The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes

Anton Mihic, Jiao Li, Yasuo Miyagi, Mark Gagliardi, Shu Hong Li, Jean Zu, Richard D. Weisel, Gordon Keller, Ren Ke Li

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

Abstract

The goal of cardiac tissue engineering is to restore function to the damaged myocardium with regenerative constructs. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can produce viable, contractile, three-dimensional grafts that function invivo. We sought to enhance the viability and functional maturation of cardiac tissue constructs by cyclical stretch. hESC-CMs seeded onto gelatin-based scaffolds underwent cyclical stretching. Histological analysis demonstrated a greater proportion of cardiac troponin T-expressing cells in stretched than non-stretched constructs, and flow sorting demonstrated a higher proportion of cardiomyocytes. Ultrastructural assessment showed that cells in stretched constructs had a more mature phenotype, characterized by greater cell elongation, increased gap junction expression, and better contractile elements. Real-time PCR revealed enhanced mRNA expression of genes associated with cardiac maturation as well as genes encoding cardiac ion channels. Calcium imaging confirmed that stretched constructs contracted more frequently, with shorter calcium cycle duration. Epicardial implantation of constructs onto ischemic rat hearts demonstrated the feasibility of this platform, with enhanced survival and engraftment of transplanted cells in the stretched constructs. This uniaxial stretching system may serve as a platform for the production of cardiac tissue-engineered constructs for translational applications.

Original languageEnglish
Pages (from-to)2798-2808
Number of pages11
JournalBiomaterials
Volume35
Issue number9
DOIs
StatePublished - Mar 2014

Keywords

  • Cardiac tissue engineering
  • Cardiomyocyte
  • Human embryonic stem cell
  • Scaffold
  • Transplantation
  • Uniaxial stretch

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