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

doi:10.1016/j.stemcr.2022.07.003

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 journal › Article › peer-review

17 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 language	English (US)
Pages (from-to)	2005-2022
Number of pages	18
Journal	Stem Cell Reports
Volume	17
Issue number	9
DOIs	https://doi.org/10.1016/j.stemcr.2022.07.003
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Garay, B. I., Givens, S., Abreu, P., Liu, M., Yücel, D., Baik, J., Stanis, N., Rothermel, T. M., Magli, A., Abrahante, J. E., Goloviznina, N. A., Soliman, H. A. N., Dhoke, N. R., Kyba, M., Alford, P. W., Dudley, S. C., van Berlo, J. H., Ogle, B., & Perlingeiro, R. R. C. (2022). Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes. Stem Cell Reports, 17(9), 2005-2022. https://doi.org/10.1016/j.stemcr.2022.07.003

Garay, BI, Givens, S, Abreu, P, Liu, M, Yücel, D, Baik, J, Stanis, N, Rothermel, TM, Magli, A, Abrahante, JE, Goloviznina, NA, Soliman, HAN, Dhoke, NR , Kyba, M , Alford, PW , Dudley, SC , van Berlo, JH , Ogle, B & Perlingeiro, RRC 2022, 'Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes', Stem Cell Reports, vol. 17, no. 9, pp. 2005-2022. https://doi.org/10.1016/j.stemcr.2022.07.003

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

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",

author = "Garay, {Bayardo I.} and Sophie Givens and Phablo Abreu and Man Liu and Doğacan Y{\"u}cel and June Baik and Noah Stanis and Rothermel, {Taylor M.} and Alessandro Magli and Abrahante, {Juan E.} and Goloviznina, {Natalya A.} and Soliman, {Hossam A.N.} and Dhoke, {Neha R.} and Michael Kyba and Alford, {Patrick W.} and Dudley, {Samuel C.} and {van Berlo}, {Jop H.} and Brenda Ogle and Perlingeiro, {Rita R.C.}",

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: {\textcopyright} 2022 The Author(s)",

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AU - Garay, Bayardo I.

AU - Givens, Sophie

AU - Abreu, Phablo

AU - Liu, Man

AU - Yücel, Doğacan

AU - Baik, June

AU - Stanis, Noah

AU - Rothermel, Taylor M.

AU - Magli, Alessandro

AU - Abrahante, Juan E.

AU - Goloviznina, Natalya A.

AU - Soliman, Hossam A.N.

AU - Dhoke, Neha R.

AU - Kyba, Michael

AU - Alford, Patrick W.

AU - Dudley, Samuel C.

AU - van Berlo, Jop H.

AU - Ogle, Brenda

AU - Perlingeiro, Rita R.C.

N1 - 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)

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Y1 - 2022/9/13

N2 - 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.

AB - 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.

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KW - PI3K-AKT

KW - calcium handling

KW - cardiomyocyte

KW - electrophysiology

KW - inhibitors

KW - maturation

KW - multinucleation

KW - pluripotent stem cells

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

Abstract

Bibliographical note

Keywords

UN SDGs

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

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

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Other files and links

Fingerprint

University Assets

Jeol JEM-1400Plus TEM

University Imaging Centers

Cite this