4.8 Article

Human Erbb2-induced Erk activity robustly stimulates cycling and functional remodeling of rat and human cardiomyocytes

Journal

ELIFE
Volume 10, Issue -, Pages -

Publisher

eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.65512

Keywords

cardiomyocyte; engineered cardiac tissue; proliferation; iPSC; Erbb2; neonatal rat; Human; Rat

Categories

Funding

  1. National Institutes of Health [U01HL134764, R01HL132389, 5T32HD040372, 1F31HL156453]
  2. Foundation Leducq Transatlantic Networks of Excellence Program
  3. Duke University Translating Duke Health: Cardiovascular Health Initiative
  4. Foundation Leducq [15CVD03]

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The study identified a specific mutant form of the human Erbb2 gene as the most potent mitogen for promoting cardiomyocyte proliferation in both human induced pluripotent stem cell-derived CMs and neonatal rat ventricular myocytes in vitro. Activation of the Erbb2/Erk axis in cardiomyocytes was suggested as a potential strategy for regenerative heart repair, with the effects being attenuated by Erk signaling inhibitors.
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 CMs (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 CMs as a potential strategy for regenerative heart repair.

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