Cardiac turnover and regeneration219c-kit-positive cardiac stem cells regulate physiological myocardial cell turnover and are not of bone marrow origin in the adult life

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Abstract

Background

Replenishment of adult mammalian cardiomyocytes is believed to be the progeny of the in situ activation of resident cardiac stem/progenitor cells (CSCs). Intriguingly, exercise training produces physiological growth of the myocardium encompassing a balanced formation of new myocytes as well as vascular cells. Thus, in the present study, we sought to assess whether new myocyte and vascular cell formation during exercise training is the direct progeny of the activation of endogenous resident c-kit-positive (c-kit-pos) CSCs. Also, we evaluated whether cardiac stem progenitor cells actually originate from circulating bone marrow derived cells as repeatedly hypothesized but never proven.

Methods

To ascertain a direct relationship between c-kit-pos CSCs and new myocardial cell generation, we released into the myocardium of male LacZ floxed-stop YFP mice a lentiviral vector carrying Cre-Recombinase under the control of the c-kit promoter (Lenti-c-kit/Cre). This strategy permanently labels with YFP only resident c-kit-pos CSCs and allows to track their cell fate. On the other hand, WT C57/BL6 mice were sub-lethally irradiated and their bone marrow reconstituted through the injection of singenic GFP-labeled bone marrow cells. Mice underwent a program of controlled swimming and were sacrificed at different time points over 28 days. Untrained mice acted as sedentary controls. To track new myocardial generation, BrdU was daily administered i.p..

Results

Physical exercise produced rapid activation of the myogenic and vasculogenic differentiation pathway in c-kit-pos CSCs during the 28 days swimming program, which was followed by an increased number of newly-formed myocytes and vascular cells/structures (BrdU-pos). Importantly, through the cre/lox recombination-based genetic fate-mapping strategy in vivo, we demonstrated that all new (BrdU-pos) myocyte formation and a significant fraction of new vascular cells during exercise training was the direct progeny of c-kit-pos CSC differentiation. Intriguingly, when GFP-pos/c-kit-pos cardiac cells were isolated from the chimeric bone marrow-transplanted animals, these cells did not show any of the fundamental properties of tissue specific cardiac stem/progenitor cells. Also, all new (BrdU-pos) myocytes in the trained chimeric mice were GFP-negative, disproving their derivation from bone marrow cells.

Conclusions

Physiologic cardiomyocyte turnover in the adult life is the direct progeny of the activation and ensuing differentiation of resident c-kit-pos CSCs. Importantly, resident CSC and cardiomyocyte replenishment are not of bone marrow origin during adulthood.

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