Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production

Yukitaka Ito, Sou Nakamura, Naoshi Sugimoto, Tomohiro Shigemori, Yoshikazu Kato, Mikiko Ohno, Shinya Sakuma, Keitaro Ito, Hiroki Kumon, Hidenori Hirose, Haruki Okamoto, Masayuki Nogawa, Mio Iwasaki, Shunsuke Kihara, Kosuke Fujio, Takuya Matsumoto, Natsumi Higashi, Kazuya Hashimoto, Akira Sawaguchi, Ken ichi HarimotoMasato Nakagawa, Takuya Yamamoto, Makoto Handa, Naohide Watanabe, Eiichiro Nishi, Fumihito Arai, Satoshi Nishimura, Koji Eto

研究成果: Contribution to journalArticle査読

125 被引用数 (Scopus)

抄録

The ex vivo generation of platelets from human-induced pluripotent cells (hiPSCs) is expected to compensate donor-dependent transfusion systems. However, manufacturing the clinically required number of platelets remains unachieved due to the low platelet release from hiPSC-derived megakaryocytes (hiPSC-MKs). Here, we report turbulence as a physical regulator in thrombopoiesis in vivo and its application to turbulence-controllable bioreactors. The identification of turbulent energy as a determinant parameter allowed scale-up to 8 L for the generation of 100 billion-order platelets from hiPSC-MKs, which satisfies clinical requirements. Turbulent flow promoted the release from megakaryocytes of IGFBP2, MIF, and Nardilysin to facilitate platelet shedding. hiPSC-platelets showed properties of bona fide human platelets, including circulation and hemostasis capacities upon transfusion in two animal models. This study provides a concept in which a coordinated physico-chemical mechanism promotes platelet biogenesis and an innovative strategy for ex vivo platelet manufacturing. Clinical-scale generation of platelets from human-induced pluripotent stem cells can be achieved in bioreactors when turbulence is factored in as an important physical regulator of thrombopoiesis.

本文言語英語
ページ(範囲)636-648.e18
ジャーナルCell
174
3
DOI
出版ステータス出版済み - 7 26 2018
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)

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