Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.

Autor:	Garay BI; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA., Givens S; Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA., Abreu P; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., Liu M; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., Yücel D; Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA., Baik J; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., Stanis N; Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Rothermel TM; Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Magli A; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., Abrahante JE; University of Minnesota Informatics Institute, Minneapolis, MN, USA., Goloviznina NA; Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA; LHI, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA., Soliman HAN; LHI, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA., Dhoke NR; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., Kyba M; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA; Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA; LHI, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA., Alford PW; Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Dudley SC Jr; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA., van Berlo JH; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA; Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA., Ogle B; Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA., Perlingeiro RRC; Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA; Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA. Electronic address: perli032@umn.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2022 Sep 13; Vol. 17 (9), pp. 2005-2022. Date of Electronic Publication: 2022 Aug 04.
DOI:	10.1016/j.stemcr.2022.07.003
Abstrakt:	Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery. Competing Interests: Conflicts of interest The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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