Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production

  • Cell. 2018 Jul 26;174(3):636-648.e18. doi: 10.1016/j.cell.2018.06.011.
Yukitaka Ito  1 ,  Sou Nakamura  2 ,  Naoshi Sugimoto  2 ,  Tomohiro Shigemori  3 ,  Yoshikazu Kato  4 ,  Mikiko Ohno  5 ,  Shinya Sakuma  6 ,  Keitaro Ito  6 ,  Hiroki Kumon  6 ,  Hidenori Hirose  3 ,  Haruki Okamoto  3 ,  Masayuki Nogawa  7 ,  Mio Iwasaki  8 ,  Shunsuke Kihara  9 ,  Kosuke Fujio  2 ,  Takuya Matsumoto  2 ,  Natsumi Higashi  2 ,  Kazuya Hashimoto  2 ,  Akira Sawaguchi  10 ,  Ken-Ichi Harimoto  2 ,  Masato Nakagawa  8 ,  Takuya Yamamoto  11 ,  Makoto Handa  7 ,  Naohide Watanabe  7 ,  Eiichiro Nishi  5 ,  Fumihito Arai  6 ,  Satoshi Nishimura  12 ,  Koji Eto  13
Affiliations
  • 1. Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Kyoto Development Center, Megakaryon Corporation, Kyoto, Japan.
  • 2. Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 3. Kyoto Development Center, Megakaryon Corporation, Kyoto, Japan.
  • 4. Mixing Technology Laboratory, SATAKE Chemical Equipment Manufacturing Ltd., Saitama, Japan.
  • 5. Department of Pharmacology, Shiga University of Medical Science, Otsu, Japan.
  • 6. Department of Micro-Nano Systems Engineering, Nagoya University, Nagoya, Japan.
  • 7. Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan.
  • 8. Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 9. Department of Fundamental Cell Technology, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 10. Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
  • 11. Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; AMED-CREST, AMED, Tokyo, Japan.
  • 12. Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
  • 13. Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. Electronic address: [email protected].
PMID: 30017246 DOI: 10.1016/j.cell.2018.06.011
Abstract

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.

Keywords
IGFBP2; MIF; Nardilysin; bioreactor; iPSC; megakaryocyte; platelet; regenerative medicine; shear stress; turbulence.
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