What we know about cardiomyocyte dedifferentiation

Abstract

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IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair

“…With our accumulating knowledge about proliferation of pre-existing cardiomyocytes as a key origin of new cardiomyocytes, the cellular and molecular regulation of cardiac dedifferentiation during heart regeneration has been informatively pursued [ 9 ]. Cellular dedifferentiation is a process by which mature cells revert from their differentiated state back to a less-differentiated state to gain progenitor properties [ 3 ], characterized by a wide range of changes at the levels of gene expression, proteins, intuitive alternation of morphology and function, arguably more accurately called cellular plasticity [ 46 ].…”

“…Therefore, it is likely that IL-6-induced adaptive dedifferentiation enforces cardiomyocytes into an intermediate, hibernating state for better survival in an unfavorable ischemic environment and, in meantime, small fraction of the dedifferentiated cells concomitantly enter cell cycle to proliferate (Fig. 7 ), a reminiscent of robust cardiac regeneration found in zebrafish and neonates [ 9 ].…”

“…In the regenerative non-mammalians such as newt, for instance, dedifferentiation of internal stump cells in response to undefined signals is an essential step to form a mass of progenitor and pluripotent cells, known as the regeneration blastema, in the early limb regenerate [ 7 ]. In the context of myocardial repair in lower vertebrates, such as zebrafish, or neonatal mice in which where cardiac proliferation is fully functional in response to acute injury [ 6 , 8 ], formation of new cardiomyocytes is found to begin with the initial step of cardiac dedifferentiation followed by mitotic cell division, suggesting that cellular dedifferentiation is a pro-regenerative prerequisite for tissue renewal [ 9 ]. Therefore, unraveling the regulatory mechanism(s) that governs dedifferentiation progression is fundamentally imperative to understand how cell cycles in adult mammalian cardiomyocyte are regulated and to develop therapeutical strategies that stimulate turnover of cardiomyocytes and promote cardiac regeneration.…”

“…Induction of cardiac dedifferential process involves multiple regulatory molecules, including microRNA, transcriptional factors, and paracrine cytokines [ 9 ]. Interleukin-6 (IL-6) family members are known to be important regulators that orchestrate dedifferential process during heart regeneration [ 10 ].…”

“…Moreover, the role of IL-6/STAT3 cascade in adult mammalian is also implicitly exemplified in a self-limited model of myocarditis in which compensatory proliferation of pre-existing cardiomyocytes was triggered by robust activation of STAT3 activity [ 15 ]. Thus, IL-6 signaling may act as one of the potent regulators of cardiac dedifferential process that has been proven as an essential step to initiate mitotic and proliferative activity in cardiomyocytes [ 9 ].…”