title: The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes.
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 in vivo. 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.
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Anton
authors.initials: A
authors.lastname: Mihic
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Jiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyagi
authors.affiliation: McEwen Centre for Regenerative Medicine, Toronto, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Gagliardi
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Zu
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada; McEwen Centre for Regenerative Medicine, Toronto, ON, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: McEwen Centre for Regenerative Medicine, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada; McEwen Centre for Regenerative Medicine, Toronto, ON, Canada. Electronic address: renkeli@uhnres.utoronto.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000648:ultrastructure; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D011923:Rats, Nude; D013314:Stress, Mechanical; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry; D014945:Wound Healing
chemical_list: D018031:Connexin 43; D002118:Calcium
keywords: Cardiac tissue engineering; Cardiomyocyte; Human embryonic stem cell; Scaffold; Transplantation; Uniaxial stretch