L Han (1,2,3), A Schneider (1,3), T Braun (1,2,3)

1: Max Planck Institute for heart and lung, Bad Nauheim, 61231, Germany; 2: Cardiac Pulmonary Institute; 3. DZHK

Irreversible cardiac fibrosis, cardiomyocyte (CM) death, and chronic dysfunction after myocardial infarction pose major global health challenges, with no curative treatments available currently. Regeneration of injured myocardium requires CM proliferation—a capacity largely lost in adult mammals. CM dedifferentiation has emerged as a key mechanism preceding proliferation, involving reversal to a juvenile-like state. Several genes and pathways have been shown to promote endogenous CM proliferation, typically following dedifferentiation.

In this study, we found that re-expression of bone morphogenetic protein 10 (BMP10) during postnatal CM development in mammals induces a dedifferentiation-like state, marked by fetal gene reactivation, sarcomere disassembly, and glycolytic reprogramming. BMP10 re-expression promotes cell cycle extension and enhanced CM proliferation under both physiological and myocardial infarction conditions. We further observed that effective CM proliferation requires the temporary disassembly of sarcomeric structures. With prolonged stimulation, CMs adapted and preserved cardiac function. However, reassembly of the contractile cytoskeleton was associated with loss of proliferative capacity, captured in our newly developed reversible system.

Despite its importance, CM dedifferentiation remains poorly defined due to a lack of robust molecular markers and limited mechanistic insight. To address this, we also established an intersectional genetic approach (ISGA) enabling specific labeling of immature or dedifferentiated CMs using two distinct recombinases driven by Tnni3 and ACTA2 promotors. This system allows us for targeted BMP10 overexpression within this cell population.