Identity Crisis for Regenerative Cardiac cKit+ Cells
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The concept that cardiac-derived cKit+ cells can regenerate the injured adult heart by transdifferentiating into functioning cardiomyocytes was proposed 14 years ago although it remains controversial because of negative data from multiple independent laboratories. Irreproducibility of cardiac cKit+ cell studies was attributed to the differences in cell isolation, selection, and expansion before in vivo application. This Viewpoint will discuss recent results that again change the formula for how cardiac cKit+ cells must be isolated and processed to be cardiomyogenic, as well as discuss the uncertain in vivo relevance of cKit+ cells as putative cardiomyocyte-producing stem cells.
Introduction to the Cardiac Regeneration cKit+ Cell Controversy
The regenerative and myogenic potential of cKit+ cardiac-resident stem cells (CSCs) remains a dominant and contentious topic. In vitro expanded cKit+ CSCs were originally described 14 years ago as a source for robust new myocyte generation when injected directly into the adult rodent heart after myocardial infarction,1 and although some laboratories have confirmed the basic principle, the magnitude of the effect remains unclear.2 More recently, Ellison et al3 showed that a clonal cKit+ cell line derived from a population of cardiac CD45− cKit+ cells was capable of widely regenerating isoproterenol-injured adult rodent hearts with abundant new cardiomyocytes, after simple tail vein infusion. However, many independent laboratories reported that adult cardiac-derived cKit+ cells did not generate appreciable new cardiomyocytes when directly injected back into the injured rat or mouse heart.4–7
In addition to controversies surrounding the regenerative potential of injected cKit+ cell formulations, until recently the field has not attempted to directly address if endogenous cardiac cKit+ cells are true cardiomyocyte producing stem cells of meaningful significance.8 …