The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin

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Graphical abstractCardiomyocyte (CM) renewal in adult myocardial tissue in response to CM loss depends on resident endogenous cardiac stem/progenitor cells (eCSCs) activation and ensuing differentiation in new fully-functional CMs.The adult mammalian heart, including the human, is unable to regenerate segmental losses after myocardial infarction. This evidence has been widely and repeatedly used up-to-today to suggest that the myocardium, contrary to most adult tissues, lacks an endogenous stem cell population or more specifically a bona-fide cardiomyocyte-generating progenitor cell of biological significance. In the last 15 years, however, the field has slowly evolved from the dogma that no new cardiomyocytes were produced from shortly after birth to the present consensus that new cardiomyocytes are formed throughout lifespan. This endogenous regenerative potential increases after various forms of injury. Nevertheless, the degree/significance and more importantly the origin of adult new cardiomyocytes remains strongly disputed. Evidence from independent laboratories has shown that the adult myocardium harbours bona-fide tissue-specific cardiac stem cells (CSCs). Their transplantation and in situ activation have demonstrated the CSCs regenerative potential and have been used to develop regeneration protocols which in pre-clinical tests have shown to be effective in the prevention and treatment of heart failure. Recent reports purportedly tracking the c-kit+CSC’s fate using Cre/lox recombination in the mouse have challenged the existence and regenerative potential of the CSCs and have raised scepticism about their role in myocardial homeostasis and regeneration. The validity of these reports, however, is controversial because they failed to show that the experimental approach used is capable to both identify and tract the fate of the CSCs. Despite these serious shortcomings, in contraposition to the CSCs, these publications have proposed the proliferation of existing adult fully-matured cardiomyocytes as the relevant mechanism to explain cardiomyocyte renewal in the adult. This review critically ponders the available evidence showing that the adult mammalian heart possesses a definable myocyte-generating progenitor cell of biological significance. This endogenous regenerative potential is expected to provide the bases for novel approaches of myocardial repair in the near future.

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