Advances in Biological Regulation xxx (2014) 1e11

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Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis Il Ho Jang a, Soon Chul Heo a, Yang Woo Kwon a, Eun Jung Choi a, Jae Ho Kim a, b, * a

Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea b Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 626-770, Gyeongsangnam-do, Republic of Korea

a b s t r a c t Keywords: Endothelial progenitor cells Formyl peptide receptor 2 Homing Angiogenesis

Endothelial progenitor cells (EPCs) hold a great promise as a therapeutic mediator in treatment of ischemic disease conditions. The discovery of EPCs in adult blood has been a cause of significant enthusiasm in the field of endothelial cell research and numerous clinical trials have been expedited. After more than a decade of research in basic science and clinical applications, limitations and new strategies of EPC therapeutics have emerged. With various phenotypes, vague definitions, and uncertain distinction from hematopoietic cells, understanding EPC biology remains challenging. However, EPCs, still hold great hope for treatment of critical ischemic injury as low concern regarding safety can accelerate the clinical applications from basic findings. This review provides an introduction to EPC as cellular therapeutics, which highlights a recent finding that EPC homing was promoted through FPR2 signaling. © 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea. Tel.: þ82 51 510 8073; fax: þ82 51 510 8076. E-mail address: [email protected] (J.H. Kim).

http://dx.doi.org/10.1016/j.jbior.2014.09.011 2212-4926/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Jang IH, et al., Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis, Advances in Biological Regulation (2014), http:// dx.doi.org/10.1016/j.jbior.2014.09.011

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Introduction Endothelial progenitor cells (EPCs) are immature cells with a capacity for proliferation, migration, and differentiation into endothelial cells (ECs) (Ribatti, 2007). Unlike ECs, EPCs show clonal expansion and stemness characteristics, including high proliferation and resistance to stress, and lack mature EC markers (Dernbach et al., 2004; He et al., 2004; Urbich and Dimmeler, 2004). Discovery of EPCs in the adult circulation led to a new concept that vasculogenesis may occur in postnatal life as angiogenesis was previously regarded as the sole mechanism of vascular growth after embryonic development (Asahara et al., 1997). Historically, detection of angioblastic activity from circulating cells dates back to 1932, as Hueper and Russel observed capillary-like formation in cultures of leukocytes (Hueper and Russell, 1932). In 1994, suspended polytetrafluoroethylene pledget retrieved from the aorta of dogs were covered with ECs and capillary-like structures (Scott et al., 1994). In 1997, Asahara et al. isolated EPCs from human peripheral blood using the surface antigen CD34 or VEGFR-2 (KDR) and showed the incorporation of EPCs into sites of active angiogenesis after transplantation into ischemic animal models (Asahara et al., 1997). Since then, various types of EPCs have been reported from different tissues using distinct markers, however, there is still no clear and unambiguous definition of EPC and EPC phenotype (Alev et al., 2011; Asahara et al., 2011). EPCs based on source tissue EPCs can be isolated from the circulation and solid tissue. EPCs in the adult circulation are believed to originate from bone marrow (BM) and the frequency of EPCs in the circulation increases with a mobilization stimulant such as granulocyte colony stimulating factor (G-CSF) (Kawamoto et al., 2009). EPCs can be harvested directly from BM or umbilical cord blood (UCB) (Ingram et al., 2004). In contrast to circulating EPCs, which are floating and nonadhesive, tissue EPCs are adhesive and are believed to originate from circulating EPCs or tissue-resident stem cells (Beltrami et al., 2003; Ii et al., 2009; Kovacic and Boehm, 2009). Endothelial colony-forming cells (ECFCs), also termed endothelial outgrowth cells (EOCs), are adherent cells generated from the culture of circulating EPCs and are regarded as homed-down tissue-resident EPCs (Critser and Yoder, 2010; Ingram et al., 2004). However, ECFCs can also be derived from primary culture of human umbilical vein and adult aortic endothelial cells (Ingram et al., 2005; Yoder, 2010), thus the exact origin of ECFC remains ambiguous. The cellular origins of circulating and tissue-resident EPCs have also not been identified. EPCs based on culture method Putative human EPCs in culture have been assigned different names and show different characteristics and function depending on the culture methods (Basile and Yoder, 2014). Circulating angiogenic cells (CACs) are derived from culture of human peripheral blood mononuclear cells (hPBMNCs) on a fibronectin-coated plate with endothelial differentiation media containing various growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor I (IGFI), and epidermal growth factor (EGF) (Kalka et al., 2000; Rehman et al., 2003). After 4 days of culture, non-adherent cells are washed off and persisting adherent cells show characteristics of EPC such as taking up acetylated low-density lipoprotein (ac-LDL) and binding to Ulex europaeus agglgutinin-I lectin (UEA-I). CACs, however, exhibit activities of contaminating platelets and monocytes and are thus regarded as an inaccurate method for identification of EPCs (Prokopi et al., 2009; Rohde et al., 2011). Heterogeneity in the culture can be reduced by maintaining EPCs through colony forming assays. Colony forming unit-Hill (CFU-Hill) cells are generated by culturing adherent hPBMNCs on fibronectin-coated plates at low-density, in which clusters of spindle-shaped cells emerge in 4e9 days (Hill et al., 2003). CFU-Hill cells show expression of surface antigens, similar to ECs, and the gene expression is distinct from that of ECs but indistinguishable from that of CACs (Ahrens et al., 2011; Desai et al., 2009; Medina et al., 2010b). However, CFU-Hill cells, like CACs, exhibit low proliferation potential and do not possess replating potential or contribute to in vivo de novo vessel formation, suggesting that EPCs cannot be identified using CFU-Hill assay (Hirschi et al., 2008; Yoder et al., 2007). ECFCs are derived from the culture of hPBMNCs or UCB MNCs on type I collagen-coated plate (Ingram Please cite this article in press as: Jang IH, et al., Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis, Advances in Biological Regulation (2014), http:// dx.doi.org/10.1016/j.jbior.2014.09.011

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et al., 2004). Adherent and cobblestone-looking colonies appear in 5 or 22 days of culture and the emerging colonies can be replated and expanded. Clonal analysis of the emerging colonies showed two different types of cells; endothelial cell colony-forming units (CFU-ECs), which show low proliferative potential and do not form vessels in vivo, and ECFCs, which show high proliferative potential and form blood vessels when transplanted in immunodeficient mice (Yoder et al., 2007). ECFCs exhibit high telomerase activity and robust replating potential, and infusion of ECFCs into various ischemia animal models such as hindlimb ischemia (Yoon et al., 2005), myocardial infarction (Dubois et al., 2010), and retinal ischemia (Medina et al., 2010a) enhances vascular recovery with incorporation of ECFCs into newly-formed vessels. Thus, ECFCs present many features of EPCs by definition. However, ECFCs appear to belong to a substantially-differentiated stage as ECFCs lack immature stem/progenitor cell-related marker expression and the cellular origin of ECFCs, whether vessel walls or non-hematopoietic BM cells, remains ambiguous (Alev et al., 2011; Yoder, 2010). Recently developed EPC colony forming assay (EPC-CFA) using semisolid medium and CD34þ or CD133þ cells from UB MNCs, hPBMNCs, or BM MNCs can identify two different types of colonies; primitive EPCs with small cells and highly-proliferative property and definitive EPCs with large cells with a vasculogenic property with developmental hierarchy from primitive EPCs to definitive EPCs and eventually to ECs (Masuda et al., 2011). In addition, EPC-CFA indicates that a single CD34þ or CD133þ cell can develop into EPCs and hematopoietic cells and suggests that the origin of EPC can be hematopoietic stem cells (HSCs). Characteristics of human EPCs according to different culture methods are summarized in Table 1. In identification of putative murine EPCs, the surface markers used are noticeably different from those used in identification of human ones. The applications of surface markers, such as Sca-1, c-Kit, Flk-1, Flt-1, CD31, Tie-2, CXCR4, CD133, or CD144, in the pursuit of murine EPCs are highly variable among individual studies (Asahara et al., 1999; Gallagher et al., 2007; Heeschen et al., 2003; Iwakura et al., 2003; Khakoo and Finkel, 2005; Krishnamurthy et al., 2011; Lyden et al., 2001; Nakajima et al., 2006; Patschan et al., 2006; Thal et al., 2012; Wang et al., 2006; Westerweel et al., 2013). Murine CACs can be identified by culturing PBMNC or BM cells on fibronectin-coated plates, however, these cells, like human CACs, are mostly pro-angiogenic myeloid cells (Basile and Yoder, 2014; Chen et al., 2012; Coffelt et al., 2010). Murine ECFCs do not appear to be present in the circulating blood at an individual animal level as the detection requires pooling of blood from 4 to 6 mice (Somani et al., 2007). EPC-CFA with murine c-KitþSca-1þlineage BM cells can identify small primitive EPCs and large

Table 1 EPCs according to culture method. Plate coating

Cell source

Culture method

Media

References In vivo tube formation

Fibronectin

PBMNC

(Rehman et al., 2003)

PBMNC

No

(Desai et al., 2009; Hill et al., 2003)

ECFC

PBMNC, CBMNC

EGM-2 with VEGF, bFGF, IGF-1, EGF, 5e20% FBS M199 with 20% FCS; Endocult Liquid Medium kit complete EGM-2

No

CFUeHill Fibronectin

At 4 day, nonadherent cells are washed off, adherent cells are kept for further culture At 2 day, nonadherent cells are transferred for the further culture - > spindle cell colony

Yes

(Ingram et al., 2004; Yoder et al., 2007)

CAC

collagen I

At 24 h, nonadhrerent cells are washed off, adherent cells are kept for further culture - > cobblestone colony EPCeCFA Primaria/semi-solid CD34/133 þ PBMNC, 18 days for one cell to media CBMNC form colony; 10 days for 2nd colony - > Hematopoietic/ Endothelial cells

Yes Methocult SF H4236 with SCF, VEGF, bFGF, EGF, IGF-1, IL-3, Heparin, 305 FBS

(Masuda et al., 2011; Masuda and Asahara, 2013)

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definitive EPCs, thus showing consistency between human and mouse (Kwon et al., 2008; Tanaka et al., 2008). However, a hierarchical relationship of primitive EPCs, definitive EPCs, and HSCs remains to be examined in a murine system. Hematopoietic connection Endothelial cells and hematopoietic cells have intimate relationship from the beginning during embryo development as EPCs (angioblasts) and HSCs are believed to originate from the common precursor, hemangioblast, a bi-potential cell that produces endothelial and hematopoietic systems (Choi et al., 1998; Huber et al., 2004; Kennedy et al., 1997). The surface markers used for isolation of EPCs in the adult show significant overlap with HSC markers; CD34, CD133, KDR, CXCR4, and CD105 for human and c-Kit, Sca-1, and CD34 in combination with Flk-1 for mouse (Timmermans et al., 2009). It is interesting to note that recent advancement in hematopoiesis has shown that development of hemangioblasts occurs through formation of hemogenic endothelium, an endothelium that generates hematopoietic cells, and the lineage tracing in mice indicates that most hematopoietic cells including HSCs originate from hemogenic endothelium during embryo development (Chen et al., 2009; Lancrin et al., 2009). Although hemogenic endothelium is believed to be present transiently during embryo development, EPC-CFA has demonstrated the existence of a single cell that generates hematopoietic and endothelial cells in the adult (Jaffredo et al., 2013; Masuda et al., 2011; Masuda and Asahara, 2013). Currently there is still no surface marker combination that can distinguish EPCs from HSCs. Treatment of ischemic injury with endothelial progenitor cells Since the discovery of EPCs, the regenerative potential of EPCs has been widely tested in preclinical and clinical trials for more than a decade (Ribatti, 2007). EPCs have been shown to contribute to neovascularization directly through incorporation into newly formed vessels or indirectly through secretion of angiogenic factors. Transplantation of BM cells from transgenic mice in which LacZ is expressed under the control of Flk-1 or Tie-2 promoter into wild type control mice has shown that LacZ-positive cells are detected in vascular structures in cardiac ischemia, corneal neovascularization, and wound healing models (Bauer et al., 2006; Iwakura et al., 2006; Murayama et al., 2002). In cases where direct vasculogenic contributions of EPCs are not detected, EPCs migrate to the ischemic injury sites and remain in the interstitial tissue and stimulate migration and proliferation of pre-existing ECs by providing paracrine factors such as VEGF, hepatocyte growth factor, angiopoietin-1, stromal cellderived factor-1a, insulin-like growth factor-1, and nitric oxide (Dai et al., 2008; Ii et al., 2005; Jujo et al., 2008; Miyamoto et al., 2007; Urbich et al., 2005). Thus, EPCs participate in tissue protection and regeneration by two different mechanisms. Regenerative potential of human EPCs was first tested in animal models. Intravenous injection of cultured hPBMNC into immunodeficient mice of a hindlimb ischemia model resulted in the restoration of blood flow at the ischemic injury site and salvation of the hindlimb (Kalka et al., 2000). Intravenous injection of cultured hPBMNC into nude rats of myocardial ischemia model resulted in the incorporation of transplanted EPCs into myocardial neovascularization and improved cardiac function (Kawamoto et al., 2001). The therapeutic potential in promoting the recovery from ischemic injury increased substantially by use of CB MNCs and enrichment of EPCs by selection of CD34þ cells (Iwasaki et al., 2006; Kawamoto et al., 2006; Kocher et al., 2001; Murohara et al., 2000). CD133 has also been a frequently-chosen surface marker for enrichment of EPCs in improving vascular recovery (Friedrich et al., 2006; Senegaglia et al., 2008, 2010). However, a detailed understanding of the contribution mechanism, for example the quantification of how much was contributed by direct incorporation through vasculogenesis and how much was contributed by angiogenic paracrine factors and a standardized method for such measurement has not yet emerged. Clinical trials with human EPCs for treatment of ischemic conditions started in the early 21st century, and 225 trials are currently listed in the U.S. National Institutes of Health. According to Asahara et al. clinical trials with human EPCs can be categorized to three generations (Asahara et al., 2011). In the first generation trials, whole MNCs from PB or BM were transplanted and showed relatively lowdegree contributions to angiogenesis and vasculogenesis with complications such as inflammation and Please cite this article in press as: Jang IH, et al., Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis, Advances in Biological Regulation (2014), http:// dx.doi.org/10.1016/j.jbior.2014.09.011

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fibrosis (Assmus et al., 2006; Dobert et al., 2004; Erbs et al., 2005; Li et al., 2007; Schachinger et al., 2004; Tatsumi et al., 2007) The second generation trials have been conducted with sorted EPCs for CD34 or CD133 expression and have been reported to show better angiogenesis and vasculogenesis with fewer complications (Ahmadi et al., 2007; Bartunek et al., 2005; Boyle et al., 2006; Kawamoto et al., 2009; Lara-Hernandez et al., 2010; Losordo et al., 2007; Stamm et al., 2007, 2003). The third generation trials are comprised of transplanting cultured and expanded CD34 þ or CD133 þ cells and are expected to yield much better outcomes based on animal experiments (Kamei et al., 2013; Kawakami et al., 2012; Masuda et al., 2014; Senegaglia et al., 2010) although evaluations in a clinical setting are necessary. Clinical trials with human EPCs can also be categorized to three groups depending on the method of introducing EPCs (Resch et al., 2012). The least invasive method involves the mobilization of the patient's own BM EPCs into the circulation by administration of G-CSF, expecting the homing of mobilized EPCs to the injury sites (Ohtsuka et al., 2004). Pilot studies for promoting myocardial regeneration showed improvement of left ventricular (LV) function, however, serious side effects, including increased in-stent restenosis and re-infarction, were also observed (Ince et al., 2005; Syed and Beeching, 2005; Tongers and Losordo, 2007; Valgimigli et al., 2005). The more invasive method consists of injection of EPCs into the circulation. Intracoronary infusion of BM EPCs to patients with myocardiac infarction showed positive LV function (Assmus et al., 2002; FernandezAviles et al., 2004; Strauer et al., 2002), followed by two phase II studies, the TOPCARE-AMI and BOOST, which showed a significant increase of LV function 4e6 months after administration of BM EPCs (Leistner et al., 2011; Schachinger et al., 2004; Wollert et al., 2004). Ten major clinical studies confirmed the safety of the procedure and the clinical benefit in more than half of studies, however, the benefits were transient and weak (Wei et al., 2009). The most invasive method involves the direct injection of EPCs into the target tissue. Intramuscular injections of autologous BM EPCs in patients with chronic limb ischemia resulted in immediate improvement and lowered amputation rates in three-year followup assessment (Matoba et al., 2008; Tateishi-Yuyama et al., 2002). Studies with patients of ischemic heart disease showed the improved ventricular function, however, larger studies are required in order to prove the beneficial effects (Hamano et al., 2001; Hattori and Matsubara, 2004; Perin et al., 2003; Tse et al., 2003). Although EPCs have been a subject of accelerated investigation since their discovery with the vision of rapid clinical applications, as more insights are gained through basic research on EPC biology, more demanding views are taking over the fervor of the pioneering period. Calculation based on the accumulated data in animal and human studies suggests that a blood volume of as much as 12 L will be necessary for isolation of EPCs for culture in order to achieve a satisfactory recovery in treatment of critical limb ischemia (Alev et al., 2011; Asahara et al., 2011). Thus, basic research such as selective mobilization of endogenous EPCs, enhancing EPC function with genetic modifications, generating EPCs from alternative sources like ES/iPS cells, and identifying/tracking the development of EPCs during embryogenesis will be necessary in order to bring EPCs to effective clinical applications. EPC homing and FPR2 A number of studies in animal models have reported homing of transplanted EPCs to sites of ischemic injury (Kalka et al., 2000; Kocher et al., 2001; Shi et al., 1998). Although the precise mechanisms of EPC homing are not completely understood, the interaction between surface molecules on EPCs and their ligands upregulated at the injury site is regarded as playing a central role (Avci-Adali et al., 2010). The increased expression of P-selectin glycoprotein ligand-1 (PSGL-1) or Eselectin on the EPC surface enhanced vascular recovery in the ischemic limb after transplanting EPCs (Foubert et al., 2007; Oh et al., 2007). Activation of b2-integrins on the EPC surface for the interaction with ICAM-1 in the ischemic muscle enhanced the homing of EPCs and EPC-induced neovascularization (Chavakis et al., 2005; Yoon et al., 2006). a4b1 integrin (very late antigen-4, VLA-4), which interacts with vascular cell adhesion molecule (VCAM) and fibronectin, also participate in homing of EPCs to ischemic tissue (Duan et al., 2006; Jin et al., 2006). Chemokines, which play important roles in angiogenesis and arteriogenesis, contribute to EPC homing (Schober and Zernecke, 2007; Weber et al., 2004). Chemokines are involved in mobilization, recruitment and adhesion of EPCs through the interaction of angiogenic chemokines such as CCL2, CXCL1, CXCL7, and Please cite this article in press as: Jang IH, et al., Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis, Advances in Biological Regulation (2014), http:// dx.doi.org/10.1016/j.jbior.2014.09.011

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Fig. 1. WKYMVm promotes homing of EPCs to ischemic injury site through FPR2.

CXCL12 (SDF-1a) at the injury site and their corresponding receptors on the EPC surface such as CCR2, CXCR2, and CXCR4 (Ceradini et al., 2004; Hristov et al., 2007; Weber et al., 1999). The interaction of CCL2/CCR2 and SDF1-a/CXCR4 is also known to direct EPCs to tumor neoangiogenesis (Guleng et al., 2005; Spring et al., 2005). As the efficient homing of EPCs to the site of therapeutic focus is a critical step in the successful treatment of ischemic conditions, further understanding of homing mechanisms of EPCs and development of a new strategy for directing EPC homing will significantly improve the therapeutic potential of EPCs. In a recent report, Heo et al. showed that activation of formyl peptide receptor 2 (FPR2) on EPC by injection of synthetic WKYMVm peptide near the ischemic injury site promoted homing of transplanted human EPCs and enhanced the vascular repair (Heo et al., 2014). FPRs, belonging to the G protein-coupled receptor family, play important roles in host defense and inflammatory regulation through promotion of chemotaxis and activation of leukocytes and phagocytes (Le et al., 2002). EPCs were generated from 7 to 10 day culture of human CB MNCs and shown to express FPR2 and FPR3. WKYMVm, a synthetic peptide identified from a library screen for activating lymphocytes, is involved in chemoattraction of human phagocytes (Bae et al., 1999; Baek et al., 1996). WKYMVm has a higher affinity for FPR2, which induces proliferation, migration, and sprouting activity of endothelial cells (Cattaneo et al., 2013; Lee et al., 2006). Heo et al. transplanted human EPCs by trail vein injection into nude mice with hindlimb ischemia and showed that repeated injection of WKYMVm into ischemic limbs led to increased homing of EPCs to the injury site and enhanced the recovery of vasculature and blood flow (Fig. 1). In addition, knockdown of FPR2 in EPCs significantly decreased the therapeutic effect of WKYMVm. EPCs can be promising cellular therapeutics with relatively low concerns regarding safety issues, however, they still show a limitation in effectiveness. Further understanding of EPC biology and development of new tools for improvement of EPC therapy, such as WKYMVm-FPR2 directed homing, will expedite the arrival of EPC therapeutics to clinical beds. Acknowledgment This work was supported for two years by Pusan National University Research Grant. Please cite this article in press as: Jang IH, et al., Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis, Advances in Biological Regulation (2014), http:// dx.doi.org/10.1016/j.jbior.2014.09.011

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