Are Resident c-Kit ⁺ Cardiac Stem Cells Really All That Are Needed to Mend a Broken Heart?

Abstract

he ability of the heart to regenerate through new myocyte formation is a subject of intense investigation. Here we will discuss a provocative new publication from Nadal-Ginard and Torella and colleagues where they report that c-kit resident cardiac stem cells are necessary and sufficient to explain cardiac regeneration fully.Nadal-Ginard and Torella and colleagues have provided yet another exciting installment in the evolving cardiac regeneration and stem cell saga. The ongoing debate centers on if and how the normal adult mammalian heart renews its myocyte pool and if and how new myocytes are generated when diseases induce myocyte death. Their recently published article 1 provides supportive evidence that c-kit-marked resident cardiac stem cells (CSCs) are both necessary and sufficient for cardiac regeneration, and that the differentiation of CSCs into cardiac myocytes constitutes the primary mechanism for cellular replacement following diffuse, isoproterenol (ISO)-induced injury to the heart. Although many of the approaches and conclusions put forth are already represented in the literature, the unique aspects of this report are the injury model used as well as the simply overwhelming amount of supportive experimentation presented. However, as in any provocative ongoing scientific saga, new results engender skepticism and lead to new questions that can only be answered by additional studies from other groups.In the recent past, 2 diametrically opposed views have emerged as to whether the heart regenerates after cardiac injury by forming new myocytes. One group 2-6 has presented strong data that the heart is a highly malleable organ that is capable of near-complete regeneration, although the cell source responsible for this regenerative potential varies from the myocytes themselves, to c-kit-positive bone marrow cells, c-kit-positive resident CSCs, cardiospheres, resident fibroblasts, or tissue residence mesenchymal stem cells of various markers. The other group, 6-8 with polar opposite views, has also published a number of articles providing equally strong data that the absolute quantity of cellular replacement monitored in the heart over time or with injury is below a biologically meaningful threshold. Members of this latter camp have also suggested that CSCs (c-kit-positive or otherwise) are not appreciably involved in contributing to the formation of new myocytes in the myocardium. 7,8 The reasons for such discordant results remain unclear, although the new report by Nadal-Ginard and Torella and colleagues adds significant new data to this debate. In this Commentary, we try our best to not take sides in this debate. Instead, we try to evaluate the data presented in this new report carefully with no inherent predilection for either group.Nadal-Ginard and Torella and colleagues used a relatively unique model of cardiac injury that involves a single injection of ISO in the rat at 5 mg/kg and 200 mg/kg in the mouse, which causes diffuse killing of myocytes primarily within the endocardium and apex of the left v...

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Arguments focus mainly on the inherent limitations of the respective CRE-based lineage-tracing strategies, including the possibility of precocious reexpression of the transgenic Kit-CRE alleles in mature cardiomyocytes, and also the possibility of abnormal progenitor phenotypes in Kit-CRE knock-in mice (Molkentin and Houser, 2013;Nadal-Ginard et al, 2014;Torella et al, 2014). In an attempt to reconcile contrasting findings, Bolli and colleagues proposed that populations of KIT high and KIT low progenitors with differing origins and lineage potentialities might co-exist in the adult heart, and that only KIT high cells, possibly an epicardial subfraction, are marked by the Kit-CRE knock-in lineage-tracing tools of van Berlo et al (Keith and Bolli, 2015).…”

How to make a cardiomyocyte

“…There is an ongoing debate fuelled by contradictory studies as to whether c-Kit + cardiac stem cells (CSC) exist and whether they can give rise to cardiomyocytes (Beltrami et al, 2003;Ellison et al, 2013;Jesty et al, 2012;van Berlo et al, 2014;Zaruba et al, 2010). The observed discrepancies could be due to different experimental methodologies (for further discussion see Molkentin and Houser, 2013;Molkentin and Houser, 2014;Nadal-Ginard et al, 2014;Torella et al, 2014). As c-Kit is a relatively ubiquitous marker (including endothelial, hematopoietic, tissue monocytes), its expression alone is insufficient to define a specific c-Kit + cell population (Smith et al, 2014).…”

Recent Developments in Cardiovascular Stem Cells

“…Even the identity of the resident CPCs remains unsettled. [39][40][41][42][43] Resident cells expressing the c-kit antigen but not markers of the hematopoietic or mast cells are considered bona fide CPCs sufficient and necessary to repair the damaged myocardium. 40,44 And yet, genetic fate mapping experiments have shown minimal contribution of the c-kit + cells to cardiac myogenesis.…”