title: The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages.
abstract: Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation.
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.|Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Masumoto
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.|Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeichiro
authors.initials: T
authors.lastname: Nakane
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, The United States of America.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tinney
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, The United States of America.
authors.forename: Fangping
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, The United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, The United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kowalski
authors.affiliation: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Minakata
authors.affiliation: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Sakata
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Jun K
authors.initials: JK
authors.lastname: Yamashita
authors.affiliation: Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, The United States of America.|Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, The United States of America.
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Keller
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D009206:Myocardium / Q000166:cytology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000648:ultrastructure; D051381:Rats; D020127:Recovery of Function; D012038:Regeneration / Q000502:physiology*; D023822:Tissue Engineering / Q000379:methods*