Key result
Active Erbb2 expression robustly drives cardiomyocyte proliferation and functional remodeling in preclinical models.
Why the study?
It is unclear whether the effects of various mitogenic pathways promoting cardiomyocyte proliferation are species-specific and how they compare in the same cardiac setting.
Constitutively active human Erbb2 robustly stimulates cardiomyocyte proliferation and functional remodeling in vitro via Erk signaling, suggesting a potential target for regenerative heart repair.
Human iPSC-CM model enables direct mitogen comparison; leaves open which pathways merit in vivo testing for post-MI repair.
Multiple mitogenic pathways capable of promoting mammalian cardiomyocyte (CM) proliferation have been identified as potential candidates for functional heart repair following myocardial infarction. However, it is unclear whether the effects of these mitogens are species-specific and how they directly compare in the same cardiac setting. Here, we examined how CM-specific lentiviral expression of various candidate mitogens affects human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) in vitro . In 2D-cultured CMs from both species, and in highly mature 3D-engineered cardiac tissues generated from NRVMs, a constitutively-active mutant form of the human gene Erbb2 (cahErbb2) was the most potent tested mitogen. Persistent expression of cahErbb2 induced CM proliferation, sarcomere loss, and remodeling of tissue structure and function, which were attenuated by small molecule inhibitors of Erk signaling. These results suggest transient activation of Erbb2/Erk axis in cardiomyocytes as a potential strategy for regenerative heart repair.
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Strash et al. (2020) studied Cardiomyocyte proliferation. Constitutively-active mutant form of the human gene Erbb2 (cahErbb2) vs. Control lentiviral vector or other mitogens (carErbb2, caCtnnb1, Ccnd2, caYap8SA) was evaluated on Cardiomyocyte proliferation (EdU incorporation and H3P expression). Lentiviral expression of a constitutively-active mutant form of human Erbb2 (cahErbb2) robustly induced cardiomyocyte proliferation, sarcomere loss, and functional remodeling in both rat and human cardiomyocytes.
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