O decades. We have (facetiously) dubbed this construct the “string theory” of c-kitpos cardiac cells (in analogy towards the theory that has been proposed to explain the physical universe105) because it reconciles multifarious and from time to time apparently discrepant results. We have also cautioned against extrapolating studies of endogenous c-kitpos cells to those of exogenous (expanded) c-kitpos cells and vice versa. To D2 Receptor Modulator Formulation recapitulate, many lines of proof help the notion that c-kit is expressed in more than 1 fetal cardiac progenitor pool (i.e., each FHF and mesenchymally transitioning proepicardium and EPDCs), and that its expression will not define 1 certain myogenic precursor. C-kit expression inside these pools may perhaps differ not simply temporally and spatially all through cardiac development but additionally when it comes to absolute protein levels. The apparently conflicting results of research of endogenous c-kitpos cells may very well be explained by the existence of two populations of intermediate cardiac precursors, low and high c-kit expressers (ckitlow and c-kithigh). The former will be derived in the FHF, give rise to cardiomyocytes and smooth muscle cells, and are likely depleted during fetal cardiomyogenesis, hence not persisting within the adult heart; if they persist, they would most likely escape isolation by standard MACS. The latter would be derived from the proepicardium, display a mesenchymal phenotype, give rise to adventitial cells (like fibroblasts), smooth muscle cells, and endothelial cells, and persist within the adult heart, using a continuous cycle of epicardial cells undergoing EMT and migrating inward into the myocardium, specially in response to injury65-67, 106. These are probably the c-kitpos cells that happen to be isolated with MACS from adult myocardium. As a result of their postulated lower levels of c-kit expression, the former might not recombine efficiently in a Cre knock-in model like the van Berlo study91, therefore yielding an underestimation from the contributions of FHF c-kitlow progenitors towards the contractile compartment (myocytes and smooth muscle) through fetal development.Circ Res. Author manuscript; accessible in PMC 2016 March 27.Keith and BolliPageThis paradigm accounts both for the robust cardiomyocytic differentiation of c-kitpos intermediates reported by Wu et al in the course of development16 and for the not too long ago observed proclivity of endogenous c-kitpos cells to differentiate additional towards interstitial and vascular lineages and much less toward contracting myocytes reported by van Berlo et al18. Moreover, it illuminates the apparent paradox regarding the mechanism of action of exogenous c-kitpos cells isolated from adult hearts. Since MSCs are recognized to perform mainly via paracrine mechanisms23, 24, the recognition that exogenous postnatal c-kitpos cardiac cells resemble the phenotype of “traditional” MSCs delivers insights into the constant functional benefits afforded by these cells in spite of the paucity of their cardiomyocytic differentiation, and aids to reconcile the recent report that endogenous c-kitpos cells contribute minimally to restoring the cardiomyocyte compartment within the adult heart18 together with the exceptional therapeutic actions of exogenous ckitpos cells3. This paradigm does not exclude the possibility that an early c-kitpos intermediate phenotype of FHF progenitors may perhaps give rise to large numbers of cardiomyocytes, as was observed by Wu et al16. While the data reviewed above indirectly help our Bcl-2 Modulator custom synthesis theorem, the presence of.
