O decades. We have (facetiously) dubbed this construct the “string theory” of c-kitpos cardiac cells (in analogy for the theory that has been proposed to clarify the physical universe105) because it reconciles multifarious and sometimes apparently discrepant benefits. We’ve got also cautioned against extrapolating studies of endogenous c-kitpos cells to these of exogenous (expanded) c-kitpos cells and vice versa. To recapitulate, various lines of evidence UCH Proteins Storage & Stability support the notion that c-kit is expressed in more than a single fetal cardiac progenitor pool (i.e., each FHF and mesenchymally transitioning proepicardium and EPDCs), and that its expression does not define one certain myogenic precursor. C-kit expression inside these pools could differ not just temporally and spatially all through cardiac development but in addition with regards to absolute protein levels. The apparently conflicting benefits of studies 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 would be derived from the FHF, give rise to cardiomyocytes and smooth muscle cells, and are most likely depleted throughout fetal cardiomyogenesis, therefore not persisting inside the adult heart; if they persist, they would likely escape isolation by conventional MACS. The latter would be derived from the proepicardium, show a mesenchymal phenotype, give rise to adventitial cells (like fibroblasts), smooth muscle cells, and endothelial cells, and persist within the adult heart, having a continuous cycle of epicardial cells undergoing EMT and migrating inward into the myocardium, especially in response to injury65-67, 106. They are probably the c-kitpos cells which can be RSV G proteins Species isolated with MACS from adult myocardium. Because of their postulated lower levels of c-kit expression, the former may not recombine effectively in a Cre knock-in model for instance the van Berlo study91, as a result yielding an underestimation of the contributions of FHF c-kitlow progenitors towards the contractile compartment (myocytes and smooth muscle) through fetal improvement.Circ Res. Author manuscript; accessible in PMC 2016 March 27.Keith and BolliPageThis paradigm accounts each for the robust cardiomyocytic differentiation of c-kitpos intermediates reported by Wu et al during development16 and for the not too long ago observed proclivity of endogenous c-kitpos cells to differentiate a lot more towards interstitial and vascular lineages and significantly less toward contracting myocytes reported by van Berlo et al18. In addition, it illuminates the apparent paradox concerning the mechanism of action of exogenous c-kitpos cells isolated from adult hearts. Since MSCs are identified to function primarily by means of paracrine mechanisms23, 24, the recognition that exogenous postnatal c-kitpos cardiac cells resemble the phenotype of “traditional” MSCs offers insights into the consistent 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 remarkable therapeutic actions of exogenous ckitpos cells3. This paradigm will not exclude the possibility that an early c-kitpos intermediate phenotype of FHF progenitors might give rise to substantial numbers of cardiomyocytes, as was observed by Wu et al16. Although the data reviewed above indirectly support our theorem, the presence of.
