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PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

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PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes. / Wickramasinghe, Nadeera M; Sachs, David; Shewale, Bhavana; Gonzalez, David M; Dhanan-Krishnan, Priyanka; Torre, Denis; LaMarca, Elizabeth; Raimo, Serena; Dariolli, Rafael; Serasinghe, Madhavika N; Mayourian, Joshua; Sebra, Robert; Beaumont, Kristin; Iyengar, Srinivas; French, Deborah L; Hansen, Arne; Eschenhagen, Thomas; Chipuk, Jerry E; Sobie, Eric A; Jacobs, Adam; Akbarian, Schahram; Ischiropoulos, Harry; Ma'ayan, Avi; Houten, Sander M; Costa, Kevin; Dubois, Nicole C.

In: CELL STEM CELL, Vol. 29, No. 4, 07.04.2022, p. 559-576.e7.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wickramasinghe, NM, Sachs, D, Shewale, B, Gonzalez, DM, Dhanan-Krishnan, P, Torre, D, LaMarca, E, Raimo, S, Dariolli, R, Serasinghe, MN, Mayourian, J, Sebra, R, Beaumont, K, Iyengar, S, French, DL, Hansen, A, Eschenhagen, T, Chipuk, JE, Sobie, EA, Jacobs, A, Akbarian, S, Ischiropoulos, H, Ma'ayan, A, Houten, SM, Costa, K & Dubois, NC 2022, 'PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes', CELL STEM CELL, vol. 29, no. 4, pp. 559-576.e7. https://doi.org/10.1016/j.stem.2022.02.011

APA

Wickramasinghe, N. M., Sachs, D., Shewale, B., Gonzalez, D. M., Dhanan-Krishnan, P., Torre, D., LaMarca, E., Raimo, S., Dariolli, R., Serasinghe, M. N., Mayourian, J., Sebra, R., Beaumont, K., Iyengar, S., French, D. L., Hansen, A., Eschenhagen, T., Chipuk, J. E., Sobie, E. A., ... Dubois, N. C. (2022). PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes. CELL STEM CELL, 29(4), 559-576.e7. https://doi.org/10.1016/j.stem.2022.02.011

Vancouver

Wickramasinghe NM, Sachs D, Shewale B, Gonzalez DM, Dhanan-Krishnan P, Torre D et al. PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes. CELL STEM CELL. 2022 Apr 7;29(4):559-576.e7. https://doi.org/10.1016/j.stem.2022.02.011

Bibtex

@article{3e0d33b29d1d4b06b395629f864899b5,
title = "PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes",
abstract = "Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.",
keywords = "Cell Differentiation, Humans, Induced Pluripotent Stem Cells/metabolism, Myocytes, Cardiac/metabolism, PPAR delta/metabolism, Pluripotent Stem Cells",
author = "Wickramasinghe, {Nadeera M} and David Sachs and Bhavana Shewale and Gonzalez, {David M} and Priyanka Dhanan-Krishnan and Denis Torre and Elizabeth LaMarca and Serena Raimo and Rafael Dariolli and Serasinghe, {Madhavika N} and Joshua Mayourian and Robert Sebra and Kristin Beaumont and Srinivas Iyengar and French, {Deborah L} and Arne Hansen and Thomas Eschenhagen and Chipuk, {Jerry E} and Sobie, {Eric A} and Adam Jacobs and Schahram Akbarian and Harry Ischiropoulos and Avi Ma'ayan and Houten, {Sander M} and Kevin Costa and Dubois, {Nicole C}",
note = "Copyright {\textcopyright} 2022 Elsevier Inc. All rights reserved.",
year = "2022",
month = apr,
day = "7",
doi = "10.1016/j.stem.2022.02.011",
language = "English",
volume = "29",
pages = "559--576.e7",
journal = "CELL STEM CELL",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

AU - Wickramasinghe, Nadeera M

AU - Sachs, David

AU - Shewale, Bhavana

AU - Gonzalez, David M

AU - Dhanan-Krishnan, Priyanka

AU - Torre, Denis

AU - LaMarca, Elizabeth

AU - Raimo, Serena

AU - Dariolli, Rafael

AU - Serasinghe, Madhavika N

AU - Mayourian, Joshua

AU - Sebra, Robert

AU - Beaumont, Kristin

AU - Iyengar, Srinivas

AU - French, Deborah L

AU - Hansen, Arne

AU - Eschenhagen, Thomas

AU - Chipuk, Jerry E

AU - Sobie, Eric A

AU - Jacobs, Adam

AU - Akbarian, Schahram

AU - Ischiropoulos, Harry

AU - Ma'ayan, Avi

AU - Houten, Sander M

AU - Costa, Kevin

AU - Dubois, Nicole C

N1 - Copyright © 2022 Elsevier Inc. All rights reserved.

PY - 2022/4/7

Y1 - 2022/4/7

N2 - Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.

AB - Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.

KW - Cell Differentiation

KW - Humans

KW - Induced Pluripotent Stem Cells/metabolism

KW - Myocytes, Cardiac/metabolism

KW - PPAR delta/metabolism

KW - Pluripotent Stem Cells

U2 - 10.1016/j.stem.2022.02.011

DO - 10.1016/j.stem.2022.02.011

M3 - SCORING: Journal article

C2 - 35325615

VL - 29

SP - 559-576.e7

JO - CELL STEM CELL

JF - CELL STEM CELL

SN - 1934-5909

IS - 4

ER -