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, Jop H. van Berlo, Brenda Ogle, Rita R.C. Perlingeiro

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2005-2022
Number of pages18
JournalStem Cell Reports
Volume17
Issue number9
DOIs
StatePublished - Sep 13 2022

Bibliographical note

Funding Information:
This project was supported by National Institutes of Health ( NIH ) grants R01 AR071439 and AR078571 , (R.R.C.P.), R01 HL104025 and HL106592 (S.C.D.), and R01 HL155993 (J.H.v.B.); National Heart, Lung, and Blood Institute ( NHLBI ) grants R01 HL137204 (B.O.), R01 AR055685 (M.K.), and T32 HL144472-01A1 (J.B.); the National Science Foundation ( NSF ) Graduate Research Fellowship Program (GRFP) (S.G.) and grant CMMI-1553255 (P.W.A.); and predoctoral fellowship from the American Heart Association (T.R.). B.I.G. was supported by NHLBI grant F30 HL151138 and National Institute of General Medical Sciences ( NIGMS ) grant T32 GM008244 . This project also received seed funds from the University of Minnesota Lillehei Heart Institute (R.R.C.P.) and the Institute for Engineering in Medicine (IEM) Group Grant (B.O.). We give special thanks to Cynthia Faraday for her support with graphic design. This work was also supported by the resources and staff at the University of Minnesota University Imaging Centers (UIC) (grant SCR_020997 ). We thank Mary Brown for assistance with T-tubule filament tracing and Gail Celio for support with transmission electron microscopy.

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • MAPK
  • PI3K-AKT
  • calcium handling
  • cardiomyocyte
  • electrophysiology
  • inhibitors
  • maturation
  • multinucleation
  • pluripotent stem cells

PubMed: MeSH publication types

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

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