Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes

Paul W. Burridge, Scott A. Metzler, Karina H. Nakayama, Oscar J. Abilez, Chelsey S. Simmons, Marc A. Bruce, Yuka Matsuura, Paul Kim, Joseph C. Wu, Manish Butte, Ngan F. Huang, Phillip C. Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Therapeutic delivery of cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) represents a novel clinical approach to regenerate the injured myocardium. However, poor survival and contractility of these cells are a signifcant bottleneck to their clinical use. To better understand the role of cell-cell communication in enhancing the phenotype and contractile properties of hPSC-CMs, we developed a three-dimensional (3D) hydrogel composed of hPSC-CMs, human pluripotent stem cell-derived endothelial cells (hPSC-ECs), and/or human amniotic mesenchymal stem cells (hAMSCs). The objective of this study was to examine the role of multi-cellular interactions among hPSC-ECs and hAMSCs on the survival and long-term contractile phenotype of hPSC-CMs in a 3D hydrogel. Quantifcation of spontaneous contractility of hPSC-CMs in tri-culture demonstrated a 6-fold increase in the area of contractile motion after 6 weeks with characteristic rhythmic contraction frequency, when compared to hPSC-CMs alone (P < 0.05). This fnding was supported by a statistically signifcant increase in cardiac troponin T protein expression in the tri-culture hydrogel construct at 6 weeks, when compared to hPSC-CMs alone (P < 0.001). The sustained hPSC-CM survival and contractility in tri-culture was associated with a signifcant upregulation in the gene expression of L-type Ca2+ ion channel, Cav1.2, and the inward-rectifer potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These fndings demonstrate that multi-cellular interactions modulate hPSC-CM phenotype, function, and survival, and they will have important implications in engineering cardiac tissues for treatment of cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)724-735
Number of pages12
JournalAmerican Journal of Translational Research
Volume6
Issue number6
StatePublished - Jan 1 2014

Keywords

  • Cardiac patch
  • Cardiomyocyte
  • Differentiation
  • Endothelial cell
  • Induced pluripotent stem cell
  • Mesenchymal stem cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

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