title: Functional and Electrical Integration of Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Myocardial Infarction Rat Heart.
abstract: In vitro expanded beating cardiac myocytes derived from induced pluripotent stem cells (iPSC-CMs) are a promising source of therapy for cardiac regeneration. Meanwhile, the cell sheet method has been shown to potentially maximize survival, functionality, and integration of the transplanted cells into the heart. It is thus hypothesized that transplanted iPSC-CMs in a cell sheet manner may contribute to functional recovery via direct mechanical effects on the myocardial infarction (MI) heart. F344/NJcl-rnu/rnu rats were left coronary artery ligated (n = 30), followed by transplantation of Dsred-labeled iPSC-CM cell sheets of murine origin over the infarct heart surface. Effects of the treatment were assessed, including in vivo molecular/cellular evaluations using a synchrotron radiation scattering technique. Ejection fraction and activation recovery interval were significantly greater from day 3 onward after iPSC-CM transplantation compared to those after sham operation. A number of transplanted iPSC-CMs were present on the heart surface expressing cardiac myosin or connexin 43 over 2 weeks, assessed by immunoconfocal microscopy, while mitochondria in the transplanted iPSC-CMs gradually showed mature structure as assessed by electron microscopy. Of note, X-ray diffraction identified 1,0 and 1,1 equatorial reflections attributable to myosin and actin-myosin lattice planes typical of organized cardiac muscle fibers within the transplanted cell sheets at 4 weeks, suggesting cyclic systolic myosin mass transfer to actin filaments in the transplanted iPSC-CMs. Transplantation of iPSC-CM cell sheets into the heart yielded functional and electrical recovery with cyclic contraction of transplanted cells in the rat MI heart, indicating that this strategy may be a promising cardiac muscle replacement therapy.
authors.affiliation: Department of Cardiac Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
authors.forename: Satsuki
authors.initials: S
authors.lastname: Fukushima
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tsuchimochi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujii
authors.forename: Naoto
authors.initials: N
authors.lastname: Yagi
authors.forename: Alberto
authors.initials: A
authors.lastname: Astolfo
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D024722:Cardiac Myosins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000096:biosynthesis; D003331:Coronary Vessels / Q000166:cytology; D005260:Female; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000637:transplantation*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D011916:Rats, Inbred F344; D013318:Stroke Volume / Q000502:physiology
chemical_list: D018031:Connexin 43; D024722:Cardiac Myosins