美国西奈山伊坎医学院Nicole C. Dubois研究团队发现,PPARdelta的激活诱导人类多能干细胞衍生的心肌细胞的代谢和收缩性成熟。该研究于2022年3月23日在线发表于国际一流学术期刊《细胞—干细胞》。
Author: 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 Jacobs, Schahram Akbarian, Harry Ischiropoulos, Avi Ma’ayan, Sander M. Houten, Kevin Costa, Nicole C. Dubois
Issue&Volume: 2022-03-23
Abstract: Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunityto study human heart development and disease, but they are functionally and structurallyimmature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathwaymodulations. Specifically, we find that peroxisome-proliferator-associated receptor(PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specificmanner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta(PPARd) activation efficiently upregulates the gene regulatory networks underlyingFAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristaeformation, 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 cardiacmaturation program but, when combined with PPARd activation, still enhances oxidativemetabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMsand identify a role for PPARd signaling in inducing the metabolic switch from glycolysisto FAO in hPSC-CMs.
DOI: 10.1016/j.stem.2022.02.011
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00097-2
Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
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