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

Research output: Contribution to journalArticle

Authors

  • Jack Hermsen
  • Luke Profio
  • Ying Zhou
  • Dona G. Isai
  • Brett N. Napiwocki
  • Adriana M. Rodriguez
  • Matthew E. Brown
  • Annie Shao
  • Donglim Park
  • Timothy A. Hacker
  • Wendy C. Crone
  • William J. Burlingham
  • Ying Ge
  • Timothy J. Kamp

External Institution(s)

  • University of Wisconsin-Madison
  • University of Kansas
  • Harvard University

Details

Original languageEnglish (US)
Pages (from-to)910-923
Number of pages14
JournalSTEM CELLS
Volume37
Issue number7
StatusPublished - Jul 2019
Peer-reviewedYes

Abstract

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.

    Research areas

  • Cardiac progenitor cells, Cardiomyocyte maturation, Epigenetics, Human pluripotent stem cells, Notch signaling

Citation formats

APA

Harvard

Biermann, M, Cai, W, Lang, D, Hermsen, J, Profio, L, Zhou, Y, Czirok, A, Isai, DG, Napiwocki, BN, Rodriguez, AM, Brown, ME, Woon, MT, Shao, A, Han, T, Park, D, Hacker, TA, Crone, WC, Burlingham, WJ, Glukhov, AV, Ge, Y & Kamp, TJ 2019, 'Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation', STEM CELLS, vol. 37, no. 7, pp. 910-923. https://doi.org/10.1002/stem.3021