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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
2022-03-27 16:15
来源：小柯机器人

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》。

通过代谢途径的调节，研究人员诱导了人类多能干细胞衍生的心肌细胞（hPSC-CM）的有效成熟。具体来说，研究人员发现过氧化物酶体相关受体（PPAR）信号以一种亚型特异性的方式调节糖酵解和脂肪酸氧化（FAO）。虽然PPARalpha（PPARa）是hPSC-CMs中最活跃的异构体，但PPARdelta（PPARd）的激活有效地上调了FAO的基因调控网络，增加了线粒体和过氧化物酶体的含量，增强了线粒体嵴的形成，并提高了FAO的通量。
 
PPARd的激活进一步增加了双核，增强了肌纤维的组织，并改善了收缩性。瞬时乳酸暴露（经常用于hPSC-CM的纯化）能够诱导一个独立的心脏成熟程序，但当与PPARd激活相结合时，仍然增强了氧化代谢。总之，研究人员报道了hPSC-CM的多种代谢修饰，并确定了PPARd信号在诱导hPSC-CM从糖酵解到FAO代谢转换中的作用。
 
据介绍，PSC-CM为研究人类心脏发育和疾病提供了前所未有的机会，但它们在功能和结构上都不成熟。
 
附：英文原文
 
Title: PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem-cell-derived cardiomyocytes

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：25.269
官方网址：https://www.cell.com/cell-stem-cell/home
投稿链接：https://www.editorialmanager.com/cell-stem-cell/default.aspx


本期文章：《细胞—干细胞》：Online/在线发表

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