Copyright © 2006, European Society of Cardiology
Much ado about bone marrow stem cells: Role in post-myocardial infarct repair
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Canada
Department of Physiology, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6
* Tel.: +1 204 235 3419; fax: +1 204 233 6723. Email address: idixon{at}sbrc.ca
Received 30 June 2006; accepted 5 July 2006
See article by Möllmann et al. [14] (pages 661–671) in this issue.
The apparent lack of regenerative capacity of cardiac myocytes has, until recently, been upheld in a number of carefully conducted studies [1,2]. Indeed, this supposition has long formed the principal obstacle to the dream of directed repair of the myocardium following massive loss of cardiomyocytes after myocardial infarction (MI). Perhaps this is why the field of experimental cardiology was set upon its ear when a number of studies were presented to challenge this basic premise [3,4]. This work supported the hypothesis that multi-potent bone marrow stem cells (BMSC) were able to migrate to ischemic heart tissue to participate in cardiac regeneration. The usual course of events that transpire following MI manifests as gross alteration of left ventricular geometry involving the altered expression of many hundreds of genes that is collectively referred to as phenotypic plasticity of the myocardium, i.e. cardiac remodelling following injury [5]. The suggestion that cardiomyocytes may regenerate has fueled discussion and investigation to explore the suggestion that the infarct scar might serve as a putative site for regeneration of cardiac muscle. Further work indicated that directed treatments of BMSCs with specific cytokines led to their transdifferentiation to cardiomyocytes at the site of tissues bordering the infarct scar [6], and justifiably, this possibility has been the focus of intense investigation since then. This work is corroborated by another body of evidence supporting the existence of pools of organ-based stem cells that may serve to complement the function of BMSCs. For example, distinct, primordial cardiac stem cells (CSCs) have been described in the heart, and moreover a pool of primitive CSCs and "lineage-committed" daughter cells are maintained via asymmetric CSC division in stem cell niches within the myocardium [7].
Whether the potency of BMSCs is sufficient to routinely differentiate to cardiomyocytes in vivo at the site of the infarction in situ, i.e. in the absence of pretreatment with a specific cytokine cocktail, is a matter of some controversy. This issue arises from a number of more recent reports indicating that the ability or tendency for BMSCs to transdifferentiate to cardiomyocytes is very low. This discrepancy in the data with respect to cardiac myocytes notwithstanding, the question remains: what precisely are BMSCs actually doing in the heart, if they are migrating there post-MI? The issue may well be far more relevant to post-infarct remodeling than previously believed. Far from the previously canonical "dead meat" descriptions of yore, there is a growing realization that the infarct scar is a dynamic tissue that, after healing is completed, is populated with fibroblasts, hypersynthetic myofibroblasts, and other differentiated cells [8]. This paradigm is supported by a large and growing body of literature [9]. However, the overwhelming emphasis in recent investigations is aimed at transdifferentiation to cardiomyocytes, and the debate is sure to continue. Nonetheless, this focus has created something of a vacuum in the literature which begets the general question – does BMSC migration to the site of injury support wound healing and post-MI infarct remodeling?
The timely paper by Möllmann et al. in this issue of Cardiovascular Research directly addresses the issue of the fate of BMSCs in damaged heart using the murine model of chronic myocardial infarction [14]. While their data is provided to illustrate the low relative potency of autologous BMSCs to transdifferentiate to cardiomyocytes in vivo, at the same time it extends knowledge of other important post-MI events significant to cardiac remodeling – that of wound healing of the infarct scar as well as neovascularization in post-MI hearts. Specifically, BMSC-derived cells in this model are very potent when participating in myocardial repair via the movement of eGFP-labelled BMSCs to the immediate locale of the infarct. There, they contribute to matrix turnover and maintenance as well as vasculoneogenesis. A number of relevant questions are brought into sharp relief in the wake of the current work. For example, precisely how these cells "home" to the site of myocardial necrosis in post-MI hearts is unknown, although various cytokines have been suggested to participate in this process, including cardiotrophin-1 (CT-1) [9]. Other work has shown that pathways that subserve major fibrogenic stimuli are derepressed in infarct scar formation, e.g. the transient loss or dropout of Smad7 expression in the infarct scar of post-MI heart [10]. To date, our understanding of BMSC participation in these events has been incomplete.
The current paper is significant and presents a number of novel implications both alone and taken together with evidence supporting the existence of cardiac pools of primordial CSCs. That is, the possibility of different pools of stem cells contributing to different modes of cardiac remodeling is intriguing. While the data presented by Möllman et al. emphasizes and strengthens other earlier arguments that BMSCs may commit to the fibroblast lineage to differentiate to fibroblasts and myofibroblasts [11], the question of pool-specific differentiation of stem cell progeny remains relatively untested (Fig. 1).
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With respect to BMSC transdifferentiation, a number of relevant questions remain and many avenues are open for further investigation of BMSC participation in cardiac wound healing. Despite recent advances, the identification of key surface proteins, cytokines, or mechanical stimuli that contribute to or trigger pleuripotent BMSCs to commit to a specific lineage are unclear, particularly under physiological (and pathophysiological) conditions. Whether reactive oxygen species (ROS) at the site of the infarct play any role in the fate of BMSC differentiation is unknown. On the other hand, TGF-β is a strong stimulus for the phenotypic transformation of relatively quiescent fibroblasts to hypersynthetic and contractile myofibroblasts [12]. In light of recent evidence that R-Smads may be activated by ROS via Nox4 following TGF-β stimulation, and that this mechanism is implicit in conversion of fibroblasts to myofibroblasts [13], one might speculate that elevated ROS may potentiate the ROS/R-Smad axis which may possibly affect stem cell transdifferentiation. All speculation notwithstanding, interest in investigation of BMSC in cardiac wound repair seems assured and may very likely reveal novel mechanisms to support this important process in the near future.
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Acknowledgements |
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IMCD is a scholar of the Myles Robinson Heart Health Fund. The Smad7 work referred to in this commentary is funded by the Heart and Stroke Foundation of Manitoba.
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References |
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 Top References |
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- Anversa P., Palackal T., Sonnenblick E.H., Olivetti G., Meggs L.G., Capasso J.M. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res (1990) 67:871–885.
[Abstract/Free Full Text] - Guerra S., Leri A., Wang X., Finato N., Di Loreto C., Beltrami C., et al. Myocyte death in the failing human heart is gender dependent. Circ Res (1999) 85:856–866.
[Abstract/Free Full Text] - Quaini F., Urbanek K., Beltrami A.P., Finato N., Beltrami C.A., Nadal-Ginard B., et al. Chimerism of the transplanted heart. N Engl J Med (2002) 346:5–15.
[Abstract/Free Full Text] - Jackson K.A., Majka S.M., Wang H., Pocius J., Hartley C.J., Majesky M.W., et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest (2001) 107:1395–1402.[CrossRef][Web of Science][Medline]
- Swynghedauw B. Phenotypic plasticity of adult myocardium: molecular mechanisms. J Exp Biol (2006) 209:2320–2327.
[Abstract/Free Full Text] - Orlic D., Kajstura J., Chimenti S., Limana F., Jakoniuk I., Quaini F., et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A (2001) 98:10344–10349.
[Abstract/Free Full Text] - Urbanek K., Cesselli D., Rota M., Nascimbene A., De Angelis A., Hosoda T., et al. From the cover: stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A (2006) 103:9226–9231.
[Abstract/Free Full Text] - Sun Y., Weber K.T. Infarct scar: a dynamic tissue. Cardiovasc Res (2000) 46:250–256.
[Abstract/Free Full Text] - Freed D.H., Cunnington R.H., Dangerfield A.L., Sutton J.S., Dixon I.M.C. Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heart. Cardiovasc Res (2005) 65:782–792.
[Abstract/Free Full Text] - Wang B., Hao J., Jones S.C., Yee M.S., Roth J.C., Dixon I.M.C. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol (2002) 282:H1685–H1696.
[Abstract/Free Full Text] - Caplan A.I., Dennis J.E. Mesenchymal stem cells as trophic mediators. J Cell Biochem (Apr 17 2006) 10.1002/jcb.20886.
- Petrov V.V., Fagard R.H., Lijnen P.J. Transforming growth factor-beta(1) induces angiotensin-converting enzyme synthesis in rat cardiac fibroblasts during their differentiation to myofibroblasts. J Renin Angiotensin Aldosterone Syst (2000) 1:342–352.
[Abstract/Free Full Text] - Cucoranu I., Clempus R., Dikalova A., Phelan P.J., Ariyan S., Dikalov S., et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res (2005) 97:900–907.
[Abstract/Free Full Text] - Möllman H., Nef H.M., Kostin S., von Kalle C., Pilz I., Weber M., et al. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc Res (2006) 71:661–671.
[Abstract/Free Full Text]
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