Adult c-kitpos Cardiac Stem Cells Are Necessary and Sufficient for Functional Cardiac Regeneration and Repair

Abstract

The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage.

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…The dedifferentiation model for the cellular sources of cardiac repair/regeneration was supported by the fact that cardiac muscles mainly regenerate from pre-existing cardiomyocytes after injury in zebrafish [8,9] and mammals [10][11][12]. The stem cell/progenitor cell model for cardiac regeneration in mammals was also recognized by the existence of Sca1 + and c-Kit + cardiac stem cells in mice [13,14], while the transdifferentiation or lineage reprogramming model was proposed partly based on the ability of cardiac fibroblast transdifferentiation into myocytes upon induction by reprogramming factors or microRNA in mice [15][16][17] and reprogramming of embryonic atrial into ventricular myocytes after injury in zebrafish [18]. In spite of great efforts, the molecular mechanisms underlying heart regeneration remain incompletely understood.…”

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

“…18) Our results showed that large amounts of new CMs were generated in this process. However, we did not investigate the activation of cardiac stem cell-like populations, such as c-kit + , Sca1 + cells.6, [19][20][21] Studies have indicated that neonatal-derived cardiac stem cells have a strong regenerative ability when compared with adult-derived cardiac stem cells. 22,23) In our results, we also noticed that there are large numbers of CMs generated in the normal development of neonatal rat.…”

Concise Review: Mechanotransduction via p190RhoGAP Regulates a Switch Between Cardiomyogenic and Endothelial Lineages in Adult Cardiac Progenitors

“…Although the intrinsic capacity of heart to regenerate is limited, recent studies suggested a measureable turnover of cardiomyocytes, with yearly rates varying from 1% to 4%-10% or even higher [2,[15][16][17]. Emerging evidence suggests that the cardiac tissue does contain endogenous pool of multipotent stem cells, which are capable of differentiating into cardiomyocytes, endothelial cells, and smooth muscle cells, and that these progenitors are essential for cardiac repair and regeneration [18][19][20][21][22][23][24][25][26]. Furthermore, it has been recently established that cardiac cell positive for c-Kit, a common marker of multipotent stem-like cells (c-Kit 1 cells), is necessary and sufficient to regenerate and repair the heart [21].…”

“…Emerging evidence suggests that the cardiac tissue does contain endogenous pool of multipotent stem cells, which are capable of differentiating into cardiomyocytes, endothelial cells, and smooth muscle cells, and that these progenitors are essential for cardiac repair and regeneration [18][19][20][21][22][23][24][25][26]. Furthermore, it has been recently established that cardiac cell positive for c-Kit, a common marker of multipotent stem-like cells (c-Kit 1 cells), is necessary and sufficient to regenerate and repair the heart [21]. Cardiosphere-derived cells (CDCs), a heterogeneous collection of cells derived from adult heart tissue with substantial clinical promise [27], are thought to contain or generate a subpopulation of c-Kit 1 cells.…”