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c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration

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Iolanda Aquila, Eleonora Cianflone, Mariangela Scalise, Fabiola Marino, Teresa Mancuso, Andrea Filardo, Andrew J. Smith, Donato Cappetta, Antonella De Angelis, Konrad Urbanek, Andrea M. Isidori, Michele Torella, Valter Agosti, Giuseppe Viglietto, Bernardo Nadal-Ginard, Georgina M. Ellison-Hughes, Daniele Torella

Original languageEnglish
Article number436
Number of pages19
JournalCell Death and Disease
Volume10
Early online date4 Jun 2019
DOIs
Publication statusPublished - 2019

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Abstract

An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kitpos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kitCre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitCreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitCreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitCreKIs severely affects CSCs myogenic potential. c-kitCreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitCreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitCreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.

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