Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissues

Hiroaki Osada; Masahide Kawatou; Daiki Fujita; Yasuhiko Tabata; Kenji Minatoya; Jun K Yamashita; Hidetoshi Masumoto

doi:10.1016/j.xjon.2021.09.038

Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissues

JTCVS Open. 2021 Oct 1:8:359-374. doi: 10.1016/j.xjon.2021.09.038. eCollection 2021 Dec.

Authors

Hiroaki Osada^{1

2}, Masahide Kawatou^{1

2}, Daiki Fujita³, Yasuhiko Tabata⁴, Kenji Minatoya¹, Jun K Yamashita², Hidetoshi Masumoto^{1

5}

Affiliations

¹ Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
³ iHeart Japan Corporation, Kyoto, Japan.
⁴ Department of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
⁵ Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.

Abstract

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.

Keywords: 3D, 3-dimensional; CM, cardiomyocyte; CUBIC, clear, unobstructed brain imaging cocktails and computational analysis sample; EC, endothelial cell; ESC, embryonic stem cell; FBS, fetal bovine serum; FS, fractional shortening; GHM, gelatin hydrogel microsphere; GMP, good manufacturing protocol; HLA, human leukocyte antigen; HiCT, human induced pluripotent stem cell–derived cardiac tissue; LSFM, light sheet fluorescence microscopy; LV, left ventricular; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; MC, mural cell; MI, myocardial infarction; SD, standard deviation; cTnT, cardiac isoform of troponin T; cardiac regenerative therapy; heart failure; hiPSC, human induced pluripotent stem cell; iPSC, induced pluripotent stem cell; induced pluripotent stem cell; transplantation; vWF, von Willebrand factor; αMEM, alpha minimum essential medium.