title: Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes.
abstract: Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day 4 mesodermal cells, and day 8, day 20, and day 30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day 20 CMs was significantly higher compared to other cells. Transplantation of day 20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment, and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day 20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time.
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.|Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Funakoshi
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Miki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Takaki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Okubo
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.|Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hatani
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Chonabayashi
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Ikue
authors.initials: I
authors.lastname: Takei
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Oishi
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Narita
authors.affiliation: Center for Research in Biological Systems and Department of Medicine, University of California at San Diego, La Jolla, California, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.|Gladstone Institute of Cardiovascular Disease, San Francisco, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D058948:Cell Tracking; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D015870:Gene Expression; D006085:Graft Survival; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D019394:Ki-67 Antigen / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D061848:Optical Imaging
chemical_list: D015415:Biomarkers; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse