TISSUE-SPECIFIC STEM CELLS Increased Mitotic Rate Coincident with Transient Telomere Lengthening Resulting from Pim-1 Overexpression in Cardiac Progenitor Cells

Cardiac regeneration following myocardial infarction rests with the potential of c-kit1 cardiac progenitor cells (CPCs) to repopulate damaged myocardium. The ability of CPCs to reconstitute the heart is restricted by patient age and disease progression. Increasing CPC proliferation, telomere length, and survival will improve the ability of autologous CPCs to be successful in myocardial regenera-tion. Prior studies have demonstrated enhancement of myocardial regeneration by engineering CPCs to express Pim-1 kinase, but cellular and molecular mechanisms for Pim-1-mediated effects on CPCs remain obscure. We find CPCs rapidly expand following overexpression of cardio-protective kinase Pim-1 (CPCeP), however, increases in mitotic rate are short-lived as late passage CPCePs proliferate similar to control CPCs. Telomere elongation consistent with a young phenotype is observed following Pim-1 modification of CPCeP; in addition, telomere elon-gation coincides with increased telomerase expression and activity. Interestingly, telomere length and telomerase activity normalize after several rounds of passaging, consistent with the ability of Pim-1 to transiently increase mitosis without resultant oncogenic transformation. Accel-erating mitosis in CPCeP without immortalization repre-sents a novel strategy to expand the CPC population in order to improve their therapeutic efficacy. STEM CELLS 2012;30:2512–2522 Disclosure of potential conflicts of interest is found at the end of this article