- Email: [email protected]
Optimizing adult mesenchymal stem cells for heart repair
Journal of Molecular and Cellular Cardiology 42 (2007) 283 – 284 www.elsevier.com/locate/yjmcc
Editorial
Optimizing adult mesenchymal stem cells for heart repair With aging of the population worldwide, acute coronary syndrome emerges as a leading cause of morbidity and mortality despite progress made in the evaluation and management of this cardiovascular condition that has now reached pandemic proportion. Advances in molecular medicine provide a platform for novel strategies of care, including disease prediction and prevention [1]. New emphasis placed on systems-based genomic approaches aims to stratify individual risk for coronary artery disease, and achieve targeted interventions for enhanced myocardial tolerance to injury [2]. As pathways of endogenous cardioprotection are increasingly deciphered, population-based validation of disease susceptibility has created the prospect for personalized medicine. Concomitantly, a paradigm shift, from palliative to curative modalities, has evolved in the approach to therapy of cardiovascular disease enabled by the emergence of stem cell technology, and the unique opportunity for myocardial regeneration [3–5]. Cell-based clinical trials utilize adult, autologous, stem cell approaches to rectify damage sustained following acute myocardial infarction or to restore pump function in congestive heart failure [6]. While improvement in ejection fraction has been demonstrated in several studies [7], discrepancies in outcome raise the issue of cellular competence and handling as an inter-trial variable [8]. In particular, it remains uncertain whether implanted somatic stem cells can reliably contribute to regeneration as these cells display a limited aptitude to engage into the cardiac differentiation program in vitro [9]. In addition, it is still unclear whether the benefit of cellular therapy is derived from cellular contribution to myocardial contractility, or whether implanted cells create an environment promoting selfrepair [10–13]. Despite initial demonstration of adult stem cell contribution to the myocardium following transplantation into a developing blastocyst [14], limited additional evidence to verify that bone marrow-derived cells unequivocally yield cardiomyocytes in vitro has been obtained to date. Yet, the variability observed in clinical trials necessitates definitive validation prior to in vivo application. In this issue of the Journal of Molecular and Cellular Cardiology, the work by Li and colleagues highlights an approach to assess the cardiomyogenic aptitude of bone marrow-derived stem cells [15]. As had previously been demonstrated with embryonic stem cells [16], this work reveals that the heart has a procardiogenic endocrine function. With coculture of bone marrow-derived mesenchymal stem cells on 0022-2828/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2006.11.003
isolated neonatal cardiomyocytes, the authors exploit the paracrine influence of the heart in driving cardiogenesis to attain functional stem cell-derived myocytes [15]. Thus, paracrine cues emitted from the embryo [14] or cardiomyocytes [15] can evoke cardiogenesis, making it possible, in principle, to steer adult-derived stem cells towards the cardiac program. Achieving full therapeutic use of this priming modality will, however, require that induction of stem cells is ultimately achieved independently of a permissive co-culture environment. Indeed, approaches of co-culture or mosaicism do not serve to generate a uniform population of stem cell progeny amenable for transplantation. Alternative tactics, such as use of DNA demethylating agents to capitalize on differential methylation as a regulatory mechanism for promoter activity of tissue-specific genes, have also been evaluated for induction of cardiogenic outcome [17]. Although often effective, this approach yields cells that have exited the cell cycle, limiting the usefulness in priming adult stem cells. A fraction of circulating bone marrow-derived stem cells are likely to be innately primed for cardiogenesis, based on the finding that female to male transplanted hearts contain Y-chromosome positive cardiomyocytes, albeit in small number [18]. Identification of cardioinductive factors, from either the embryo or the host heart, may thus be necessary in recruiting a cell population uniformly primed from cardiogenesis. Furthermore, it is essential that such an approach maintains the proliferation capacity of primed cells for scaled-up production and reliable clinical application. As the paracrine micro-environment seems most efficacious in achieving stem cell cardiogenesis [14–16], a method that recapitulates the natural embryonic program deserves further scrutiny. Recent works evaluating factors secreted by the endoderm were able to demonstrate its cardiomyogenic aptitude on both human mesenchymal and embryonic stem cells [19,20]. Components of the endodermal secretome, as identified by genomics and proteomics, have yielded a cocktail of secreted proteins effective in inducing the cardiac program [20]. This approach demonstrates the feasibility of deriving a cardiac population from human mesenchymal stem cells through mimicry of the embryonic cardiogenic program, while avoiding cell-to-cell interaction [20]. Thus, with such “cocktail-based” approach, bone marrow-derived stem cell capacity to differentiate into cardiomyocytes is separated from fusogenic phenomena for reliable high throughput validation. In addition,
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with recombinant application of appropriate inductive factors, one may be able to recruit or potentially induce cardiogenic priming from adult stem cells, as demonstrated for the human mesenchymal stem cell population [20]. With the emergence of cell-based therapeutics into the clinical arena, the prospect of curing heart disease is promising. Early experience from this therapy evokes memories of initial data obtained in trials using angiotensin-converting enzyme inhibitors or beta-blockers, both now mainstays of therapy in heart disease. A limiting factor to establishing the benefit of a stem cell-based approach is the lack of current understanding concerning which cell type is the most efficacious, and what is the specific contribution to repair once implanted [21]. With appropriate validation of cellular phenotypes and priming for optimal performance, the next generation of trials should achieve increasing inter-trial consistency and a demonstrable benefit to the patients in great need of this therapy. Acknowledgments Supported by NIH, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, and Mayo Clinic Clinician-Investigator Program. AB is a Clinician Investigator Scholar and AT is Marriott Family Professor of Cardiovascular Research at Mayo Clinic. References [1] Bell J. Predicting disease using genomics. Nature 2004;429:453–6. [2] Watkins H, Farrall M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev, Genet 2006;7:163–73. [3] Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature 2002;415:240–3. [4] Dimmeler S, Zeiher A, Schneider M. Unchain my heart: scientific foundations of cardiac repair. J Clin Invest 2005;115:572–83. [5] Murry CE, Field LJ, Menasché P. Cell-based cardiac repair: reflections at the 10-year point. Circulation 2005;112:3174–83. [6] Sanchez P, San Roman J, Villa A, Fernandez M, Fernandez-Aviles F. Contemplating the bright future of stem cell therapy for cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006;3:S138–51. [7] Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355: 1210–21. [8] Rosenzweig A. Cardiac cell therapy-mixed results from mixed cells. N Engl J Med 2006;355:1274–7. [9] Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol 2005;23:845–56.
[10] Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005;11:367–8. [11] Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006;12:459–65. [12] Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren J, et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006;203:2315–27. [13] Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res 2006;98:1414–21. [14] Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, OrtizGonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–9. [15] Li XH, Yu XY, Lin QX, Deng CY, Shan ZX, Yang M, et al. Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. J Mol Cell Cardiol 2007. doi:10.1016/j. yjmcc.2006.07.002. [16] Behfar A, Zingman L, Hodgson D, Rauzier J, Kane G, Terzic A, et al. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J 2002;16:1558–66. [17] Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100:II247–56. [18] Deb A, Wang S, Skelding KA, Miller D, Simper D, Caplice NM. Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 2003;107:1247–9. [19] Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al. Differentiation of human embryonic stem cells to cardiomyocytes. Circulation 2003;107:2733–40. [20] Behfar A, Terzic A. Derivation of a cardiopoietic population from human mesenchymal stem cells yields cardiac progeny. Nat Clin Pract Cardiovasc Med 2006;3:S78–82. [21] Chien KR. Lost and found: cardiac stem cell therapy revisited. J Clin Invest 2006;116:1838–40.
Atta Behfar Andre Terzic* Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA E-mail address: [email protected]. *Corresponding author. 200 First Street SW, Rochester, MN 55905, USA. 6 November 2006
Editorial
Optimizing adult mesenchymal stem cells for heart repair With aging of the population worldwide, acute coronary syndrome emerges as a leading cause of morbidity and mortality despite progress made in the evaluation and management of this cardiovascular condition that has now reached pandemic proportion. Advances in molecular medicine provide a platform for novel strategies of care, including disease prediction and prevention [1]. New emphasis placed on systems-based genomic approaches aims to stratify individual risk for coronary artery disease, and achieve targeted interventions for enhanced myocardial tolerance to injury [2]. As pathways of endogenous cardioprotection are increasingly deciphered, population-based validation of disease susceptibility has created the prospect for personalized medicine. Concomitantly, a paradigm shift, from palliative to curative modalities, has evolved in the approach to therapy of cardiovascular disease enabled by the emergence of stem cell technology, and the unique opportunity for myocardial regeneration [3–5]. Cell-based clinical trials utilize adult, autologous, stem cell approaches to rectify damage sustained following acute myocardial infarction or to restore pump function in congestive heart failure [6]. While improvement in ejection fraction has been demonstrated in several studies [7], discrepancies in outcome raise the issue of cellular competence and handling as an inter-trial variable [8]. In particular, it remains uncertain whether implanted somatic stem cells can reliably contribute to regeneration as these cells display a limited aptitude to engage into the cardiac differentiation program in vitro [9]. In addition, it is still unclear whether the benefit of cellular therapy is derived from cellular contribution to myocardial contractility, or whether implanted cells create an environment promoting selfrepair [10–13]. Despite initial demonstration of adult stem cell contribution to the myocardium following transplantation into a developing blastocyst [14], limited additional evidence to verify that bone marrow-derived cells unequivocally yield cardiomyocytes in vitro has been obtained to date. Yet, the variability observed in clinical trials necessitates definitive validation prior to in vivo application. In this issue of the Journal of Molecular and Cellular Cardiology, the work by Li and colleagues highlights an approach to assess the cardiomyogenic aptitude of bone marrow-derived stem cells [15]. As had previously been demonstrated with embryonic stem cells [16], this work reveals that the heart has a procardiogenic endocrine function. With coculture of bone marrow-derived mesenchymal stem cells on 0022-2828/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2006.11.003
isolated neonatal cardiomyocytes, the authors exploit the paracrine influence of the heart in driving cardiogenesis to attain functional stem cell-derived myocytes [15]. Thus, paracrine cues emitted from the embryo [14] or cardiomyocytes [15] can evoke cardiogenesis, making it possible, in principle, to steer adult-derived stem cells towards the cardiac program. Achieving full therapeutic use of this priming modality will, however, require that induction of stem cells is ultimately achieved independently of a permissive co-culture environment. Indeed, approaches of co-culture or mosaicism do not serve to generate a uniform population of stem cell progeny amenable for transplantation. Alternative tactics, such as use of DNA demethylating agents to capitalize on differential methylation as a regulatory mechanism for promoter activity of tissue-specific genes, have also been evaluated for induction of cardiogenic outcome [17]. Although often effective, this approach yields cells that have exited the cell cycle, limiting the usefulness in priming adult stem cells. A fraction of circulating bone marrow-derived stem cells are likely to be innately primed for cardiogenesis, based on the finding that female to male transplanted hearts contain Y-chromosome positive cardiomyocytes, albeit in small number [18]. Identification of cardioinductive factors, from either the embryo or the host heart, may thus be necessary in recruiting a cell population uniformly primed from cardiogenesis. Furthermore, it is essential that such an approach maintains the proliferation capacity of primed cells for scaled-up production and reliable clinical application. As the paracrine micro-environment seems most efficacious in achieving stem cell cardiogenesis [14–16], a method that recapitulates the natural embryonic program deserves further scrutiny. Recent works evaluating factors secreted by the endoderm were able to demonstrate its cardiomyogenic aptitude on both human mesenchymal and embryonic stem cells [19,20]. Components of the endodermal secretome, as identified by genomics and proteomics, have yielded a cocktail of secreted proteins effective in inducing the cardiac program [20]. This approach demonstrates the feasibility of deriving a cardiac population from human mesenchymal stem cells through mimicry of the embryonic cardiogenic program, while avoiding cell-to-cell interaction [20]. Thus, with such “cocktail-based” approach, bone marrow-derived stem cell capacity to differentiate into cardiomyocytes is separated from fusogenic phenomena for reliable high throughput validation. In addition,
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with recombinant application of appropriate inductive factors, one may be able to recruit or potentially induce cardiogenic priming from adult stem cells, as demonstrated for the human mesenchymal stem cell population [20]. With the emergence of cell-based therapeutics into the clinical arena, the prospect of curing heart disease is promising. Early experience from this therapy evokes memories of initial data obtained in trials using angiotensin-converting enzyme inhibitors or beta-blockers, both now mainstays of therapy in heart disease. A limiting factor to establishing the benefit of a stem cell-based approach is the lack of current understanding concerning which cell type is the most efficacious, and what is the specific contribution to repair once implanted [21]. With appropriate validation of cellular phenotypes and priming for optimal performance, the next generation of trials should achieve increasing inter-trial consistency and a demonstrable benefit to the patients in great need of this therapy. Acknowledgments Supported by NIH, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, and Mayo Clinic Clinician-Investigator Program. AB is a Clinician Investigator Scholar and AT is Marriott Family Professor of Cardiovascular Research at Mayo Clinic. References [1] Bell J. Predicting disease using genomics. Nature 2004;429:453–6. [2] Watkins H, Farrall M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev, Genet 2006;7:163–73. [3] Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature 2002;415:240–3. [4] Dimmeler S, Zeiher A, Schneider M. Unchain my heart: scientific foundations of cardiac repair. J Clin Invest 2005;115:572–83. [5] Murry CE, Field LJ, Menasché P. Cell-based cardiac repair: reflections at the 10-year point. Circulation 2005;112:3174–83. [6] Sanchez P, San Roman J, Villa A, Fernandez M, Fernandez-Aviles F. Contemplating the bright future of stem cell therapy for cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006;3:S138–51. [7] Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355: 1210–21. [8] Rosenzweig A. Cardiac cell therapy-mixed results from mixed cells. N Engl J Med 2006;355:1274–7. [9] Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol 2005;23:845–56.
[10] Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005;11:367–8. [11] Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006;12:459–65. [12] Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren J, et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006;203:2315–27. [13] Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res 2006;98:1414–21. [14] Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, OrtizGonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–9. [15] Li XH, Yu XY, Lin QX, Deng CY, Shan ZX, Yang M, et al. Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. J Mol Cell Cardiol 2007. doi:10.1016/j. yjmcc.2006.07.002. [16] Behfar A, Zingman L, Hodgson D, Rauzier J, Kane G, Terzic A, et al. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J 2002;16:1558–66. [17] Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100:II247–56. [18] Deb A, Wang S, Skelding KA, Miller D, Simper D, Caplice NM. Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 2003;107:1247–9. [19] Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al. Differentiation of human embryonic stem cells to cardiomyocytes. Circulation 2003;107:2733–40. [20] Behfar A, Terzic A. Derivation of a cardiopoietic population from human mesenchymal stem cells yields cardiac progeny. Nat Clin Pract Cardiovasc Med 2006;3:S78–82. [21] Chien KR. Lost and found: cardiac stem cell therapy revisited. J Clin Invest 2006;116:1838–40.
Atta Behfar Andre Terzic* Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA E-mail address: [email protected]. *Corresponding author. 200 First Street SW, Rochester, MN 55905, USA. 6 November 2006