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

Mitch Biermann, Wenxuan Cai, Di Lang, Jack Hermsen, Luke Profio, Ying Zhou, A. Czirók, Dona G. Isai, Brett N. Napiwocki, Adriana M. Rodriguez, Matthew E. Brown, Marites T. Woon, Annie Shao, Tianxiao Han, Donglim Park, Timothy A. Hacker, Wendy C. Crone, William J. Burlingham, Alexey V. Glukhov, Ying Ge & 1 others Timothy J. Kamp

Research output: Contribution to journalReview article

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.

Original languageEnglish
JournalStem Cells
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Pluripotent Stem Cells
Cardiac Myocytes
Epigenomics
Poly C
Stem Cells
Poly I-C
Myofibrils
Chromatin Immunoprecipitation
Therapeutic Uses
Cell Size
Capsules
Cell Differentiation
Transcription Factors
Ligands
Transplants
Phenotype
Kidney

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation. / Biermann, Mitch; Cai, Wenxuan; Lang, Di; Hermsen, Jack; Profio, Luke; Zhou, Ying; Czirók, A.; Isai, Dona G.; Napiwocki, Brett N.; Rodriguez, Adriana M.; Brown, Matthew E.; Woon, Marites T.; Shao, Annie; Han, Tianxiao; Park, Donglim; Hacker, Timothy A.; Crone, Wendy C.; Burlingham, William J.; Glukhov, Alexey V.; Ge, Ying; Kamp, Timothy J.

In: Stem Cells, 01.01.2019.

Research output: Contribution to journalReview article

Biermann, M, Cai, W, Lang, D, Hermsen, J, Profio, L, Zhou, Y, Czirók, 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. https://doi.org/10.1002/stem.3021
Biermann, Mitch ; Cai, Wenxuan ; Lang, Di ; Hermsen, Jack ; Profio, Luke ; Zhou, Ying ; Czirók, A. ; Isai, Dona G. ; Napiwocki, Brett N. ; Rodriguez, Adriana M. ; Brown, Matthew E. ; Woon, Marites T. ; Shao, Annie ; Han, Tianxiao ; Park, Donglim ; Hacker, Timothy A. ; Crone, Wendy C. ; Burlingham, William J. ; Glukhov, Alexey V. ; Ge, Ying ; Kamp, Timothy J. / Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation. In: Stem Cells. 2019.
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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.",
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AU - Biermann, Mitch

AU - Cai, Wenxuan

AU - Lang, Di

AU - Hermsen, Jack

AU - Profio, Luke

AU - Zhou, Ying

AU - Czirók, A.

AU - Isai, Dona G.

AU - Napiwocki, Brett N.

AU - Rodriguez, Adriana M.

AU - Brown, Matthew E.

AU - Woon, Marites T.

AU - Shao, Annie

AU - Han, Tianxiao

AU - Park, Donglim

AU - Hacker, Timothy A.

AU - Crone, Wendy C.

AU - Burlingham, William J.

AU - Glukhov, Alexey V.

AU - Ge, Ying

AU - Kamp, Timothy J.

PY - 2019/1/1

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N2 - 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.

AB - 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.

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