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 - Funding Information:
We thank the ISMMS Flow Cytometry Core (Christopher Bare and Xuqiang Qiao), Microscopy Core (William Jansen, Allison Sowa, Esperanza Agullo Pascual, and Shilpa Dilipkumar), Biorepository and Pathology Core (Michael Donovan, Olha Fedorshyn, and Anastasiya Dzuhun), Stem Cell Shared Resource facilities and the NYU Genome Technology Center (Adriana Heguy and Sitharam Ramaswami) for their technical assistance. Drs. Jinqi Gong and Jaehee Shim provided assistance with calcium transient measurements and analysis. Dr. Irene C. Turnbull is ethically opposed to research involving human embryonic stem cells and tissues derived from elective abortions; Dr. Turnbull performed the functional measurements and data analysis of human engineered tissues and instructed on use of MatFiber to quantify myofibril organization. We thank her for her invaluable contributions to this project. This work was funded by NIH/NHLBI R01HL134956 and R56HL128646 and The Mindich Child Health and Development Institute seed funding to N.C.D. N.M.W. was supported by a Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG). N.M.W. and N.C.D. designed and performed experiments and analyzed data. D.S. D.T. A.M. and K.C. analyzed RNA-seq and ATAC-seq data. D.M.G. B.S. P.D.-K. E.L. S.R. R.D. M.N.S. R.S. K.B. S.I. J.M. J.E.C. E.A.S. H.I. and S.A. performed experiments and data analysis. A.H. and T.E. shared expertise and materials for generating EHTs from hPSC-CMs. N.M.W. and N.C.D. wrote the manuscript with input from all authors. The authors declare no competing interest. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.
Funding Information:
We thank the ISMMS Flow Cytometry Core (Christopher Bare and Xuqiang Qiao), Microscopy Core (William Jansen, Allison Sowa, Esperanza Agullo Pascual, and Shilpa Dilipkumar), Biorepository and Pathology Core (Michael Donovan, Olha Fedorshyn, and Anastasiya Dzuhun), Stem Cell Shared Resource facilities and the NYU Genome Technology Center (Adriana Heguy and Sitharam Ramaswami) for their technical assistance. Drs. Jinqi Gong and Jaehee Shim provided assistance with calcium transient measurements and analysis. Dr. Irene C. Turnbull is ethically opposed to research involving human embryonic stem cells and tissues derived from elective abortions; Dr. Turnbull performed the functional measurements and data analysis of human engineered tissues and instructed on use of MatFiber to quantify myofibril organization. We thank her for her invaluable contributions to this project. This work was funded by NIH / NHLBI R01HL134956 and R56HL128646 and The Mindich Child Health and Development Institute seed funding to N.C.D. N.M.W. was supported by a Training Program in Stem Cell Biology fellowship from the New York State Department of Health ( NYSTEM-C32561GG ).
Publisher Copyright:
© 2022 Elsevier Inc.
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 - PPAR signaling
KW - cardiac maturation
KW - fatty acid oxidation
KW - metabolism
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85127475461&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2022.02.011
DO - 10.1016/j.stem.2022.02.011
M3 - Article
C2 - 35325615
AN - SCOPUS:85127475461
SN - 1934-5909
VL - 29
SP - 559-576.e7
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 4
ER -