie the lineage skewing characteristic of aging HSCs [34, 35], this phenotype also depends on intrinsic factors, as shown by the general upregulation of lymphoid genes within old HSCs. The molecular explanation for these changes points to a deterioration of the epigenetic programs in aging HSCs, as genes responsible for chromatin remodeling and chromatin-dependent transcriptional silencing are downregulated in these HSCs [36, 37]. Finally, aging HSCs show increased levels of the cyclindependent kinase inhibitor p16INK4a and its absence from aged HSCs mitigates their repopulation defects [38]. Altogether, these data point toward a key role for stem cell intrinsic factors in the control of the physiological impact of aging. Aging stem cell populations also exhibit cell-extrinsic variations that contribute to their decline in activity. For instance, C AlphaMed Press 2013 V
854
ageing affects the functionality of self-renewing factors in the niche, as demonstrated for the GSC niches of Drosophila. In the case of the male, both stem cell number and their proliferation rate decline with time and so does the concentration of the niche factor Upd [32]. Recent research has deciphered the molecular details of Upd drop in aging testes. Thus, the IGF-II messenger RNA-binding protein (Imp) stabilizes upd RNA by protecting it from small interfering RNA-mediated degradation. Because imp RNA is a target of the heterochronic microRNA let-7 and since let-7 levels are doubled in the first 4 weeks after eclosion, aging results in a decrease in the amount of Imp (and, thus, of Upd) available in the niche [39]. Similarly, ovarian GSCs show reduced BMP signaling activity with time but the molecular mechanisms behind this decline are at present unknown [33]. An important corollary to the above data is that niche age constrains the output of regenerative therapies. Hence, older niches may not be as effective in sustaining the self-renewal of transplanted stem cells in cell therapies. A possible solution to this problem may lie in the manipulation of stem cells and their microenvironments. In this scenario, studies in the mouse blood system have identified the mammalian target of rapamycin (mTOR) pathway and the small GTPase CDC42 as pharmacological targets for rejuvenating HSCs [40, 41]. In addition, aging niches may help select the fittest stem cells, maintaining those with a higher proliferative potential, either because they are less dependent on niche signals to survive or because they develop a lower threshold to trigger survival signaling. In this regard, it is necessary to note that niches are plastic and can be manipulated genetically. For instance, the ectopic expression of Upd in the niche cells of aging Drosophila testes rescues the reduction in stem cell number and their proliferation capacity typical of old males [32]. Because niche activity is genetically controlled and many of the pathways involved in niche-stem cell interactions are conserved in evolution, it is likely that the capacity to rejuvenate invertebrate stem cells after genetic manipulation of niches is a property also of vertebrate tissues. In fact, muscle stem cell (MSC) manipulation can reverse the decline in muscle regeneration of aged mice. Under homeostatic conditions, the muscle fiber, the primary component of the MSC niche, produces the mitogenic factor Fgf2, which in turn induces quiescent MSCs to cycle and repair muscle. To prevent the precocious depletion of MSCs and to maintain the muscle regenerative capacity, quiescent MSCs secrete the Fgf-signaling inhibitor Sprouty. However, aged muscle fibers increase the amount of secreted Fgf2, thus leading to declines in MSC function and numbers during homeostasis. Reducing experimentally the level of Fgf signaling in MSCs prevents their depletion. Conversely, removal of Sprouty from MSCs results in the loss of cell quiescence and in diminished muscle regenerative capacity [42]. Thus, at least in this particular vertebrate niche and in the GSC niche in Drosophila males, the self-renewing potential of associated stem cells is amenable to genetic treatment, perhaps pointing to a general property of tissue-specific stem cell niches across evolution.
NICHE RESPONSES TO CHANGES IN THE ENVIRONMENT: DORMANT STEM CELLS, ADAPTIVE GROWTH, AND SYSTEMIC SIGNALING Fully formed organs in adult animals show a distinct capacity for tissue renovation under normal physiological conditions. C AlphaMed Press 2013 V
Dynamic Stem Cell Niches in Tissue Homeostasis
Organs too possess a regenerative capacity that is essential for tissue repair after damage. These homeostatic and regenerative capacities of mature tissues are attributable in part to resident stem cell populations within the tissue. For instance, in humans and mice, the progeny of resident intestinal stem cells (ISCs) constantly replenish the epithelium lining the lumen of the gut, replacing differentiated enterocytes every week on average. The fine balance between cell replacement and cell proliferation and differentiation within the tissue thus ensures proper gut homeostasis at a remarkable rate [43]. A similar dependence on stem cell populations has been described for the homeostasis of the hematopoietic system, the skin, or the bone skeleton in mammals [44]. While homeostasis relies on transiently quiescent stem cell populations, tissue regeneration often involves the reactivation of longterm quiescent stem cells that, upon injury, can replenish the damaged tissue. The conditional activation of these long-lived or “dormant” stem cells, able to sense the damage and to react to it, is a direct consequence of the coordinated action of the stem cells and their microenvironment. A particularly well-studied case of dormant stem cells is that of the blood system in vertebrates. Dormant HSCs show the highest selfrenewal potential of all HSCs in adult healthy mice, as shown by label-retaining experiments and functional transplantation assays. Nevertheless, they divide five times per lifetime on average. Although the mechanism(s) underlying activation of dormant HSCs are not understood, chemotherapy, toxic insult, or anemia trigger the efficient transformation of dormant HSCs into rapidly dividing HSCs, able to produce active progenitors that give rise to mature blood cell types (reviewed in [45]). Interestingly, these mitotically active dormant HSCs return to their deeply quiescent state once homeostasis is restored. As discussed above, stem cell fate is influenced by the integration of signals of different origin by their hosting niches. Thus, since dormant HSCs reside in their own niches, these most likely regulate the activation and re-entry into quiescence of the dormant HSCs [46]. Whether these particular niches abide by the same regulatory rules as the rest of the HSC niches present in the hematopoietic system is still unknown but the study of dormant stem cells highlights once more the crucial role of niches in controlling tissue homeostasis in physiology and pathology. Finally, dormant stem cells have been also identified in other tissues such as the Drosophila hindgut [47] and postulated to exist within the heterogenic hair FSC population in mice [48], indicating that dormant stem cell subpopulations may be a widespread characteristic of adult tissues. Remodeling of organs in response to environmental change is a life-long property in many organisms and examples include the resizing of mammary glands during pregnancy or the stimulation of erythropoiesis as a consequence of low oxygen concentrations. Thus, organs grow or shrink in response to environmental stimuli that implicate changes in the control of cell proliferation and/or differentiation. The case of the mammary gland is remarkable, as the specialized epithelium characteristic of this organ is able to grow and shrink four- to fivefold during pregnancy/lactation and postlactation regression cycles. The mammary epithelium is composed mainly of luminal, alveolar, and myoepithelial cells, all of which coordinate cell proliferation and differentiation during development, adulthood, and pregnancy (reviewed in [49]). The main subtypes of the STEM CELLS
Rojas-Rıos, Gonzalez-Reyes epithelium, the luminal and myoepithelial cell lineages, derive from long-lived, unipotent stem cell precursors also present in the adult organ and that are responsible for the massive cell expansion observed during several cycles of pregnancy [50]. The regulation of these adaptive mechanisms is largely unknown, but the intestine of adult flies has shed some light into the molecular and cellular variations underlying “adaptive growth.” Upon food stimulation of Drosophila adults, stem cell niches in the intestine secrete the insulin-like peptide Drosophila insulin-like peptide 3 to induce stem cell proliferation and tissue growth. Surprisingly, this insulin-mediated induction of cell proliferation alters the normal mode of division of ISCs and drives symmetric divisions at the expense of asymmetric ones. Thus, the number of both ISCs and of their offspring increases (up to 300-fold!), accounting for tissue enlargement [51]. Importantly for the purpose of this review, cycles of fastening and refeeding showed that adaptive growth of the adult midgut is reversible depending of dietary fluctuations, demonstrating once more the capacity of niches to regulate the activity of resident stem cells according to changing environmental conditions. Considering the important role that stem cell populations play in tissue homeostasis, the response of tissues to environmental and systemic signals requires the adaptation of stem cells and their microenvironments to extrinsic factors. Thus, it comes as no surprise that several types of stem cells have been found to modulate their proliferation in response to systemic signals. For instance, Drosophila neuroblasts, the multipotent NSCs responsible for the development of the nervous system of the larva and adult, normally go through a phase of quiescence to separate distinct onsets of embryonic and postembryonic proliferation. Exit from quiescence in larval stages is regulated by the production of insulin-like peptides from a population of adjacent glial cells that activates the phosphoinositide-3 kinase/Akt pathway in neuroblasts. Glial secretion of the active peptides in turn depends on the amino acid-sensing and TOR pathways in the fat body. Thus, a systemic signal emanating from the fat body, the fly’s equivalent to the liver and adipose tissue, regulates reactivation of quiescent NSCs of the larval brain in response to dietary information [52, 53]. This paradigm of systemic signals determining the output of stem cell populations is not restricted to the fly’s central nervous system, as Drosophila GSCs and ISCs have also been shown to respond to the nutritional state of the organism [54]. In vertebrates, perhaps one of the bestcharacterized physiological changes eliciting a particular response from stem cell populations is that of the circadian rhythms. Circadian oscillations impinge on the release of HSC from the bone marrow, on the ability of HSCs to synthesize DNA, on the frequency of colony-forming progenitors in both human and mice, and on the engraftment of transplanted HSCs [55, 56]. Most likely, these phenotypes reflect an influence of the circadian rhythms on the timing of cell division of hematopoietic cells through the regulation of niche activity, a process that involves the sympathetic nervous system [57].
SIGNAL DELIVERY
IN
NICHES
Morphogens are signaling molecules originally defined as secreted and diffusible proteins whose function depends on their concentration gradient through tissues (for a compre-
www.StemCells.com
855
hensive review see [58]). Inherent to the model of morphogen action is the mechanism(s) by which producing cells deliver the signals to the receiving cells. Work in Drosophila imaginal discs has shown the existence of a specific type of cellular projections termed cytonemes that are responsible for morphogen delivery and for morphogen signal reception [59– 62]. Cytonemes are filopodia-like extensions of the plasma membrane of approximately 0.2 mm in diameter able to form intercellular bridges. Morphogens and their receptors are found decorating cytonemes that emanate either from the producing cells (the former) or the receiving cells (the latter) [60, 63]. The role of cytonemes in conveying patterning information and in regulating signaling in developing tissues is conserved during evolution, as cytoneme-like filopodia have been observed during vertebrate limb or neural tube development or in mouse blastocysts [64] (reviewed in [65]). Morphogens play important roles in the correct maintenance of stem cell populations within their niches both in vertebrate and invertebrate systems. For instance, Hh, the BMPhomolog Decapentaplegic (Dpp), Upd, and Upd 3 (another ligand of the JAK/STAT pathway) are well-known participants of niche homeostasis in the intestine, ovary, testis, or lymph gland in Drosophila [63, 66–69]; Sonic Hh is necessary to define NSC positional identity in the adult brain or to sustain proper hematopoiesis in mice [12, 70, 71]; Wnt ligands are key niche molecules in the hematopoietic system, the developing brain, the skin, or the intestinal crypts of mice [72–75]; and Hh, BMPs, the fibroblast growth factor, and the vasculoendothelial growth factor are also required in the hematopoietic system of fish and mice (reviewed in [70–72]). We have recently reported that cytonemes are involved in the delivery of Hh in the GSC niche of the Drosophila female [63]. We found that the ligand of the Hh signaling pathway is localized specifically in short cytonemes (0.5–1 mm in length) projected by a particular type of niche cells, the Cap cells. Interestingly, disrupting cytoneme production and/or kinetics resulted in the loss of GSCs, indicating that the Hh-decorated short cytonemes are truly essential for stem cell maintenance in the fly ovarian niche. The above cellular extensions could be the mechanism by which cells establish signaling synapses. Thus, the points of contact between cytonemes and the receiving cells may define the precise places for receptor activation and for the initiation of signal transduction. It would be very interesting to devise an experimental system to visualize live cytonemes and the formation of signaling synapses in active niches and to compare their dynamics after manipulation. A direct consequence of cytoneme-mediated signaling in niches is that the spreading of the signals depends on the reach of the cytonemes. The short cytonemes in the Drosophila ovary allow only juxtacrine signaling. However, in experimental niches in which Hh signaling is impaired in specific support cells cytonemes emanating from normal support cells can grow significantly longer (up to 6 mm in length). Importantly, these long cytonemes show a directed growth toward the signaling-deficient area of the niche [63]. The simplest explanation for this behavior is that Drosophila ovarian niches are plastic structures with the capacity to sense the signaling status of its cellular components and to react to perturbations by increasing the range of signal delivery from healthy support cells. Since signaling in the GSC niche determines the C AlphaMed Press 2013 V
856
outcome of stem cell proliferation, this plasticity offers the ovary the ability to adapt to physiological or pathological changes that may affect its fitness. Should this be a general property of stem cell niches, it could represent an important advantage for the integration of systemic and local signals implicated in tissue homeostasis. In this scenario, it is worth
Dynamic Stem Cell Niches in Tissue Homeostasis
noting that cytonemes similar to those described in the ovarian niche of the fly have been reported in other invertebrate niches such as the nematode gonad, the earwig ovary, or the lymph gland in the Drosophila larva, pointing toward a more general role for this type of cell-cell signaling in stem cell niches [76–79]. In spite of its potential implications for niche
Figure 1. Niche activity is influenced by local signals, systemic factors, and physiological and pathological conditions. (A): Schematic representation of a cellular niche, some input signals that affect stem cell behavior, and the output responses of the stem cell population. Support cells (blue) interact with the stem cell (green) via adhesion molecules and secreted signals that regulate stem cell proliferation and behavior. The ECM (orange fibers), present in the majority of niches, interacts with stem cells and support cells. Niche activity is influenced by a series of factors, comprising local signals (short-range and long-range), systemic factors (such as nutritional status, developmental changes, or circadian oscillations), and physiological and pathological alterations (including aging, adaptive growth, tissue damage, and disease). Depending on the above conditions, niches are plastic in their response to external stimuli and they can give rise to daughter stem cells, to differentiating siblings (brown or purple cells) or to a mixture of both. (B): In contrast with the normal situation, in which local signals operating in the niche ensure that germline stem cells of the Drosophila ovary divide asymmetrically to produce GSCs and cystoblasts, if a local signal is deficient, as in the case of the removal of the short-range ligand Hh from the support cells, stem cells enter differentiation and are lost from the niche. (C): Adaptive growth of the mammary gland during pregnancy and lactation involves massive expansion of unipotent stem cells. (D): In the vertebrate blood system, aged hematopoietic stem cells (HSCs) show a lessening in their self-renewal properties and a pronounced decrease in the production of lymphoid and erythroid lineages, whereas the myeloid lineage is maintained or even increased. These alterations are a consequence of changes in the HSCs and in the niche cells (see text for details). Abbreviation: ECM, extracellular matrix. C AlphaMed Press 2013 V
STEM CELLS
Rojas-Rıos, Gonzalez-Reyes
857
signaling and stem cell maintenance, a deep understanding of the molecular and cellular mechanisms behind ligand delivery, release, and signal uptake by cytonemes in stem cell niches is lacking and it awaits further experimentation.
PERSPECTIVES The ability of organs to adapt to cellular dysfunction, physical damage, or physiological changes relies heavily on the properties of stem cells and niches. Both homed stem cell populations and their support microenvironments provide tissues with the plasticity necessary for their adaptation to local or systemic variations, a characteristic that allows organs respond to nutritional stress or aging, among other challenges (see Figure 1). There are however some aspects of stem cell and niche behavior that need be comprehended before a more complete picture on stem cell biology in vivo is attained. For instance, the cycling between quiescent and active forms of stem cells is far from understood and a number crucial questions are still open: what parameters do the dormant HSCs and their niches sense to induce stem cell reactivation? How do they return to a quiescent state once the damage has been healed? In this regard, while it is clear that the pulse of high proliferation observed during facultative tissue repair after damage ought to be controlled to prevent deleterious growth, as in the case of the adult Drosophila hindgut, the mechanisms behind this necessary regulation are still missing. A second important point is the degree to which niche cells regulate stem cell proliferation and differentiation. While local signals acting on adjacent stem cells are known to exert a tight regulation of stem cell numbers, systemic signals have the ability to target stem cell proliferation specifically too. This property is most likely a consequence of the control that niches—as sensors of external signals—impose on stem cell populations. How systemic signals ensure the appropriate response from stem cell populations in target tissues to accommodate physiological demands is still an unresolved question and the identification of the precise molecules involved and their mode of action require a vigorous endeavor from researchers. Finally, and particularly relevant in the case of tissue homeostasis and regeneration, is the occurrence of stem cell turn-over. Stem cells are known to be lost
REFERENCES 1 Morrison SJ, Spradling AC. Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132:598–611. 2 Aichinger E, Kornet N, Friedrich T et al. Plant stem cell niches. Annu Rev Plant Biol 2012;63:615–636. 3 Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7–25. 4 Lander AD, Kimble J, Clevers H et al. What does the concept of the stem cell niche really mean today? BMC Biol 2012; 10:19. 5 Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 2011;145:851–862.
www.StemCells.com
from niches either because they differentiate or because they undergo cell death. Since stem cell populations can be kept stable for long periods of time in adult life, stem cell replacement takes place during tissue homeostasis. It is known that replacing mechanisms include symmetric stem cell division to replenish the stem cell pool and/or dedifferentiation of committed cells. Whatever the situation, stem cell replacement implicates that the system auto-regulates so that the replacing cell outcompetes the stem cell expelled from the niche. Whether this selection depends on variations happening naturally among the stem cell pools so that some are fitter than others or whether stem cell substitution is a stochastic process and it is only niche occupancy what matters remains to be elucidated. In any case, the intrinsic properties of stem cells and their close interaction with the niche make the host tissues resilient to demanding conditions during organism aging and physiological variation—something we, long-lived organisms, benefit from.
ACKNOWLEDGMENTS We wish to thank members of the Gonzalez-Reyes laboratory and M.J. Sanchez for critical reading of the manuscript and M.C. Dıaz de la Loza for the design of Figure 1. This work was supported by the Spanish Ministerio de Economıa y Competitividad and the FEDER program (BMC2012–35446), by the Junta de Andalucıa (Proyecto de Excelencia P09-CVI5058), and by the CONSOLIDER program (CSD-2007-00008). P.R.-R. was funded by an I3P-CSIC studentship. P.R.-R. is currently affiliated with the Institute of Human Genetics, CNRS UPR1142, 141, rue de la Cardonille, 34396 Montpellier, Cedex 5, France.
AUTHOR CONTRIBUTION P.R.-R.: manuscript writing; A.G.-R.: financial support and manuscript writing.
DISCLOSURE
OF
POTENTIAL CONFLICTS
OF INTEREST
The authors declare no competing financial interests.
6 Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006;7:333–337. 7 Pearson J, Lopez-Onieva L, Rojas-Rios P et al. Recent advances in Drosophila stem cell biology. Int J Dev Biol 2009;53:1329– 1339. 8 Joshi PM, Riddle MR, Djabrayan NJ et al. Caenorhabditis elegans as a model for stem cell biology. Dev Dyn 2010;239:1539–1554. 9 Ding L, Saunders TL, Enikolopov G et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012;481: 457–462. 10 O’Reilly AM, Lee HH, Simon MA. Integrins control the positioning and proliferation of follicle stem cells in the Drosophila ovary. J Cell Biol 2008;182:801–815. 11 Nystul T, Spradling A. An epithelial niche in the Drosophila ovary undergoes long-
range stem cell replacement. Cell Stem Cell 2007;1:277–285. 12 Ihrie RA, Shah JK, Harwell CC et al. Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity. Neuron 2011;71:250–262. 13 Kuang S, Rudnicki MA. The emerging biology of satellite cells and their therapeutic potential. Trends Mol Med 2008;14:82–91. 14 Raymond K, Deugnier MA, Faraldo MM et al. Adhesion within the stem cell niches. Curr Opin Cell Biol 2009;21:623–629. 15 Marthiens V, Kazanis I, Moss L et al. Adhesion molecules in the stem cell niche— More than just staying in shape? J Cell Sci 2010;123:1613–1622. 16 Song X, Xie T. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci USA 2002;99:14813–14818. C AlphaMed Press 2013 V
858
17 Song X, Zhu CH, Doan C et al. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 2002; 296:1855–1857. 18 Gonzalez-Reyes A. Stem cells, niches and cadherins: A view from Drosophila. J Cell Sci 2003;116:949–954. 19 Bentzinger CF, Wang YX, von Maltzahn J et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 2013;12:75–87. 20 Brafman DA, Phung C, Kumar N et al. Regulation of endodermal differentiation of human embryonic stem cells through integrin-ECM interactions. Cell Death Differ 2013;20:369–381. 21 Buzanska L, Ruiz A, Zychowicz M et al. Patterned growth and differentiation of human cord blood-derived neural stem cells on bio-functionalized surfaces. Acta Neurobiol Exp (Wars) 2009;69:24–36. 22 Chen SS, Fitzgerald W, Zimmerberg J et al. Cell-cell and cell-extracellular matrix interactions regulate embryonic stem cell differentiation. Stem Cells 2007;25:553–561. 23 Yamashita YM, Fuller MT, Jones DL. Signaling in stem cell niches: Lessons from the Drosophila germline. J Cell Sci 2005;118:665– 672. 24 Plikus MV, Mayer JA, de la Cruz D et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 2008;451:340–344. 25 Plikus MV, Baker RE, Chen CC et al. Selforganizing and stochastic behaviors during the regeneration of hair stem cells. Science 2011;332:586–589. 26 Vied C, Reilein A, Field NS et al. Regulation of stem cells by intersecting gradients of long-range niche signals. Dev Cell 2012;23: 836–848. 27 O’Brien LE, Bilder D. Beyond the niche: Tissue-level coordination of stem cell dynamics. Annu Rev Cell Dev Biol 2013;29:107–136. 28 Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13:376–389. 29 van Wijngaarden P, Franklin RJ. Ageing stem and progenitor cells: Implications for rejuvenation of the central nervous system. Development 2013;140:2562–2575. 30 Conboy IM, Conboy MJ, Wagers AJ et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433:760–764. 31 Bouab M, Paliouras GN, Aumont A et al. Aging of the subventricular zone neural stem cell niche: Evidence for quiescence-associated changes between early and mid-adulthood. Neuroscience 2011;173:135–149. 32 Boyle M, Wong C, Rocha M et al. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 2007;1:470–478. 33 Pan L, Chen S, Weng C et al. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 2007;1:458–469. 34 Ergen AV, Boles NC, Goodell MA. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 2012;119:2500–2509. C AlphaMed Press 2013 V
Dynamic Stem Cell Niches in Tissue Homeostasis
35 Vas V, Senger K, Dorr K et al. Aging of the microenvironment influences clonality in hematopoiesis. PLoS One 2012;7:e42080. 36 Chambers SM, Shaw CA, Gatza C et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 2007;5:e201. 37 Beerman I, Bock C, Garrison BS et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 2013; 12:413–425. 38 Janzen V, Forkert R, Fleming HE et al. Stem-cell ageing modified by the cyclindependent kinase inhibitor p16INK4a. Nature 2006;443:421–426. 39 Toledano H, D’Alterio C, Czech B et al. The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche. Nature 2012;485:605–610. 40 Chen C, Liu Y, Liu Y et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009;2:ra75. 41 Florian MC, D€ orr K, Niebel A et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 2012;10:520–530. 42 Chakkalakal JV, Jones KM, Basson MA et al. The aged niche disrupts muscle stem cell quiescence. Nature 2012;490:355–360. 43 Jiang H, Edgar BA. Intestinal stem cell function in Drosophila and mice. Curr Opin Genet Dev 2012;22:354–360. 44 Bianco P, Riminucci M, Gronthos S et al. Bone marrow stromal stem cells: Nature, biology, and potential applications. Stem Cells 2001;19:180–192. 45 Trumpp A, Essers M, Wilson A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol 2010;10:201–209. 46 Sottocornola R, Lo Celso C. Dormancy in the stem cell niche. Stem Cell Res Ther 2012; 3:10. 47 Fox DT, Spradling AC. The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissue damage. Cell Stem Cell 2009;5:290–297. 48 Fuchs E. The tortoise and the hair: Slowcycling cells in the stem cell race. Cell 2009; 137:811–819. 49 Watson CJ, Khaled WT. Mammary development in the embryo and adult: A journey of morphogenesis and commitment. Development 2008;135:995–1003. 50 Van Keymeulen A, Rocha AS, Ousset M et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 2011;479:189–193. 51 O’Brien LE, Soliman SS, Li X et al. Altered modes of stem cell division drive adaptive intestinal growth. Cell 2011;147: 603–614. 52 Chell JM, Brand AH. Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 2010;143:1161–1173. 53 Sousa-Nunes R, Yee LL, Gould AP. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 2011;471:508–512. 54 Jasper H, Jones DL. Metabolic regulation of stem cell behavior and implications for aging. Cell Metab 2010;12:561–565.
55 D’Hondt L, McAuliffe C, Damon J et al. Circadian variations of bone marrow engraftability. J Cell Physiol 2004;200:63–70. 56 Mendez-Ferrer S, Lucas D, Battista M et al. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008;452:442–447. 57 Mendez-Ferrer S, Chow A, Merad M et al. Circadian rhythms influence hematopoietic stem cells. Curr Opin Hematol 2009;16: 235–242. 58 Rogers KW, Schier AF. Morphogen gradients: From generation to interpretation. Annu Rev Cell Dev Biol 2011;27:377–407. 59 Ramirez-Weber FA, Kornberg TB. Cytonemes: Cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell 1999;97:599–607. 60 Roy S, Hsiung F, Kornberg TB. Specificity of Drosophila cytonemes for distinct signaling pathways. Science 2011;332:354–358. 61 Sherer NM, Mothes W. Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. Trends Cell Biol 2008;18:414–420. 62 Hsiung F, Ramirez-Weber FA, Iwaki DD et al. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 2005;437:560–563. 63 Rojas-Rios P, Guerrero I, Gonzalez-Reyes A. Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol 2012;10: e1001298. 64 Sanders TA, Llagostera E, Barna M. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature 2013;497:628–632. 65 Gradilla AC, Guerrero I. Cytoneme-mediated cell-to-cell signaling during development. Cell Tissue Res 2013;352:59–66. 66 Crozatier M, Meister M. Drosophila haematopoiesis. Cell Microbiol 2007;9:1117– 1126. 67 Resende LP, Jones DL. Local signaling within stem cell niches: Insights from Drosophila. Curr Opin Cell Biol 2012;24:225–231. 68 Harris RE, Ashe HL. Cease and desist: Modulating short-range Dpp signalling in the stem-cell niche. EMBO Rep 2011;12:519–526. 69 Michel M, Kupinski AP, Raabe I et al. Hh signalling is essential for somatic stem cell maintenance in the Drosophila testis niche. Development 2012;139:2663–2669. 70 Kaimakis P, Crisan M, Dzierzak E. The biochemistry of hematopoietic stem cell development. Biochim Biophys Acta 2013; 1830:2395–2403. 71 Faigle R, Song H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 2013;1830: 2435–2448. 72 van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009;71: 241–260. 73 Haegebarth A, Clevers H. Wnt signaling, lgr5, and stem cells in the intestine and skin. Am J Pathol 2009;174:715–721. 74 Kalani MY, Cheshier SH, Cord BJ et al. Wnt-mediated self-renewal of neural stem/ progenitor cells. Proc Natl Acad Sci USA 2008;105:16970–16975.
STEM CELLS
Rojas-Rıos, Gonzalez-Reyes 75 Reya T, Duncan AW, Ailles L et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409–414. 76 Crittenden SL, Leonhard KA, Byrd DT et al. Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol Biol Cell 2006;17:3051–3061.
www.StemCells.com
859
77 Krzemien J, Dubois L, Makki R et al. Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre. Nature 2007;446:325–328. 78 Mandal L, Martinez-Agosto JA, Evans CJ et al. A hedgehog- and antennapediadependent niche maintains Drosophila hae-
matopoietic precursors. Nature 2007;446: 320–324. 79 Tworzydlo W, Kloc M, Bilinski SM. Female germline stem cell niches of earwigs are structurally simple and different from those of Drosophila melanogaster. J Morphol 2010;271:634–640.
C AlphaMed Press 2013 V
Centro Andaluz de Biologıa del Desarrollo, CSIC/ Universidad Pablo de Olavide/JA, Carretera de Utrera km 1, Sevilla, Spain Correspondence: Acaimo Gonzalez-Reyes, Ph.D., Andalusian Centre for Developmental Biology (CABD), CSIC/UPO/JA, Ctra. de Utrera km 1, Seville, Spain. Telephone: 34-954-348672; Fax: 34954-349376; e-mail: [email protected] Received September 3, 2013; accepted for publication November 9, 2013; first published online in STEM CELLS EXPRESS December 19, 2013. C AlphaMed Press V
1066-5099/2014/$30.00/0 http://dx.doi.org/ 10.1002/stem.1621
ABSTRACT Stem cell activity is tightly regulated during development and in adult tissues through the combined action of local and systemic effectors. While stem cells and their microenvironments are capable of sustaining homeostasis in normal physiological circumstances, they also provide host tissues with a remarkable plasticity to respond to perturbations. Here, we review recent discoveries that shed light on the adaptive response of niches to systemic signals and aging, and on the ability of niches to modulate signaling upon local perturbations. These characteristics of stem cells and their niches give organs an essential advantage to deal with aging, injury or pathological conditions. STEM CELLS 2014;32:852–859
INTRODUCTION Stem cells are essential during development and in adulthood in most multicellular organisms, as they are responsible for the generation of tissue-specific cell types. Stem cells are uncommitted cells with the potential to form one, many, or all cell types present in an organism. They self-renew and, in adult animals, are able to adapt to changing physiological conditions, to respond to tissue damage and to replenish the host tissue. Adult stem cells are found in specific locations or niches that are ultimately responsible for the maintenance of stem cell populations, their controlled proliferation, and the differentiation of their progeny into multiple cellular lineages. Niches provide stem cells specific signals and physical support in the form of specialized cells and/or extracellular matrix (ECM) [1–4]. The ability of adult stem cell populations to drive adaptive growth under challenging physiological conditions and to sustain tissue homeostasis and repair has raised high expectations for the use of these cells in regenerative medicine. In the last decade, an increasing number of studies on stem cell behavior and the influence that niches exert in the control of stem cell proliferation, self-renewal, and differentiation have advanced our knowledge of the molecular mechanisms involved in stem cell biology [5]. However, multiple questions related to the proper functioning of stem cell niches and how they react to pathological conditions or to physiological variations remain to
Stem Cells 2014;32:852–859 www.StemCells.com
be answered. In this concise review, we will highlight recent advances in our understanding of the cellular mechanisms behind niche signaling and the plasticity of niches in response to external stimuli. The use of model systems, such as the fruit fly Drosophila melanogaster, the nematode Caenorhabdites elegans, or the mouse, has paved the road for a deeper understanding of the behavior of tissuespecific stem cell populations.
CELLULAR
AND INTERSTITIAL NICHE COMPONENTS
Niche components often include populations of support cells and/or ECM, which can be arranged to conform microenvironments of different complexity both in invertebrate and vertebrate organs. The so-called cellular niches contain support cells that could be either postmitotic, as in the germline stem cell (GSC) niche in C. elegans or in the Drosophila female [6–8], or retain proliferative capacity, as described for the perivascular stromal cells and the endothelial cells in the perivascular hematopoietic stem cell (HSC) niche in mice [9]. Niches lacking cellular components have also been reported. These a-cellular niches are defined by the absence of a dedicated set of support cells and by the presence of basement membrane, a specialized ECM found at the basal side of epithelial monolayers. A canonical example of an epithelial niche is that of the somatic follicle stem cells (FSCs) of the Drosophila ovary. Here, the maintenance and proliferation of FSCs are controlled by their C AlphaMed Press 2013 V
Rojas-Rıos, Gonzalez-Reyes integrin-mediated interaction with the basement membrane [10]. Interestingly, in addition to defining a novel niche organization, the FSC niche has also provided the basis to demonstrate that stem cell replacement can be mediated by stem cell interniche migration and by competition for niche occupancy [11]. Finally, more complex niches composed of both support cells and an interacting ECM can also be found in adult organs. The subventricular zone (SVZ) of the forebrain of postnatal rodents, home to neural progenitor cells closely associated with transit amplifying cells, young neurons, blood vessels, ependymal cells lining the ventricles, and the ECM, represents a clear example [12]. Niche activity depends on cell-cell and/or cell-matrix interactions, as shown in Drosophila, mouse, and human models. Thus, adhesion to the surrounding tissues is fundamental for stem cell retention, proliferation, and controlled differentiation in mammalian blood, neural, epidermal, muscular, spermatogonial, and prostate niches [13–15]. In the Drosophila ovary, adhesion to the ECM (via integrins) or to niche support cells (via cadherins) prevents the loss of FSCs and GSCs, respectively [10, 16–18]. Importantly, in addition to mediating adhesion, matrix-stem cell interactions also modulate signaling events. For instance, in muscle satellite cells in mice the binding of the ECM component Fibronectin to the satellite cell-expressed Syndecan-4 potentiates the ability of Wnt7a factor to stimulate satellite cell expansion [19]. Considering the essential role of satellite cells in muscle regeneration and the fact that Fibronectin is synthesized and secreted by the satellite stem cells themselves, these findings give another twist to the story and emphasize the importance of the stem cell-niche interactions in homeostasis and repair. Experiments in vitro have also identified a number of interactions between ECM components and cultured stem cells that regulate stem cell differentiation. Thus, fibronectin and vitronectin interact, respectively, with integrins a5 and aV, both present in human embryonic stem cells (ESCs), to promote definitive endoderm differentiation [20]. Similarly, the adhesiveness of nonhuman primate ESCs to various biological and nonbiological substrates and of human cord bloodderived neural stem cells (NSCs) to poly(L-lysine) or fibronectin determines their differentiation potential [21, 22]. Niche support cells and surrounding tissues have been reported to secrete factors that activate signaling in stem cells in vertebrate and invertebrate systems [23]. Whereas the large majority of the niche molecules described act at shortrange and affect the stem cell pool within the niche, recent reports have also placed the focus on long-range signaling as a means to regulate stem cell behavior and tissue response to environmental variations. In the mouse skin, cycling dermal bone morphogenetic protein (BMP) signaling controls stem cell activity during hair follicle regeneration, supporting a role for inter-organ signaling in stem cell homeostasis [24, 25]. Similarly, the intersection of opposing long-range gradients of Hedgehog (Hh) and Unpaired (Upd, a cytokine that acts as ligand of the Janus Kinase/Signal Transducer and Activator of Transcription, JAK/STAT, pathway) regulates Drosophila FSC behavior and numbers, indicating that epithelial niches can also be defined by long-range signaling [26]. These examples of the regulation of stem cell homeostasis by a macroenvironment create a new paradigm in which to elucidate niche function and they point to a higher level coordination of niche activity to ensure whole organ dynamics [27].
www.StemCells.com
853
While the above properties depict stem cell niches as entities able to self-regulate stem cell maintenance, proliferation, and differentiation, their activity is integrated in the overall homeostasis of organs and whole organisms. Thus, systemic signaling or pathological conditions influence the output of niche operation, as reviewed below.
AGING
OF
STEM CELLS
AND
THEIR NICHES
Aging is concomitant with altered tissue maintenance and repair. Because stem cell activity is key to maintaining tissue homeostasis and since tissue attrition correlates with decreased stem cell homing abilities, self-renewal, and cell repopulation capacity, stem cell aging lies beneath the aging of tissues [28, 29]. This is best exemplified in the study of parabiotic mice pairs in which a young and an old mice share the circulatory system. These heterochronic parabioses showed the existence of systemic factors present in younger mice that could rejuvenate aged progenitor cells and that these factors change with age, thus jeopardizing successful tissue regeneration in older animals [30]. The analysis of the SVZ niche in mice has also provided solid evidence of the transition into a quiescent state of aging adult NSCs. In this system, the contribution of the SVZ niche to the numbers of olfactory-bulb neuroblasts greatly diminishes with time. This decrease in SVZ-niche activity correlates with changes in the behavior of forebrain-derived adult NSCs, as middle-aged NSCs divide less frequently than young ones [31]. Aging is known to affect directly stem cells (intrinsic factors) and to provoke changes in their microenvironment (extrinsic factors). In either case, the modifications in the stem cells and their niches result in impaired niche activity. Examples of agedependent stem cell intrinsic factors can be found in the Drosophila germline niches and the blood system in mice. In Drosophila adults, the number of GSCs present in their niches decreases with age. The adhesion molecule Drosophila ECadherin is an essential protein required to attain stem cell maintenance within the niche. Since its amounts are reduced in aged male and female GSCs, loss of DE-Cadherin contributes to the stem cell loss observed in aged GSC niches [32, 33]. In the vertebrate blood system, HSCs show a diminished regenerative potential in serial transplantation assays upon aging, indicating a lessening in their intrinsic self-renewal properties. Aging HSCs are also characterized by a pronounced decrease in the production of lymphoid and erythroid lineages, whereas the myeloid lineage is maintained or even increased [28]. While recent data indicate that environmental (external) factors partially underlie the lineage skewing characteristic of aging HSCs [34, 35], this phenotype also depends on intrinsic factors, as shown by the general upregulation of lymphoid genes within old HSCs. The molecular explanation for these changes points to a deterioration of the epigenetic programs in aging HSCs, as genes responsible for chromatin remodeling and chromatin-dependent transcriptional silencing are downregulated in these HSCs [36, 37]. Finally, aging HSCs show increased levels of the cyclindependent kinase inhibitor p16INK4a and its absence from aged HSCs mitigates their repopulation defects [38]. Altogether, these data point toward a key role for stem cell intrinsic factors in the control of the physiological impact of aging. Aging stem cell populations also exhibit cell-extrinsic variations that contribute to their decline in activity. For instance, C AlphaMed Press 2013 V
854
ageing affects the functionality of self-renewing factors in the niche, as demonstrated for the GSC niches of Drosophila. In the case of the male, both stem cell number and their proliferation rate decline with time and so does the concentration of the niche factor Upd [32]. Recent research has deciphered the molecular details of Upd drop in aging testes. Thus, the IGF-II messenger RNA-binding protein (Imp) stabilizes upd RNA by protecting it from small interfering RNA-mediated degradation. Because imp RNA is a target of the heterochronic microRNA let-7 and since let-7 levels are doubled in the first 4 weeks after eclosion, aging results in a decrease in the amount of Imp (and, thus, of Upd) available in the niche [39]. Similarly, ovarian GSCs show reduced BMP signaling activity with time but the molecular mechanisms behind this decline are at present unknown [33]. An important corollary to the above data is that niche age constrains the output of regenerative therapies. Hence, older niches may not be as effective in sustaining the self-renewal of transplanted stem cells in cell therapies. A possible solution to this problem may lie in the manipulation of stem cells and their microenvironments. In this scenario, studies in the mouse blood system have identified the mammalian target of rapamycin (mTOR) pathway and the small GTPase CDC42 as pharmacological targets for rejuvenating HSCs [40, 41]. In addition, aging niches may help select the fittest stem cells, maintaining those with a higher proliferative potential, either because they are less dependent on niche signals to survive or because they develop a lower threshold to trigger survival signaling. In this regard, it is necessary to note that niches are plastic and can be manipulated genetically. For instance, the ectopic expression of Upd in the niche cells of aging Drosophila testes rescues the reduction in stem cell number and their proliferation capacity typical of old males [32]. Because niche activity is genetically controlled and many of the pathways involved in niche-stem cell interactions are conserved in evolution, it is likely that the capacity to rejuvenate invertebrate stem cells after genetic manipulation of niches is a property also of vertebrate tissues. In fact, muscle stem cell (MSC) manipulation can reverse the decline in muscle regeneration of aged mice. Under homeostatic conditions, the muscle fiber, the primary component of the MSC niche, produces the mitogenic factor Fgf2, which in turn induces quiescent MSCs to cycle and repair muscle. To prevent the precocious depletion of MSCs and to maintain the muscle regenerative capacity, quiescent MSCs secrete the Fgf-signaling inhibitor Sprouty. However, aged muscle fibers increase the amount of secreted Fgf2, thus leading to declines in MSC function and numbers during homeostasis. Reducing experimentally the level of Fgf signaling in MSCs prevents their depletion. Conversely, removal of Sprouty from MSCs results in the loss of cell quiescence and in diminished muscle regenerative capacity [42]. Thus, at least in this particular vertebrate niche and in the GSC niche in Drosophila males, the self-renewing potential of associated stem cells is amenable to genetic treatment, perhaps pointing to a general property of tissue-specific stem cell niches across evolution.
NICHE RESPONSES TO CHANGES IN THE ENVIRONMENT: DORMANT STEM CELLS, ADAPTIVE GROWTH, AND SYSTEMIC SIGNALING Fully formed organs in adult animals show a distinct capacity for tissue renovation under normal physiological conditions. C AlphaMed Press 2013 V
Dynamic Stem Cell Niches in Tissue Homeostasis
Organs too possess a regenerative capacity that is essential for tissue repair after damage. These homeostatic and regenerative capacities of mature tissues are attributable in part to resident stem cell populations within the tissue. For instance, in humans and mice, the progeny of resident intestinal stem cells (ISCs) constantly replenish the epithelium lining the lumen of the gut, replacing differentiated enterocytes every week on average. The fine balance between cell replacement and cell proliferation and differentiation within the tissue thus ensures proper gut homeostasis at a remarkable rate [43]. A similar dependence on stem cell populations has been described for the homeostasis of the hematopoietic system, the skin, or the bone skeleton in mammals [44]. While homeostasis relies on transiently quiescent stem cell populations, tissue regeneration often involves the reactivation of longterm quiescent stem cells that, upon injury, can replenish the damaged tissue. The conditional activation of these long-lived or “dormant” stem cells, able to sense the damage and to react to it, is a direct consequence of the coordinated action of the stem cells and their microenvironment. A particularly well-studied case of dormant stem cells is that of the blood system in vertebrates. Dormant HSCs show the highest selfrenewal potential of all HSCs in adult healthy mice, as shown by label-retaining experiments and functional transplantation assays. Nevertheless, they divide five times per lifetime on average. Although the mechanism(s) underlying activation of dormant HSCs are not understood, chemotherapy, toxic insult, or anemia trigger the efficient transformation of dormant HSCs into rapidly dividing HSCs, able to produce active progenitors that give rise to mature blood cell types (reviewed in [45]). Interestingly, these mitotically active dormant HSCs return to their deeply quiescent state once homeostasis is restored. As discussed above, stem cell fate is influenced by the integration of signals of different origin by their hosting niches. Thus, since dormant HSCs reside in their own niches, these most likely regulate the activation and re-entry into quiescence of the dormant HSCs [46]. Whether these particular niches abide by the same regulatory rules as the rest of the HSC niches present in the hematopoietic system is still unknown but the study of dormant stem cells highlights once more the crucial role of niches in controlling tissue homeostasis in physiology and pathology. Finally, dormant stem cells have been also identified in other tissues such as the Drosophila hindgut [47] and postulated to exist within the heterogenic hair FSC population in mice [48], indicating that dormant stem cell subpopulations may be a widespread characteristic of adult tissues. Remodeling of organs in response to environmental change is a life-long property in many organisms and examples include the resizing of mammary glands during pregnancy or the stimulation of erythropoiesis as a consequence of low oxygen concentrations. Thus, organs grow or shrink in response to environmental stimuli that implicate changes in the control of cell proliferation and/or differentiation. The case of the mammary gland is remarkable, as the specialized epithelium characteristic of this organ is able to grow and shrink four- to fivefold during pregnancy/lactation and postlactation regression cycles. The mammary epithelium is composed mainly of luminal, alveolar, and myoepithelial cells, all of which coordinate cell proliferation and differentiation during development, adulthood, and pregnancy (reviewed in [49]). The main subtypes of the STEM CELLS
Rojas-Rıos, Gonzalez-Reyes epithelium, the luminal and myoepithelial cell lineages, derive from long-lived, unipotent stem cell precursors also present in the adult organ and that are responsible for the massive cell expansion observed during several cycles of pregnancy [50]. The regulation of these adaptive mechanisms is largely unknown, but the intestine of adult flies has shed some light into the molecular and cellular variations underlying “adaptive growth.” Upon food stimulation of Drosophila adults, stem cell niches in the intestine secrete the insulin-like peptide Drosophila insulin-like peptide 3 to induce stem cell proliferation and tissue growth. Surprisingly, this insulin-mediated induction of cell proliferation alters the normal mode of division of ISCs and drives symmetric divisions at the expense of asymmetric ones. Thus, the number of both ISCs and of their offspring increases (up to 300-fold!), accounting for tissue enlargement [51]. Importantly for the purpose of this review, cycles of fastening and refeeding showed that adaptive growth of the adult midgut is reversible depending of dietary fluctuations, demonstrating once more the capacity of niches to regulate the activity of resident stem cells according to changing environmental conditions. Considering the important role that stem cell populations play in tissue homeostasis, the response of tissues to environmental and systemic signals requires the adaptation of stem cells and their microenvironments to extrinsic factors. Thus, it comes as no surprise that several types of stem cells have been found to modulate their proliferation in response to systemic signals. For instance, Drosophila neuroblasts, the multipotent NSCs responsible for the development of the nervous system of the larva and adult, normally go through a phase of quiescence to separate distinct onsets of embryonic and postembryonic proliferation. Exit from quiescence in larval stages is regulated by the production of insulin-like peptides from a population of adjacent glial cells that activates the phosphoinositide-3 kinase/Akt pathway in neuroblasts. Glial secretion of the active peptides in turn depends on the amino acid-sensing and TOR pathways in the fat body. Thus, a systemic signal emanating from the fat body, the fly’s equivalent to the liver and adipose tissue, regulates reactivation of quiescent NSCs of the larval brain in response to dietary information [52, 53]. This paradigm of systemic signals determining the output of stem cell populations is not restricted to the fly’s central nervous system, as Drosophila GSCs and ISCs have also been shown to respond to the nutritional state of the organism [54]. In vertebrates, perhaps one of the bestcharacterized physiological changes eliciting a particular response from stem cell populations is that of the circadian rhythms. Circadian oscillations impinge on the release of HSC from the bone marrow, on the ability of HSCs to synthesize DNA, on the frequency of colony-forming progenitors in both human and mice, and on the engraftment of transplanted HSCs [55, 56]. Most likely, these phenotypes reflect an influence of the circadian rhythms on the timing of cell division of hematopoietic cells through the regulation of niche activity, a process that involves the sympathetic nervous system [57].
SIGNAL DELIVERY
IN
NICHES
Morphogens are signaling molecules originally defined as secreted and diffusible proteins whose function depends on their concentration gradient through tissues (for a compre-
www.StemCells.com
855
hensive review see [58]). Inherent to the model of morphogen action is the mechanism(s) by which producing cells deliver the signals to the receiving cells. Work in Drosophila imaginal discs has shown the existence of a specific type of cellular projections termed cytonemes that are responsible for morphogen delivery and for morphogen signal reception [59– 62]. Cytonemes are filopodia-like extensions of the plasma membrane of approximately 0.2 mm in diameter able to form intercellular bridges. Morphogens and their receptors are found decorating cytonemes that emanate either from the producing cells (the former) or the receiving cells (the latter) [60, 63]. The role of cytonemes in conveying patterning information and in regulating signaling in developing tissues is conserved during evolution, as cytoneme-like filopodia have been observed during vertebrate limb or neural tube development or in mouse blastocysts [64] (reviewed in [65]). Morphogens play important roles in the correct maintenance of stem cell populations within their niches both in vertebrate and invertebrate systems. For instance, Hh, the BMPhomolog Decapentaplegic (Dpp), Upd, and Upd 3 (another ligand of the JAK/STAT pathway) are well-known participants of niche homeostasis in the intestine, ovary, testis, or lymph gland in Drosophila [63, 66–69]; Sonic Hh is necessary to define NSC positional identity in the adult brain or to sustain proper hematopoiesis in mice [12, 70, 71]; Wnt ligands are key niche molecules in the hematopoietic system, the developing brain, the skin, or the intestinal crypts of mice [72–75]; and Hh, BMPs, the fibroblast growth factor, and the vasculoendothelial growth factor are also required in the hematopoietic system of fish and mice (reviewed in [70–72]). We have recently reported that cytonemes are involved in the delivery of Hh in the GSC niche of the Drosophila female [63]. We found that the ligand of the Hh signaling pathway is localized specifically in short cytonemes (0.5–1 mm in length) projected by a particular type of niche cells, the Cap cells. Interestingly, disrupting cytoneme production and/or kinetics resulted in the loss of GSCs, indicating that the Hh-decorated short cytonemes are truly essential for stem cell maintenance in the fly ovarian niche. The above cellular extensions could be the mechanism by which cells establish signaling synapses. Thus, the points of contact between cytonemes and the receiving cells may define the precise places for receptor activation and for the initiation of signal transduction. It would be very interesting to devise an experimental system to visualize live cytonemes and the formation of signaling synapses in active niches and to compare their dynamics after manipulation. A direct consequence of cytoneme-mediated signaling in niches is that the spreading of the signals depends on the reach of the cytonemes. The short cytonemes in the Drosophila ovary allow only juxtacrine signaling. However, in experimental niches in which Hh signaling is impaired in specific support cells cytonemes emanating from normal support cells can grow significantly longer (up to 6 mm in length). Importantly, these long cytonemes show a directed growth toward the signaling-deficient area of the niche [63]. The simplest explanation for this behavior is that Drosophila ovarian niches are plastic structures with the capacity to sense the signaling status of its cellular components and to react to perturbations by increasing the range of signal delivery from healthy support cells. Since signaling in the GSC niche determines the C AlphaMed Press 2013 V
856
outcome of stem cell proliferation, this plasticity offers the ovary the ability to adapt to physiological or pathological changes that may affect its fitness. Should this be a general property of stem cell niches, it could represent an important advantage for the integration of systemic and local signals implicated in tissue homeostasis. In this scenario, it is worth
Dynamic Stem Cell Niches in Tissue Homeostasis
noting that cytonemes similar to those described in the ovarian niche of the fly have been reported in other invertebrate niches such as the nematode gonad, the earwig ovary, or the lymph gland in the Drosophila larva, pointing toward a more general role for this type of cell-cell signaling in stem cell niches [76–79]. In spite of its potential implications for niche
Figure 1. Niche activity is influenced by local signals, systemic factors, and physiological and pathological conditions. (A): Schematic representation of a cellular niche, some input signals that affect stem cell behavior, and the output responses of the stem cell population. Support cells (blue) interact with the stem cell (green) via adhesion molecules and secreted signals that regulate stem cell proliferation and behavior. The ECM (orange fibers), present in the majority of niches, interacts with stem cells and support cells. Niche activity is influenced by a series of factors, comprising local signals (short-range and long-range), systemic factors (such as nutritional status, developmental changes, or circadian oscillations), and physiological and pathological alterations (including aging, adaptive growth, tissue damage, and disease). Depending on the above conditions, niches are plastic in their response to external stimuli and they can give rise to daughter stem cells, to differentiating siblings (brown or purple cells) or to a mixture of both. (B): In contrast with the normal situation, in which local signals operating in the niche ensure that germline stem cells of the Drosophila ovary divide asymmetrically to produce GSCs and cystoblasts, if a local signal is deficient, as in the case of the removal of the short-range ligand Hh from the support cells, stem cells enter differentiation and are lost from the niche. (C): Adaptive growth of the mammary gland during pregnancy and lactation involves massive expansion of unipotent stem cells. (D): In the vertebrate blood system, aged hematopoietic stem cells (HSCs) show a lessening in their self-renewal properties and a pronounced decrease in the production of lymphoid and erythroid lineages, whereas the myeloid lineage is maintained or even increased. These alterations are a consequence of changes in the HSCs and in the niche cells (see text for details). Abbreviation: ECM, extracellular matrix. C AlphaMed Press 2013 V
STEM CELLS
Rojas-Rıos, Gonzalez-Reyes
857
signaling and stem cell maintenance, a deep understanding of the molecular and cellular mechanisms behind ligand delivery, release, and signal uptake by cytonemes in stem cell niches is lacking and it awaits further experimentation.
PERSPECTIVES The ability of organs to adapt to cellular dysfunction, physical damage, or physiological changes relies heavily on the properties of stem cells and niches. Both homed stem cell populations and their support microenvironments provide tissues with the plasticity necessary for their adaptation to local or systemic variations, a characteristic that allows organs respond to nutritional stress or aging, among other challenges (see Figure 1). There are however some aspects of stem cell and niche behavior that need be comprehended before a more complete picture on stem cell biology in vivo is attained. For instance, the cycling between quiescent and active forms of stem cells is far from understood and a number crucial questions are still open: what parameters do the dormant HSCs and their niches sense to induce stem cell reactivation? How do they return to a quiescent state once the damage has been healed? In this regard, while it is clear that the pulse of high proliferation observed during facultative tissue repair after damage ought to be controlled to prevent deleterious growth, as in the case of the adult Drosophila hindgut, the mechanisms behind this necessary regulation are still missing. A second important point is the degree to which niche cells regulate stem cell proliferation and differentiation. While local signals acting on adjacent stem cells are known to exert a tight regulation of stem cell numbers, systemic signals have the ability to target stem cell proliferation specifically too. This property is most likely a consequence of the control that niches—as sensors of external signals—impose on stem cell populations. How systemic signals ensure the appropriate response from stem cell populations in target tissues to accommodate physiological demands is still an unresolved question and the identification of the precise molecules involved and their mode of action require a vigorous endeavor from researchers. Finally, and particularly relevant in the case of tissue homeostasis and regeneration, is the occurrence of stem cell turn-over. Stem cells are known to be lost
REFERENCES 1 Morrison SJ, Spradling AC. Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132:598–611. 2 Aichinger E, Kornet N, Friedrich T et al. Plant stem cell niches. Annu Rev Plant Biol 2012;63:615–636. 3 Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7–25. 4 Lander AD, Kimble J, Clevers H et al. What does the concept of the stem cell niche really mean today? BMC Biol 2012; 10:19. 5 Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 2011;145:851–862.
www.StemCells.com
from niches either because they differentiate or because they undergo cell death. Since stem cell populations can be kept stable for long periods of time in adult life, stem cell replacement takes place during tissue homeostasis. It is known that replacing mechanisms include symmetric stem cell division to replenish the stem cell pool and/or dedifferentiation of committed cells. Whatever the situation, stem cell replacement implicates that the system auto-regulates so that the replacing cell outcompetes the stem cell expelled from the niche. Whether this selection depends on variations happening naturally among the stem cell pools so that some are fitter than others or whether stem cell substitution is a stochastic process and it is only niche occupancy what matters remains to be elucidated. In any case, the intrinsic properties of stem cells and their close interaction with the niche make the host tissues resilient to demanding conditions during organism aging and physiological variation—something we, long-lived organisms, benefit from.
ACKNOWLEDGMENTS We wish to thank members of the Gonzalez-Reyes laboratory and M.J. Sanchez for critical reading of the manuscript and M.C. Dıaz de la Loza for the design of Figure 1. This work was supported by the Spanish Ministerio de Economıa y Competitividad and the FEDER program (BMC2012–35446), by the Junta de Andalucıa (Proyecto de Excelencia P09-CVI5058), and by the CONSOLIDER program (CSD-2007-00008). P.R.-R. was funded by an I3P-CSIC studentship. P.R.-R. is currently affiliated with the Institute of Human Genetics, CNRS UPR1142, 141, rue de la Cardonille, 34396 Montpellier, Cedex 5, France.
AUTHOR CONTRIBUTION P.R.-R.: manuscript writing; A.G.-R.: financial support and manuscript writing.
DISCLOSURE
OF
POTENTIAL CONFLICTS
OF INTEREST
The authors declare no competing financial interests.
6 Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006;7:333–337. 7 Pearson J, Lopez-Onieva L, Rojas-Rios P et al. Recent advances in Drosophila stem cell biology. Int J Dev Biol 2009;53:1329– 1339. 8 Joshi PM, Riddle MR, Djabrayan NJ et al. Caenorhabditis elegans as a model for stem cell biology. Dev Dyn 2010;239:1539–1554. 9 Ding L, Saunders TL, Enikolopov G et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012;481: 457–462. 10 O’Reilly AM, Lee HH, Simon MA. Integrins control the positioning and proliferation of follicle stem cells in the Drosophila ovary. J Cell Biol 2008;182:801–815. 11 Nystul T, Spradling A. An epithelial niche in the Drosophila ovary undergoes long-
range stem cell replacement. Cell Stem Cell 2007;1:277–285. 12 Ihrie RA, Shah JK, Harwell CC et al. Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity. Neuron 2011;71:250–262. 13 Kuang S, Rudnicki MA. The emerging biology of satellite cells and their therapeutic potential. Trends Mol Med 2008;14:82–91. 14 Raymond K, Deugnier MA, Faraldo MM et al. Adhesion within the stem cell niches. Curr Opin Cell Biol 2009;21:623–629. 15 Marthiens V, Kazanis I, Moss L et al. Adhesion molecules in the stem cell niche— More than just staying in shape? J Cell Sci 2010;123:1613–1622. 16 Song X, Xie T. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci USA 2002;99:14813–14818. C AlphaMed Press 2013 V
858
17 Song X, Zhu CH, Doan C et al. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 2002; 296:1855–1857. 18 Gonzalez-Reyes A. Stem cells, niches and cadherins: A view from Drosophila. J Cell Sci 2003;116:949–954. 19 Bentzinger CF, Wang YX, von Maltzahn J et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 2013;12:75–87. 20 Brafman DA, Phung C, Kumar N et al. Regulation of endodermal differentiation of human embryonic stem cells through integrin-ECM interactions. Cell Death Differ 2013;20:369–381. 21 Buzanska L, Ruiz A, Zychowicz M et al. Patterned growth and differentiation of human cord blood-derived neural stem cells on bio-functionalized surfaces. Acta Neurobiol Exp (Wars) 2009;69:24–36. 22 Chen SS, Fitzgerald W, Zimmerberg J et al. Cell-cell and cell-extracellular matrix interactions regulate embryonic stem cell differentiation. Stem Cells 2007;25:553–561. 23 Yamashita YM, Fuller MT, Jones DL. Signaling in stem cell niches: Lessons from the Drosophila germline. J Cell Sci 2005;118:665– 672. 24 Plikus MV, Mayer JA, de la Cruz D et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 2008;451:340–344. 25 Plikus MV, Baker RE, Chen CC et al. Selforganizing and stochastic behaviors during the regeneration of hair stem cells. Science 2011;332:586–589. 26 Vied C, Reilein A, Field NS et al. Regulation of stem cells by intersecting gradients of long-range niche signals. Dev Cell 2012;23: 836–848. 27 O’Brien LE, Bilder D. Beyond the niche: Tissue-level coordination of stem cell dynamics. Annu Rev Cell Dev Biol 2013;29:107–136. 28 Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13:376–389. 29 van Wijngaarden P, Franklin RJ. Ageing stem and progenitor cells: Implications for rejuvenation of the central nervous system. Development 2013;140:2562–2575. 30 Conboy IM, Conboy MJ, Wagers AJ et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433:760–764. 31 Bouab M, Paliouras GN, Aumont A et al. Aging of the subventricular zone neural stem cell niche: Evidence for quiescence-associated changes between early and mid-adulthood. Neuroscience 2011;173:135–149. 32 Boyle M, Wong C, Rocha M et al. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 2007;1:470–478. 33 Pan L, Chen S, Weng C et al. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 2007;1:458–469. 34 Ergen AV, Boles NC, Goodell MA. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 2012;119:2500–2509. C AlphaMed Press 2013 V
Dynamic Stem Cell Niches in Tissue Homeostasis
35 Vas V, Senger K, Dorr K et al. Aging of the microenvironment influences clonality in hematopoiesis. PLoS One 2012;7:e42080. 36 Chambers SM, Shaw CA, Gatza C et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 2007;5:e201. 37 Beerman I, Bock C, Garrison BS et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 2013; 12:413–425. 38 Janzen V, Forkert R, Fleming HE et al. Stem-cell ageing modified by the cyclindependent kinase inhibitor p16INK4a. Nature 2006;443:421–426. 39 Toledano H, D’Alterio C, Czech B et al. The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche. Nature 2012;485:605–610. 40 Chen C, Liu Y, Liu Y et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009;2:ra75. 41 Florian MC, D€ orr K, Niebel A et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 2012;10:520–530. 42 Chakkalakal JV, Jones KM, Basson MA et al. The aged niche disrupts muscle stem cell quiescence. Nature 2012;490:355–360. 43 Jiang H, Edgar BA. Intestinal stem cell function in Drosophila and mice. Curr Opin Genet Dev 2012;22:354–360. 44 Bianco P, Riminucci M, Gronthos S et al. Bone marrow stromal stem cells: Nature, biology, and potential applications. Stem Cells 2001;19:180–192. 45 Trumpp A, Essers M, Wilson A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol 2010;10:201–209. 46 Sottocornola R, Lo Celso C. Dormancy in the stem cell niche. Stem Cell Res Ther 2012; 3:10. 47 Fox DT, Spradling AC. The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissue damage. Cell Stem Cell 2009;5:290–297. 48 Fuchs E. The tortoise and the hair: Slowcycling cells in the stem cell race. Cell 2009; 137:811–819. 49 Watson CJ, Khaled WT. Mammary development in the embryo and adult: A journey of morphogenesis and commitment. Development 2008;135:995–1003. 50 Van Keymeulen A, Rocha AS, Ousset M et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 2011;479:189–193. 51 O’Brien LE, Soliman SS, Li X et al. Altered modes of stem cell division drive adaptive intestinal growth. Cell 2011;147: 603–614. 52 Chell JM, Brand AH. Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 2010;143:1161–1173. 53 Sousa-Nunes R, Yee LL, Gould AP. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 2011;471:508–512. 54 Jasper H, Jones DL. Metabolic regulation of stem cell behavior and implications for aging. Cell Metab 2010;12:561–565.
55 D’Hondt L, McAuliffe C, Damon J et al. Circadian variations of bone marrow engraftability. J Cell Physiol 2004;200:63–70. 56 Mendez-Ferrer S, Lucas D, Battista M et al. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008;452:442–447. 57 Mendez-Ferrer S, Chow A, Merad M et al. Circadian rhythms influence hematopoietic stem cells. Curr Opin Hematol 2009;16: 235–242. 58 Rogers KW, Schier AF. Morphogen gradients: From generation to interpretation. Annu Rev Cell Dev Biol 2011;27:377–407. 59 Ramirez-Weber FA, Kornberg TB. Cytonemes: Cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell 1999;97:599–607. 60 Roy S, Hsiung F, Kornberg TB. Specificity of Drosophila cytonemes for distinct signaling pathways. Science 2011;332:354–358. 61 Sherer NM, Mothes W. Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. Trends Cell Biol 2008;18:414–420. 62 Hsiung F, Ramirez-Weber FA, Iwaki DD et al. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 2005;437:560–563. 63 Rojas-Rios P, Guerrero I, Gonzalez-Reyes A. Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol 2012;10: e1001298. 64 Sanders TA, Llagostera E, Barna M. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature 2013;497:628–632. 65 Gradilla AC, Guerrero I. Cytoneme-mediated cell-to-cell signaling during development. Cell Tissue Res 2013;352:59–66. 66 Crozatier M, Meister M. Drosophila haematopoiesis. Cell Microbiol 2007;9:1117– 1126. 67 Resende LP, Jones DL. Local signaling within stem cell niches: Insights from Drosophila. Curr Opin Cell Biol 2012;24:225–231. 68 Harris RE, Ashe HL. Cease and desist: Modulating short-range Dpp signalling in the stem-cell niche. EMBO Rep 2011;12:519–526. 69 Michel M, Kupinski AP, Raabe I et al. Hh signalling is essential for somatic stem cell maintenance in the Drosophila testis niche. Development 2012;139:2663–2669. 70 Kaimakis P, Crisan M, Dzierzak E. The biochemistry of hematopoietic stem cell development. Biochim Biophys Acta 2013; 1830:2395–2403. 71 Faigle R, Song H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 2013;1830: 2435–2448. 72 van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009;71: 241–260. 73 Haegebarth A, Clevers H. Wnt signaling, lgr5, and stem cells in the intestine and skin. Am J Pathol 2009;174:715–721. 74 Kalani MY, Cheshier SH, Cord BJ et al. Wnt-mediated self-renewal of neural stem/ progenitor cells. Proc Natl Acad Sci USA 2008;105:16970–16975.
STEM CELLS
Rojas-Rıos, Gonzalez-Reyes 75 Reya T, Duncan AW, Ailles L et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409–414. 76 Crittenden SL, Leonhard KA, Byrd DT et al. Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol Biol Cell 2006;17:3051–3061.
www.StemCells.com
859
77 Krzemien J, Dubois L, Makki R et al. Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre. Nature 2007;446:325–328. 78 Mandal L, Martinez-Agosto JA, Evans CJ et al. A hedgehog- and antennapediadependent niche maintains Drosophila hae-
matopoietic precursors. Nature 2007;446: 320–324. 79 Tworzydlo W, Kloc M, Bilinski SM. Female germline stem cell niches of earwigs are structurally simple and different from those of Drosophila melanogaster. J Morphol 2010;271:634–640.
C AlphaMed Press 2013 V
