Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissuesCentral MessagePerspective
Hiroaki Osada, MD, PhD,
Masahide Kawatou, MD, PhD,
Daiki Fujita, MS,
Yasuhiko Tabata, PhD, DMedSci, DPharm,
Kenji Minatoya, MD, PhD,
Jun K. Yamashita, MD, PhD,
Hidetoshi Masumoto, MD, PhD
Affiliations
Hiroaki Osada, MD, PhD
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Masahide Kawatou, MD, PhD
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Daiki Fujita, MS
iHeart Japan Corporation, Kyoto, Japan
Yasuhiko Tabata, PhD, DMedSci, DPharm
Department of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
Kenji Minatoya, MD, PhD
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Jun K. Yamashita, MD, PhD
Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; Jun K. Yamashita, MD, PhD, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Hidetoshi Masumoto, MD, PhD
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan; Address for reprints: Hidetoshi Masumoto, MD, PhD, Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Objectives: To establish a protocol to prepare and transplant clinical-grade human induced pluripotent stem cell (hiPSC)-derived cardiac tissues (HiCTs) and to evaluate the therapeutic potential in an animal myocardial infarction (MI) model. Methods: We simultaneously differentiated clinical-grade hiPSCs into cardiovascular cell lineages with or without the administration of canonical Wnt inhibitors, generated 5- layer cell sheets with insertion of gelatin hydrogel microspheres (GHMs) (HiCTs), and transplanted them onto an athymic rat MI model. Cardiac function was evaluated by echocardiography and cardiac magnetic resonance imaging and compared with that in animals with sham and transplantation of 5-layer cell sheets without GHMs. Graft survival, ventricular remodeling, and neovascularization were evaluated histopathologically. Results: The administration of Wnt inhibitors significantly promoted cardiomyocyte (CM) (P < .0001) and vascular endothelial cell (EC) (P = .006) induction, which resulted in cellular components of 52.0 ± 6.1% CMs and 9.9 ± 3.0% ECs. Functional analyses revealed the significantly lowest left ventricular end-diastolic volume and highest ejection fraction in the HiCT group. Histopathologic evaluation revealed that the HiCT group had a significantly larger median engrafted area (4 weeks, GHM(-) vs HiCT: 0.4 [range, 0.2-0.7] mm2 vs 2.2 [range, 1.8-3.1] mm2; P = .005; 12 weeks, 0 [range, 0-0.2] mm2 vs 1.9 [range, 0.1-3.2] mm2; P = .026), accompanied by the smallest scar area and highest vascular density at the MI border zone. Conclusions: Transplantation of HiCTs generated from clinical-grade hiPSCs exhibited a prominent therapeutic potential in a rat MI model and may provide a promising therapeutic strategy in cardiac regenerative medicine.
