“String Theory” of c-kit ^pos Cardiac Cells

Abstract

Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kitpos cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have dubbed this conceptual construct “string theory of c-kitpos cardiac cells” because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C-kitpos cells derived from the first heart field (FHF) exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kitpos cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype, and are capable of contributing significantly only to non-myocytic lineages (fibroblasts, smooth muscle cells, endothelial cells). If these two populations (FHF and proepicardium) express different levels of c-kit, the cardiomyogenic potential of FHF progenitors might be reconciled with recent results of c-kitpos cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, non-cardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c-kitpos cell administration to ischemically damaged hearts despite the observed paucity of cardiomyogenic differentiation of these cells.

Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit + Lineages in the Heart

“…This finding led the authors to conclude that cKit + cardiac cells “ may be dedicated vascular endothelial progenitor cells…[not] capable of regenerating the heart with new contracting myocardium to a physiologically meaningful extent ” 11 . However, since cKit expression occurs in several cardiac and extra-cardiac cell lineages 27 , the role and identity of cardiac cKit + cells remained elusive. Do the endothelial cells and cardiomyocytes arise from the same cKit -expressing lineage, or are there multiple cKit + lineages in the heart?…”

“…Do the endothelial cells and cardiomyocytes arise from the same cKit -expressing lineage, or are there multiple cKit + lineages in the heart? 27 Why do cKit + cells differentiate into far fewer cardiomyocytes than endothelium? Are they bona fide cardiovascular progenitors or do they represent non-cardiomyogenic cells that stochastically (trans)differentiate into myocardium?…”

c-kit + Cardiac Stem Cells

“…Ex vivo manipulation of this cardiac stem cell population unequivocally has demonstrated the repair potential of these cells following adoptive transfer in pathological heart tissue in a variety of small 2 and large animal models 3 . That being said, the controversy has been the true identity of a putative cardiac stem cell as recent studies have shown that this cell in question does not have significant cardiomyocyte forming potential and although it may have exogenous repair processes, its endogenous repair potential is not robust 4 . The presented notion in 2003 was that the tyrosine kinase protein CD117 or c-kit was a bona fide marker to identify and study resident cardiac stem cells and these cells were an endogenous cardiac precursor cell (CPC) in the adult heart 1 .…”

“…It is critical to point out that all of these studies do not take away from studies explicitly showing that adoptive transfer of exogenously expanded and maintained c-kit+ CPCs can restore cardiac function in a damaged heart as a consequence of forming cardiomyocytes, endothelial and smooth muscle cells along with the ability to release paracrine mediators at the site of injury 4, 16 . The well-documented efficacy of exogenous CPCs and the recent availability of these novel lineage tracing mice models provided the perfect opportunity to develop a system assessing exogenous CPCs ability to form cardiac lineages to endogenous c-kit precursors.…”

“…However, most importantly, since the first identification of this adult c-kit+ CPC population over a decade ago, a plethora of studies have either showed direct cardiac regeneration by CPC transplantation or enhancement of cardiac function due to activation of resident c-kit+ cells via paracrine/autocrine mechanisms 4, 16 . Exciting pre-clinical results formed the basis of a recently conducted phase 1 clinical trial designed to examine the safety and feasibility of c-kit+ CSCs for treatment of patients with heart failure 19 , and a new study has been initiated studying a combination of c-kit CPCs and bone marrow-derived stem cells 20 .…”