Intramyocardial Transplantation of Human iPS Cell-Derived Cardiac Spheroids Improves Cardiac Function in Heart Failure Animals

Shinji Kawaguchi; Yusuke Soma; Kazuaki Nakajima; Hideaki Kanazawa; Shugo Tohyama; Ryota Tabei; Akinori Hirano; Noriko Handa; Yoshitake Yamada; Shigeo Okuda; Shuji Hishikawa; Takumi Teratani; Satoshi Kunita; Yoshikazu Kishino; Marina Okada; Sho Tanosaki; Shota Someya; Yuika Morita; Hidenori Tani; Yujiro Kawai; Masataka Yamazaki; Akira Ito; Rei Shibata; Toyoaki Murohara; Yasuhiko Tabata; Eiji Kobayashi; Hideyuki Shimizu; Keiichi Fukuda; Jun Fujita

doi:10.1016/j.jacbts.2020.11.017

Intramyocardial Transplantation of Human iPS Cell-Derived Cardiac Spheroids Improves Cardiac Function in Heart Failure Animals

JACC Basic Transl Sci. 2021 Feb 19;6(3):239-254. doi: 10.1016/j.jacbts.2020.11.017. eCollection 2021 Mar.

Authors

Shinji Kawaguchi¹, Yusuke Soma², Kazuaki Nakajima², Hideaki Kanazawa², Shugo Tohyama^{2

3}, Ryota Tabei², Akinori Hirano¹, Noriko Handa⁴, Yoshitake Yamada⁵, Shigeo Okuda⁵, Shuji Hishikawa⁴, Takumi Teratani⁴, Satoshi Kunita⁴, Yoshikazu Kishino², Marina Okada², Sho Tanosaki², Shota Someya², Yuika Morita², Hidenori Tani², Yujiro Kawai¹, Masataka Yamazaki¹, Akira Ito⁶, Rei Shibata⁷, Toyoaki Murohara⁸, Yasuhiko Tabata⁹, Eiji Kobayashi^{3

4}, Hideyuki Shimizu¹, Keiichi Fukuda², Jun Fujita^{2

10}

Affiliations

¹ Department of Cardiovascular Surgery, Keio University School of Medicine, Tokyo, Japan.
² Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
³ Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan.
⁴ Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
⁵ Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
⁶ Department of Chemical Systems Engineering, School of Engineering, Nagoya University, Nagoya, Japan.
⁷ Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁸ Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹ Laboratory of Biomaterials, Department of Regeneration Science, Engineering Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
¹⁰ Endowed Course for Severe Heart Failure Treatment Ⅱ, Keio University School of Medicine, Tokyo, Japan.

Abstract

The severe shortage of donor hearts hampered the cardiac transplantation to patients with advanced heart failure. Therefore, cardiac regenerative therapies are eagerly awaited as a substitution. Human induced pluripotent stem cells (hiPSCs) are realistic cell source for regenerative cardiomyocytes. The hiPSC-derived cardiomyocytes are highly expected to help the recovery of heart. Avoidance of teratoma formation and large-scale culture of cardiomyocytes are definitely necessary for clinical setting. The combination of pure cardiac spheroids and gelatin hydrogel succeeded to recover reduced ejection fraction. The feasible transplantation strategy including transplantation device for regenerative cardiomyocytes are established in this study.

Keywords: CM, cardiomyocyte; CMR, cardiac magnetic resonance; CS, cardiac spheroid; ECG, electrocardiogram; EF, ejection fraction; FAC, fractional area change; GH, gelatin hydrogel; HF, heart failure; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; VEGF, vascular endothelial growth factor; cardiac spheroids; cardiomyocyte; cell transplantation; dp/dtmax, maximum rate of left ventricular pressure rise; hPSC, human pluripotent stem cell; heart failure; hiPSC, human induced pluripotent stem cell; human iPS cells; sCM, single cardiomyocyte.