Journal of Biological Chemistry · 2010 · 123 citations · 29 references
Life SciencesBiomedical SciencesDevelopmental BiologyCell TherapyRegenerative MedicineStem Cell BiologyBone Morphogenetic Protein SignalingBone RegenerationMesenchymal Stem Cell TherapyStem Cell DifferentiationStem Cell Signaling PathwaysWnt SignalingCanonical Wnt PathwayCanonical Wnt SignalingMyocardial RegenerationOsteogenic DifferentiationSecreted Frizzled-related ProteinsSelf-renewalSelf-renewal RegulationWnt Signaling In Stem Cell Maintenance
Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing. Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing. IntroductionBone marrow-derived mesenchymal stem cells (MSCs) 2The abbreviations used are: MSCmesenchymal stem cellsFRP2secreted Frizzled-related protein 2BMPbone morphogenic proteinHSChematopoietic stem cellCRDcysteine-rich domain. are an attractive candidate for cell-mediated wound repair. Because of their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration (1Jorgensen C. Gordeladze J. Noel D. Curr. Opin. Biotechnol. 2004; 15: 406-410Crossref PubMed Scopus (156) Google Scholar, 2Deleted in proofGoogle Scholar). 3U.S. National Library of Medicine, U.S. Department of Health & Human Services, Clinicaltrials.gov, Lister Hill National Center for Biomedical Communications. MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success (3Orlic D. Kajstura J. Chimenti S. Jakoniuk I. Anderson S.M. Li B. Pickel J. McKay R. Nadal-Ginard B. Bodine D.M. Leri A. Anversa P. Nature. 2001; 410: 701-705Crossref PubMed Scopus (4670) Google Scholar). These promising results are inconsistent, partly due to the low levels of engraftment of MSCs within the injured tissues (4Iso Y. Spees J.L. Serrano C. Bakondi B. Pochampally R. Song Y.H. Sobel B.E. Delafontaine P. Prockop D.J. Biochem. Biophys. Res. Commun. 2007; 354: 700-706Crossref PubMed Scopus (313) Google Scholar). Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy.Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5Satija N.K. Gurudutta G.U. Sharma S. Afrin F. Gupta P. Verma Y.K. Singh V.K. Tripathi R.P. Stem Cells Dev. 2007; 16: 7-23Crossref PubMed Scopus (146) Google Scholar, 6Schofield R. Biomed. Pharmacother. 1983; 37: 375-380PubMed Google Scholar). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5Satija N.K. Gurudutta G.U. Sharma S. Afrin F. Gupta P. Verma Y.K. Singh V.K. Tripathi R.P. Stem Cells Dev. 2007; 16: 7-23Crossref PubMed Scopus (146) Google Scholar). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7Reya T. Clevers H. Nature. 2005; 434: 843-850Crossref PubMed Scopus (2986) Google Scholar, 8McReynolds L.J. Gupta S. Figueroa M.E. Mullins M.C. Evans T. Blood. 2007; 110: 3881-3890Crossref PubMed Scopus (58) Google Scholar, 9Suzuki T. Chiba S. Int. J. Hematol. 2005; 82: 285-294Crossref PubMed Scopus (58) Google Scholar). Although no data are available to demonstrate the role of these pathways in MSC self-renewal, the Wnt and BMP cascades are involved in MSC lineage commitment. Canonical Wnt signaling directs osteogenic differentiation of MSCs by stimulating the expression of osteocalcin (10Gaur T. Rich L. Lengner C.J. Hussain S. Trevant B. Ayers D. Stein J.L. Bodine P.V. Komm B.S. Stein G.S. Lian J.B. J. Cell Physiol. 2006; 208: 87-96Crossref PubMed Scopus (88) Google Scholar), this pathway is also involved in early chondrogenesis (11Goldring M.B. Tsuchimochi K. Ijiri K. J. Cell Biochem. 2006; 97: 33-44Crossref PubMed Scopus (827) Google Scholar). The BMP pathway also modulates osteogenic differentiation of MSCs by controlling osteocalcin (12Manton K.J. Leong D.F. Cool S.M. Nurcombe V. Stem Cells. 2007; 25: 2845-2854Crossref PubMed Scopus (88) Google Scholar), and BMP2 induces chondrocyte fate determination (13Denker A.E. Haas A.R. Nicoll S.B. Tuan R.S. Differentiation. 1999; 64: 67-76Crossref PubMed Scopus (215) Google Scholar). The Wnt cascade is involved in other cellular processes besides differentiation; canonical Wnt signaling inhibition, through the activity of Dkk-1, increases human MSC proliferation without overt differentiation (14Gregory K.E. Ono R.N. Charbonneau N.L. Kuo C.L. Keene D.R. Bächinger H.P. Sakai L.Y. J. Biol. Chem. 2005; 280: 27970-27980Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). The mechanisms by which MSCs modulate these signaling events during growth and/or lineage commitment remain unknown. The data herein, describe the ability of sFRP2 to promote MSC self-renewal by inhibition of both the Wnt and BMP pathways.Secreted frizzled-related protein-2 (sFRP2) has recently been implicated by our group and others as a mediator of MSC-driven myocardial and wound repair; however, the mechanisms are unclear. sFRP2-mediated regeneration can be attributed, at least in part, to its paracrine role in mediating myocardial survival by inhibiting apoptosis (15Mirotsou M. Zhang Z. Deb A. Zhang L. Gnecchi M. Noiseux N. Mu H. Pachori A. Dzau V. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 1643-1648Crossref PubMed Scopus (444) Google Scholar). However, there are compelling data that sFRP2 has direct effects on MSCs themselves. Overexpression of sFRP2 by MSCs results in increased MSC proliferation and long-term engraftment in vivo (16Alfaro M.P. Pagni M. Vincent A. Atkinson J. Hill M.F. Cates J. Davidson J.M. Rottman J. Lee E. Young P.P. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 18366-18371Crossref PubMed Scopus (144) Google Scholar).The members of the secreted frizzled-related protein (sFRPs) family contain a region with high homology to the cysteine-rich domain (CRD) of the Wnt-pathway frizzled receptors (17Rattner A. Hsieh J.C. Smallwood P.M. Gilbert D.J. Copeland N.G. Jenkins N.A. Nathans J. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 2859-2863Crossref PubMed Scopus (485) Google Scholar). sFRPs bind Wnt glycoproteins through the CRD, preventing them from reaching their cognate receptors (18Finch P.W. He X. Kelley M.J. Uren A. Schaudies R.P. Popescu N.C. Rudikoff S. Aaronson S.A. Varmus H.E. Rubin J.S. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 6770-6775Crossref PubMed Scopus (361) Google Scholar). The five mammalian members, sFRP1–5, have been associated with several developmental and disease processes (19Ezan J. Leroux L. Barandon L. Dufourcq P. Jaspard B. Moreau C. Allières C. Daret D. Couffinhal T. Duplàa C. Cardiovasc. Res. 2004; 63: 731-738Crossref PubMed Scopus (75) Google Scholar, 20Hoang B. Moos Jr., M. Vukicevic S. Luyten F.P. J. Biol. Chem. 1996; 271: 26131-26137Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Their documented effect thus far has been that of Wnt inhibition (18Finch P.W. He X. Kelley M.J. Uren A. Schaudies R.P. Popescu N.C. Rudikoff S. Aaronson S.A. Varmus H.E. Rubin J.S. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 6770-6775Crossref PubMed Scopus (361) Google Scholar).Here, we demonstrate that sFRP2 plays dual and important roles in increasing MSC self-renewal by inhibiting both the Wnt and BMP pathways. We show that sFRP2 confers apoptotic resistance to MSCs in parallel to Wnt pathway inhibition. sFRP2 affects the rate of MSC multilineage differentiation; processes directed by Wnt and BMP signaling. This article is the first to demonstrate that sFRP2 directly inhibits BMP signaling in MSCs. The data contained within describe the mechanisms by which sFRP2 enhances MSC self-renewal to promote MSC-mediated wound healing.DISCUSSIONMSCs are utilized in a variety of preclinical models to ameliorate wound healing. Enhanced cardiac tissue repair mediated by MSCs, in concert with clinical studies suggesting that their clinical use is feasible and safe, have spurred a number of clinical trials using bone marrow-derived MSCs as regenerative cell therapy. At least 14 trials are currently ongoing using MSCs to treat myocardial disease (clinicaltrials.gov).3 However, our understanding on how MSCs mediate cardiac and soft tissue repair, including aspects that regulate MSC self renewal, remains incomplete.sFRP2 has been identified as a factor mediating myocardial repair and wound granulation tissue formation by MSCs (15Mirotsou M. Zhang Z. Deb A. Zhang L. Gnecchi M. Noiseux N. Mu H. Pachori A. Dzau V. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 1643-1648Crossref PubMed Scopus (444) Google Scholar, 16Alfaro M.P. Pagni M. Vincent A. Atkinson J. Hill M.F. Cates J. Davidson J.M. Rottman J. Lee E. Young P.P. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 18366-18371Crossref PubMed Scopus (144) Google Scholar). Although sFRP2 has been postulated to function as a paracrine modulator of cardiomyocyte apoptosis (30Zhang Z. Deb A. Zhang Z. Pachori A. He W. Guo J. Pratt R. Dzau V.J. J. Mol. Cell Cardiol. 2009; 46: 370-377Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), we have provided compelling data that sFRP2 is an important autocrine factor for MSCs themselves. sFRP2 overexpression directly up-regulated MSC proliferation in vitro and enhanced their long-term engraftment in mouse models of myocardial injury and wound granulation tissue. In these studies we sought to better clarify how sFRP2 was coordinating repair by MSCs at the cellular level. Our studies showed that sFRP2 is an important modulator of MSC self-renewal. In addition to its published role to enhance proliferation (16Alfaro M.P. Pagni M. Vincent A. Atkinson J. Hill M.F. Cates J. Davidson J.M. Rottman J. Lee E. Young P.P. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 18366-18371Crossref PubMed Scopus (144) Google Scholar), we report that it also inhibits both MSC apoptosis and their differentiation along osteogenic and chondrogenic lineages.Our previous study showed that sFRP2 resulted in a dose-dependent increase in human and murine MSC proliferation in vitro. Conversely, addition of recombinant Wnt3a (or its overexpression in MSCs) resulted in a decreased proliferation rate. Dkk1, an inhibitor of canonical Wnt signaling, has been demonstrated to increase human MSC proliferation and entry into the cell cycle in vitro (14Gregory K.E. Ono R.N. Charbonneau N.L. Kuo C.L. Keene D.R. Bächinger H.P. Sakai L.Y. J. Biol. Chem. 2005; 280: 27970-27980Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Taken together with our findings that sFRP2 was able to decrease functional canonical Wnt signaling in MSCs (16Alfaro M.P. Pagni M. Vincent A. Atkinson J. Hill M.F. Cates J. Davidson J.M. Rottman J. Lee E. Young P.P. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 18366-18371Crossref PubMed Scopus (144) Google Scholar), these data suggested that sFRP2 increased proliferation through inhibition of canonical Wnt signaling.The sFRP family has also been termed the secreted apoptosis-related proteins, or SARPs, and as their name suggests has been documented to play important roles in the cytoprotection of distinct cells (31Melkonyan H.S. Chang W.C. Shapiro J.P. Mahadevappa M. Fitzpatrick P.A. Kiefer M.C. Tomei L.D. Umansky S.R. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 13636-13641Crossref PubMed Scopus (289) Google Scholar). Herein we demonstrated that sFRP2 served to protect MSCs from apoptosis under basal and hypoxic conditions. This pro-survival effect was likely to be mediated by sFRP2 inhibition of canonical Wnt signaling as sFRP2 decreased both β-catenin and cleaved caspase 3 levels. The anti-apoptotic action of sFRP2 in MSCs closely mirrors its recently reported paracrine anti-apoptotic effects on cardiomyocytes through direct binding of Wnt3a and inhibition of Wnt3a-induced activation of caspase activities (30Zhang Z. Deb A. Zhang Z. Pachori A. He W. Guo J. Pratt R. Dzau V.J. J. Mol. Cell Cardiol. 2009; 46: 370-377Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar).MSCs are capable of differentiating into multiple connective tissue lineages, in particular bone, cartilage and of MSCs along these at low levels is by conditions. for and of and osteogenic lineages, we showed that sFRP2 inhibited differentiation of MSCs along both cartilage and osteogenic in vitro. We further demonstrated a decrease in levels of a factor for osteogenic commitment. Wnt and BMP pathways regulate and BMP is a of both osteogenic and chondrogenic differentiation of MSCs, we the effect of sFRP2 on the BMP pathway. Our data provided that sFRP2 inhibited BMP sFRP2 inhibited levels of BMP as as BMP of occurred within of protein and was by the addition of the Wnt These data suggested that sFRP2 inhibition of BMP signaling from the pathways and occurred of its effect on Wnt inhibition. BMP signaling inhibition occurred both with the addition of recombinant sFRP2 as as in cells suggesting that sFRP2 inhibited BMP in a by which sFRP2 directly inhibits BMP signaling in mammalian cells is this as to its involvement in BMP signaling the of in the and by of in the L. PubMed Scopus Google Scholar). The BMP which is to BMP to binding Y. B. H. D. Full Text PDF PubMed Scopus Google Scholar). inhibits BMP signaling by inhibiting the activity of the that In this developmental process the effect of on allows of by H. Cell Dev. Biol. 2004; PubMed Scopus Google and BMP pathway inhibition. In a in vitro mouse sFRP2 with to the of B. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). report suggests sFRP2 may play a role in BMP inhibition in the of murine BMP and sFRP2 into the the of BMP K. M.P. Dev. Biol. PubMed Scopus Google Scholar, in proofGoogle Scholar, in proofGoogle Scholar). This study the BMP inhibition was an or a direct effect of this we show inhibition of BMP signaling molecules, by overexpression of sFRP2 by MSCs, by the addition of recombinant mouse sFRP2 to the extracellular This inhibition to functional inhibition of BMP signaling by a decrease in both chondrogenic and osteogenic lineage commitment of MSCs. our data with the available sFRP2 and its we that the effects of sFRP2 as a BMP inhibitor are in the extracellular Our results the expression of sFRP2 in MSCs inhibits both canonical Wnt and BMP signaling. The cellular effects of sFRP2 on apoptosis, and differentiation MSC self-renewal and engraftment within the have highlighted the of in osteogenic differentiation of MSCs cardiac cell therapy. We assessed heterotopic in independent in vivo models MSC cell therapy. Our data showed that in the of myocardial and within granulation tissue in sFRP2-expressing MSCs demonstrated of ectopic These data that sFRP2-mediated inhibition of differentiation may reduce the of heterotopic cartilage and/or bone tissues with MSC direct of of cells into preclinical studies show engraftment with or no MSCs Hence, a better understanding of the molecular as that modulate MSC and differentiation may the of MSC cardiac and wound therapy. IntroductionBone marrow-derived mesenchymal stem cells (MSCs) 2The abbreviations used are: MSCmesenchymal stem cellsFRP2secreted Frizzled-related protein 2BMPbone morphogenic proteinHSChematopoietic stem cellCRDcysteine-rich domain. are an attractive candidate for cell-mediated wound repair. Because of their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration (1Jorgensen C. Gordeladze J. Noel D. Curr. Opin. Biotechnol. 2004; 15: 406-410Crossref PubMed Scopus (156) Google Scholar, 2Deleted in proofGoogle Scholar). 3U.S. National Library of Medicine, U.S. Department of Health & Human Services, Clinicaltrials.gov, Lister Hill National Center for Biomedical Communications. MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success (3Orlic D. Kajstura J. Chimenti S. Jakoniuk I. Anderson S.M. Li B. Pickel J. McKay R. Nadal-Ginard B. Bodine D.M. Leri A. Anversa P. Nature. 2001; 410: 701-705Crossref PubMed Scopus (4670) Google Scholar). These promising results are inconsistent, partly due to the low levels of engraftment of MSCs within the injured tissues (4Iso Y. Spees J.L. Serrano C. Bakondi B. Pochampally R. Song Y.H. Sobel B.E. Delafontaine P. Prockop D.J. Biochem. Biophys. Res. Commun. 2007; 354: 700-706Crossref PubMed Scopus (313) Google Scholar). Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy.Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5Satija N.K. Gurudutta G.U. Sharma S. Afrin F. Gupta P. Verma Y.K. Singh V.K. Tripathi R.P. Stem Cells Dev. 2007; 16: 7-23Crossref PubMed Scopus (146) Google Scholar, 6Schofield R. Biomed. Pharmacother. 1983; 37: 375-380PubMed Google Scholar). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5Satija N.K. Gurudutta G.U. Sharma S. Afrin F. Gupta P. Verma Y.K. Singh V.K. Tripathi R.P. Stem Cells Dev. 2007; 16: 7-23Crossref PubMed Scopus (146) Google Scholar). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7Reya T. Clevers H. Nature. 2005; 434: 843-850Crossref PubMed Scopus (2986) Google Scholar, 8McReynolds L.J. Gupta S. Figueroa M.E. Mullins M.C. Evans T. Blood. 2007; 110: 3881-3890Crossref PubMed Scopus (58) Google Scholar, 9Suzuki T. Chiba S. Int. J. Hematol. 2005; 82: 285-294Crossref PubMed Scopus (58) Google Scholar). Although no data are available to demonstrate the role of these pathways in MSC self-renewal, the Wnt and BMP cascades are involved in MSC lineage commitment. Canonical Wnt signaling directs osteogenic differentiation of MSCs by stimulating the expression of osteocalcin (10Gaur T. Rich L. Lengner C.J. Hussain S. Trevant B. Ayers D. Stein J.L. Bodine P.V. Komm B.S. Stein G.S. Lian J.B. J. Cell Physiol. 2006; 208: 87-96Crossref PubMed Scopus (88) Google Scholar), this pathway is also involved in early chondrogenesis (11Goldring M.B. Tsuchimochi K. Ijiri K. J. Cell Biochem. 2006; 97: 33-44Crossref PubMed Scopus (827) Google Scholar). The BMP pathway also modulates osteogenic differentiation of MSCs by controlling osteocalcin (12Manton K.J. Leong D.F. Cool S.M. Nurcombe V. Stem Cells. 2007; 25: 2845-2854Crossref PubMed Scopus (88) Google Scholar), and BMP2 induces chondrocyte fate determination (13Denker A.E. Haas A.R. Nicoll S.B. Tuan R.S. Differentiation. 1999; 64: 67-76Crossref PubMed Scopus (215) Google Scholar). The Wnt cascade is involved in other cellular processes besides differentiation; canonical Wnt signaling inhibition, through the activity of Dkk-1, increases human MSC proliferation without overt differentiation (14Gregory K.E. Ono R.N. Charbonneau N.L. Kuo C.L. Keene D.R. Bächinger H.P. Sakai L.Y. J. Biol. Chem. 2005; 280: 27970-27980Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). The mechanisms by which MSCs modulate these signaling events during growth and/or lineage commitment remain unknown. The data herein, describe the ability of sFRP2 to promote MSC self-renewal by inhibition of both the Wnt and BMP pathways.Secreted frizzled-related protein-2 (sFRP2) has recently been implicated by our group and others as a mediator of MSC-driven myocardial and wound repair; however, the mechanisms are unclear. sFRP2-mediated regeneration can be attributed, at least in part, to its paracrine role in mediating myocardial survival by inhibiting apoptosis (15Mirotsou M. Zhang Z. Deb A. Zhang L. Gnecchi M. Noiseux N. Mu H. Pachori A. Dzau V. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 1643-1648Crossref PubMed Scopus (444) Google Scholar). However, there are compelling data that sFRP2 has direct effects on MSCs themselves. Overexpression of sFRP2 by MSCs results in increased MSC proliferation and long-term engraftment in vivo (16Alfaro M.P. Pagni M. Vincent A. Atkinson J. Hill M.F. Cates J. Davidson J.M. Rottman J. Lee E. Young P.P. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 18366-18371Crossref PubMed Scopus (144) Google Scholar).The members of the secreted frizzled-related protein (sFRPs) family contain a region with high homology to the cysteine-rich domain (CRD) of the Wnt-pathway frizzled receptors (17Rattner A. Hsieh J.C. Smallwood P.M. Gilbert D.J. Copeland N.G. Jenkins N.A. Nathans J. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 2859-2863Crossref PubMed Scopus (485) Google Scholar). sFRPs bind Wnt glycoproteins through the CRD, preventing them from reaching their cognate receptors (18Finch P.W. He X. Kelley M.J. Uren A. Schaudies R.P. Popescu N.C. Rudikoff S. Aaronson S.A. Varmus H.E. Rubin J.S. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 6770-6775Crossref PubMed Scopus (361) Google Scholar). The five mammalian members, sFRP1–5, have been associated with several developmental and disease processes (19Ezan J. Leroux L. Barandon L. Dufourcq P. Jaspard B. Moreau C. Allières C. Daret D. Couffinhal T. Duplàa C. Cardiovasc. Res. 2004; 63: 731-738Crossref PubMed Scopus (75) Google Scholar, 20Hoang B. Moos Jr., M. Vukicevic S. Luyten F.P. J. Biol. Chem. 1996; 271: 26131-26137Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Their documented effect thus far has been that of Wnt inhibition (18Finch P.W. He X. Kelley M.J. Uren A. Schaudies R.P. Popescu N.C. Rudikoff S. Aaronson S.A. Varmus H.E. Rubin J.S. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 6770-6775Crossref PubMed Scopus (361) Google Scholar).Here, we demonstrate that sFRP2 plays dual and important roles in increasing MSC self-renewal by inhibiting both the Wnt and BMP pathways. We show that sFRP2 confers apoptotic resistance to MSCs in parallel to Wnt pathway inhibition. sFRP2 affects the rate of MSC multilineage differentiation; processes directed by Wnt and BMP signaling. This article is the first to demonstrate that sFRP2 directly inhibits BMP signaling in MSCs. The data contained within describe the mechanisms by which sFRP2 enhances MSC self-renewal to promote MSC-mediated wound healing.
29
Bone marrow cells regenerate infarcted myocardium
Donald Orlic, Jan Kajstura, Stefano Chimenti et al. · Nature · 2001 · 5.2K citations
Mary B. Goldring, Kaneyuki Tsuchimochi, Kosei Ijiri · Journal of Cellular Biochemistry · 2005 · 1.1K citations · Full text