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

Nadeera M. Wickramasinghe, David Sachs, Bhavana Shewale, David M. Gonzalez, Priyanka Dhanan-Krishnan, Denis Torre, Elizabeth LaMarca, Serena Raimo, Rafael Dariolli, Madhavika N. Serasinghe, Joshua Mayourian, Robert Sebra, Kristin Beaumont, Srinivas Iyengar, Deborah L. French, Arne Hansen, Thomas Eschenhagen, Jerry E. Chipuk, Eric A. Sobie, Adam JacobsSchahram Akbarian, Harry Ischiropoulos, Avi Ma'ayan, Sander M. Houten, Kevin Costa, Nicole C. Dubois

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)559-576.e7
JournalCell Stem Cell
Volume29
Issue number4
DOIs
StatePublished - 7 Apr 2022

Keywords

  • PPAR signaling
  • cardiac maturation
  • fatty acid oxidation
  • metabolism
  • stem cells

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