Restoration of Cardiac Progenitor Cells After Myocardial Infarction by Self-Proliferation and Selective Homing of Bone Marrow–Derived Stem Cells

Abstract

Tissue-specific progenitor cells contribute to local cellular regeneration and maintain organ function. Recently, we have determined that cardiac side-population (CSP) cells represent a distinct cardiac progenitor cell population, capable of in vitro differentiation into functional cardiomyocytes. The response of endogenous CSP to myocardial injury, however, and the cellular mechanisms that maintain this cardiac progenitor cell pool in vivo remain unknown. In this report we demonstrate that local progenitor cell proliferation maintains CSP under physiologic conditions, with little contribution from extracardiac stem cell sources. Following myocardial infarction in adult mice, however, CSP cells are acutely depleted, both within the infarct and noninfarct areas. CSP pools are subsequently reconstituted to baseline levels within 7 days after myocardial infarction, through both proliferation of resident CSP cells, as well as through homing of bone marrow-derived stem cells (BMC) to specific areas of myocardial injury and immunophenotypic conversion of BMC to adopt a CSP phenotype. We, therefore, conclude that following myocardial injury, cardiac progenitor cell populations are acutely depleted and are reconstituted to normal levels by both self-proliferation and selective homing of BMC. Understanding and enhancing such processes hold enormous potential for therapeutic myocardial regeneration.T issue-specific progenitor cell populations maintain the regenerative capacity of terminally differentiated organs, both under basal conditions and following local tissue injury. Side population (SP) cells, characterized by their intrinsic capacity to efflux Hoechst dye through ATP-binding cassette transporters, contribute to the long-term regenerative potential of hematopoietic and extrahematopoietic tissues. 1 Recently, we have demonstrated that cardiac SP (CSP) cells, immunophenotypically distinct from bone marrow (BM)-derived stem cells (BMC), are present in the adult heart and are capable of both biochemical and functional cardiomyogenic differentiation into mature cardiomyocytes, thereby identifying CSP as a distinct cardiac progenitor cell population. 2 Supplementation of cardiac progenitor cell pools after myocardial infarction (MI) with exogenous cells has been shown to improve ventricular function by regenerating myocardium and cardiac vasculature. [3][4][5] The response of endogenous CSP cells to myocardial injury, however, and the cellular mechanisms that maintain this endogenous cardiac progenitor cell pool under basal and after injury conditions remain unknown. We, therefore, serially assessed CSP pools in hearts following MI and determined the role of selfproliferation and BMC in reconstituting cardiac progenitor pools. Methods and MaterialsCSP were isolated from mouse hearts as described previously. 2 MI was performed in mice via permanent coronary ligation. 6 BM transplantation was performed in lethally irradiated mice using marrow isolated from C57bl/6-Tg(ACTbEGFP) mice. 7 All animals were obtained from The ...

Bones of contention: Marrow-derived cells in myocardial regeneration

“…My second point has to do with broadening the scope of this debate beyond just bone marrow, which I feel justified in doing since you invoked recent studies on reprogramming of somatic cells. My lab as well as many other well respected research groups have used selected c-kit+ cell populations derived from bone marrow as well as from other tissues that generate cells populations expressing various cardiogenic markers including those of cardiomyocytes following adoptive transfer to cardiomyopathically injured recipients [8][9][10][11][12]. While the process may be relatively inefficient at present, there is every reason to expect that the remarkable salutary effects mediated by adoptive transfer of stem cells in experimental animal models will readily be applied to translational therapy once underlying mechanisms are more fully understood.…”

Cardiac repair by stem cells

“…26 CSP are able to transform to cardiomyocytes if interaction (not implying cell fusion) with adult cardiomyocytes is allowed. CSP can be derived from BMC 27 (see below). Cells expressing the homeobox gene islet-1 (isl-1) are also present in the adult heart, although in small number and restricted to the right side.…”

“…32 Regarding CSP, it has been shown that, after AMI, BMC home specific areas of myocardial injury and convert to CSP phenotype. 27 On the other hand, independent clonal studies have demonstrated that adult marrow stromal cells can originate the so-called cardiomyogenic cells (CMG), which differentiate to cardiomyocytes. 6,33 Among BMC, the stromal cells, often also called mesenchymal stem cells (MSC), seem more plastic than the other cell types regarding multilineage differentiation.…”

“…6,27 In mouse heart, BMC accumulate selectively near the damaged area. 4,13 In chicken embryonic heart, injected BMC also migrate toward the lesion.…”

“…2,23 It must be remembered that at least some cardiac progenitor pools (CSP, CMG) can be refilled by circulating BMC. 27,33 ESC will need more time to enter into therapeutics, but this does not mean they are less important as an object of investigation. On the contrary, the study of proliferation and differentiation of ESC should inspire regenerative medicine.…”