Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation.

Autor: Biermann M; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Cai W; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Lang D; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Hermsen J; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Profio L; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Zhou Y; Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA., Czirok A; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA., Isai DG; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA., Napiwocki BN; Department of Engineering Physics, University of Wisconsin-Madison, Madison, Wisconsin., Rodriguez AM; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Brown ME; Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA., Woon MT; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Shao A; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Han T; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Park D; Department of Virology, Harvard University, Boston, Massachusetts, USA., Hacker TA; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Crone WC; Department of Engineering Physics, University of Wisconsin-Madison, Madison, Wisconsin.; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA., Burlingham WJ; Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA., Glukhov AV; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Ge Y; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Kamp TJ; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Jazyk: angličtina
Zdroj: Stem cells (Dayton, Ohio) [Stem Cells] 2019 Jul; Vol. 37 (7), pp. 910-923. Date of Electronic Publication: 2019 May 14.
DOI: 10.1002/stem.3021
Abstrakt: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) exhibit a fetal phenotype that limits in vitro and therapeutic applications. Strategies to promote cardiomyocyte maturation have focused interventions on differentiated hPSC-CMs, but this study tests priming of early cardiac progenitor cells (CPCs) with polyinosinic-polycytidylic acid (pIC) to accelerate cardiomyocyte maturation. CPCs were differentiated from hPSCs using a monolayer differentiation protocol with defined small molecule Wnt temporal modulation, and pIC was added during the formation of early CPCs. pIC priming did not alter the expression of cell surface markers for CPCs (>80% KDR+/PDGFRα+), expression of common cardiac transcription factors, or final purity of differentiated hPSC-CMs (∼90%). However, CPC differentiation in basal medium revealed that pIC priming resulted in hPSC-CMs with enhanced maturity manifested by increased cell size, greater contractility, faster electrical upstrokes, increased oxidative metabolism, and more mature sarcomeric structure and composition. To investigate the mechanisms of CPC priming, RNAseq revealed that cardiac progenitor-stage pIC modulated early Notch signaling and cardiomyogenic transcriptional programs. Chromatin immunoprecipitation of CPCs showed that pIC treatment increased deposition of the H3K9ac activating epigenetic mark at core promoters of cardiac myofilament genes and the Notch ligand, JAG1. Inhibition of Notch signaling blocked the effects of pIC on differentiation and cardiomyocyte maturation. Furthermore, primed CPCs showed more robust formation of hPSC-CMs grafts when transplanted to the NSGW mouse kidney capsule. Overall, epigenetic modulation of CPCs with pIC accelerates cardiomyocyte maturation enabling basic research applications and potential therapeutic uses. Stem Cells 2019;37:910-923.
(© 2019 AlphaMed Press.)
Databáze: MEDLINE
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