Human Erbb2-induced Erk activity robustly stimulates cycling and functional remodeling of rat and human cardiomyocytes
- Duke University, United States
Abstract
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 cardiomyocytes as a potential strategy for regenerative heart repair.
Data availability
All data generated or analyzed during this study are included in the manuscript and supplemental source data file for all Figures.
Article and author information
Author details
Funding
National Institutes of Health (Research Project Cooperative Agreement,U01HL134764)
- Nenad Bursac
National Institutes of Health (Research Project Grant,R01HL132389)
- Nenad Bursac
National Institutes of Health (Training Grant,5T32HD040372)
- Nicholas Strash
- Sophia DeLuca
Foundation Leducq (Transatlantic Networks of Excellence Program,15CVD03)
- Nenad Bursac
Duke University (Translating Duke Health: Cardiovascular Health Initiative)
- Nenad Bursac
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#A100-18-04) at Duke University.
Copyright
© 2021, Strash et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Human Erbb2-induced Erk activity robustly stimulates cycling and functional remodeling of rat and human cardiomyocytes
eLife 10:e65512.
https://doi.org/10.7554/eLife.65512
