Journal of molecular and cellular cardiologyApr 21, 2026

Partial reprogramming with OSK helps heart muscle cells revert, divide, and supports natural heart repair after heart attack

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 22, 2026

Abstract

Transient overexpression of OSK (OCT4, SOX2, KLF4) leads to a dedifferentiated state in cardiomyocytes without c-Myc.

Myocardial infarction results in permanent loss of heart cells due to limited regeneration capacity.
OSK promotes a dedifferentiated state in heart cells, characterized by the disassembly of sarcomeres.
This dedifferentiation helps heart cells overcome barriers to cell division, leading to the formation of cells with high growth potential.
The approach enhances cardiac repair after myocardial infarction, indicating a novel strategy for treatment.
OSK does not directly cause heart cells to enter the cell cycle but primes them for regeneration.

Simplified

Myocardial infarction (MI) leads to irreversible loss of cardiomyocytes (CMs), owing to the limited regenerative capacity of the adult mammalian heart. Previous studies indicate that the Yamanaka factors (OSKM) can induce CM dedifferentiation and proliferation; however, the inclusion of the proto-oncogene c-Myc poses serious safety concerns for clinical translation. Here, we show that transient overexpression of OSK (OCT4, SOX2, KLF4)-without c-Myc-does not directly trigger CM cell-cycle re-entry. Instead, it initiates a dedifferentiated state marked by sarcomere disassembly. This OSK-induced priming overcomes the cytokinesis barrier in proliferating CMs both in vitro and in vivo, yielding mononuclear CMs with high proliferative potential and ultimately enhancing cardiac repair after MI. Our findings reveal that OSK promotes regeneration primarily by priming dedifferentiation and overcoming cytokinesis bottlenecks, rather than by directly inducing CM S-phase entry, and establish OSK as a novel, safer reprogramming-based strategy for the treatment of MI.

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Competing interests

Declaration of competing interest All the authors declared no competing interests.

PubMed

Partial reprogramming with OSK helps heart muscle cells revert, divide, and supports natural heart repair after heart attack

Abstract

Full Text

Funding

Competing interests

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