Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes

Ryota Tabei, Shinji Kawaguchi, Hideaki Kanazawa, Shugo Tohyama, Akinori Hirano, Noriko Handa, Shuji Hishikawa, Takumi Teratani, Satoshi Kunita, Junichi Fukuda, Yoshihiro Mugishima, Tsuneyoshi Suzuki, Kazuaki Nakajima, Tomohisa Seki, Yoshikazu Kishino, Marina Okada, Masataka Yamazaki, Kazuma Okamoto, Hideyuki Shimizu, Eiji KobayashiYasuhiko Tabata, Jun Fujita, Keiichi Fukuda

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BACKGROUND: Induced pluripotent stem cell (iPSC)‒based regenerative therapy is a promising strategy for cardiovascular disease treatment; however, the method is limited by the myocardial retention of grafted iPSCs. Thus, an injection protocol that efficiently introduces and retains human iPSC-derived cardiomyocytes (hiPSC-CMs) within the myocardium is urgently needed. The objective of the present study was to develop a method to improve the retention of hiPSCs in the myocardium for cardiac therapy. METHODS: We efficiently produced hiPSC-CM spheroids in 3-dimensional (3D) culture using microwell plates, and developed an injection device for optimal 3D distribution of the spheroids in the myocardial layer. Device biocompatibility was assessed with purified hiPSC-CM spheroids. Device effectiveness was evaluated in 10- to 15-month-old farm pigs (n = 15) and 5- to 24-month-old micro-minipigs (n = 20). The pigs were euthanized after injection, and tissues were harvested for retention and histologic analysis. RESULTS: We demonstrated an injection device for direct intramyocardial transplantation of hiPSC-CM spheroids from large-scale culture. The device had no detrimental effects on cell viability, spheroid shape, or size. Direct epicardial injection of spheroids mixed with gelatin hydrogel into beating porcine hearts using this device resulted in better distribution and retention of transplanted spheroids in a layer within the myocardium than did conventional needle injection procedures. CONCLUSIONS: The combination of the newly developed transplant device and spheroid formation promotes the retention of transplanted CMs. These findings support the clinical application of hiPSC-CM spheroid‒based cardiac regenerative therapy in patients with heart failure.

Original languageEnglish
Pages (from-to)203-214
Number of pages12
JournalJournal of Heart and Lung Transplantation
Volume38
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1

Fingerprint

Cardiac Myocytes
Transplants
Equipment and Supplies
Injections
Induced Pluripotent Stem Cells
Myocardium
Swine
Miniature Swine
Hydrogel
Gelatin
Therapeutics
Needles
Cell Survival
Cardiovascular Diseases
Heart Failure
Transplantation

Keywords

  • cardiac regeneration
  • cell transplantation
  • gelatin hydrogel
  • induced pluripotent stem cells
  • spheroids
  • transplantation device

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes. / Tabei, Ryota; Kawaguchi, Shinji; Kanazawa, Hideaki; Tohyama, Shugo; Hirano, Akinori; Handa, Noriko; Hishikawa, Shuji; Teratani, Takumi; Kunita, Satoshi; Fukuda, Junichi; Mugishima, Yoshihiro; Suzuki, Tsuneyoshi; Nakajima, Kazuaki; Seki, Tomohisa; Kishino, Yoshikazu; Okada, Marina; Yamazaki, Masataka; Okamoto, Kazuma; Shimizu, Hideyuki; Kobayashi, Eiji; Tabata, Yasuhiko; Fujita, Jun; Fukuda, Keiichi.

In: Journal of Heart and Lung Transplantation, Vol. 38, No. 2, 01.02.2019, p. 203-214.

Research output: Contribution to journalArticle

Tabei, R, Kawaguchi, S, Kanazawa, H, Tohyama, S, Hirano, A, Handa, N, Hishikawa, S, Teratani, T, Kunita, S, Fukuda, J, Mugishima, Y, Suzuki, T, Nakajima, K, Seki, T, Kishino, Y, Okada, M, Yamazaki, M, Okamoto, K, Shimizu, H, Kobayashi, E, Tabata, Y, Fujita, J & Fukuda, K 2019, 'Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes', Journal of Heart and Lung Transplantation, vol. 38, no. 2, pp. 203-214. https://doi.org/10.1016/j.healun.2018.11.002
Tabei, Ryota ; Kawaguchi, Shinji ; Kanazawa, Hideaki ; Tohyama, Shugo ; Hirano, Akinori ; Handa, Noriko ; Hishikawa, Shuji ; Teratani, Takumi ; Kunita, Satoshi ; Fukuda, Junichi ; Mugishima, Yoshihiro ; Suzuki, Tsuneyoshi ; Nakajima, Kazuaki ; Seki, Tomohisa ; Kishino, Yoshikazu ; Okada, Marina ; Yamazaki, Masataka ; Okamoto, Kazuma ; Shimizu, Hideyuki ; Kobayashi, Eiji ; Tabata, Yasuhiko ; Fujita, Jun ; Fukuda, Keiichi. / Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes. In: Journal of Heart and Lung Transplantation. 2019 ; Vol. 38, No. 2. pp. 203-214.
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T1 - Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cell‒derived cardiomyocytes

AU - Tabei, Ryota

AU - Kawaguchi, Shinji

AU - Kanazawa, Hideaki

AU - Tohyama, Shugo

AU - Hirano, Akinori

AU - Handa, Noriko

AU - Hishikawa, Shuji

AU - Teratani, Takumi

AU - Kunita, Satoshi

AU - Fukuda, Junichi

AU - Mugishima, Yoshihiro

AU - Suzuki, Tsuneyoshi

AU - Nakajima, Kazuaki

AU - Seki, Tomohisa

AU - Kishino, Yoshikazu

AU - Okada, Marina

AU - Yamazaki, Masataka

AU - Okamoto, Kazuma

AU - Shimizu, Hideyuki

AU - Kobayashi, Eiji

AU - Tabata, Yasuhiko

AU - Fujita, Jun

AU - Fukuda, Keiichi

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N2 - BACKGROUND: Induced pluripotent stem cell (iPSC)‒based regenerative therapy is a promising strategy for cardiovascular disease treatment; however, the method is limited by the myocardial retention of grafted iPSCs. Thus, an injection protocol that efficiently introduces and retains human iPSC-derived cardiomyocytes (hiPSC-CMs) within the myocardium is urgently needed. The objective of the present study was to develop a method to improve the retention of hiPSCs in the myocardium for cardiac therapy. METHODS: We efficiently produced hiPSC-CM spheroids in 3-dimensional (3D) culture using microwell plates, and developed an injection device for optimal 3D distribution of the spheroids in the myocardial layer. Device biocompatibility was assessed with purified hiPSC-CM spheroids. Device effectiveness was evaluated in 10- to 15-month-old farm pigs (n = 15) and 5- to 24-month-old micro-minipigs (n = 20). The pigs were euthanized after injection, and tissues were harvested for retention and histologic analysis. RESULTS: We demonstrated an injection device for direct intramyocardial transplantation of hiPSC-CM spheroids from large-scale culture. The device had no detrimental effects on cell viability, spheroid shape, or size. Direct epicardial injection of spheroids mixed with gelatin hydrogel into beating porcine hearts using this device resulted in better distribution and retention of transplanted spheroids in a layer within the myocardium than did conventional needle injection procedures. CONCLUSIONS: The combination of the newly developed transplant device and spheroid formation promotes the retention of transplanted CMs. These findings support the clinical application of hiPSC-CM spheroid‒based cardiac regenerative therapy in patients with heart failure.

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KW - cardiac regeneration

KW - cell transplantation

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KW - induced pluripotent stem cells

KW - spheroids

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