PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes
Standard
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, Jahrgang 29, Nr. 4, 07.04.2022, S. 559-576.e7.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
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 -