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

Bayardo I Garay; Sophie Givens; Phablo Abreu; Man Liu; Doğacan Yücel; June Baik; Noah Stanis; Taylor M Rothermel; Alessandro Magli; Juan E Abrahante; Natalya A Goloviznina; Hossam A N Soliman; Neha R Dhoke; Michael Kyba; Patrick W Alford; Samuel C Dudley Jr; Jop H van Berlo; Brenda Ogle; Rita R C Perlingeiro

doi:10.1016/j.stemcr.2022.07.003

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

Stem Cell Reports. 2022 Sep 13;17(9):2005-2022. doi: 10.1016/j.stemcr.2022.07.003. Epub 2022 Aug 4.

Authors

Bayardo I Garay¹, Sophie Givens², Phablo Abreu³, Man Liu³, Doğacan Yücel⁴, June Baik³, Noah Stanis⁵, Taylor M Rothermel⁵, Alessandro Magli³, Juan E Abrahante⁶, Natalya A Goloviznina⁷, Hossam A N Soliman⁸, Neha R Dhoke³, Michael Kyba⁹, Patrick W Alford⁵, Samuel C Dudley Jr³, Jop H van Berlo¹⁰, Brenda Ogle², Rita R C Perlingeiro¹¹

Affiliations

¹ Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
² Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
³ Lillehei Heart Institute (LHI), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
⁴ Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
⁵ Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.
⁶ University of Minnesota Informatics Institute, Minneapolis, MN, USA.
⁷ Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA; LHI, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
⁸ LHI, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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.

Abstract

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.

Keywords: MAPK; PI3K-AKT; calcium handling; cardiomyocyte; electrophysiology; inhibitors; maturation; multinucleation; pluripotent stem cells.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / physiology
Cells, Cultured
Humans
Induced Pluripotent Stem Cells* / metabolism
Infant, Newborn
Myocytes, Cardiac / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism

Substances

Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding