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Cell. 2018 Jul 26;174(3):636-648.e18. doi: 10.1016/j.cell.2018.06.011. Epub 2018 Jul 12.

Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production.

Author information

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: kojieto@cira.kyoto-u.ac.jp.

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

PMID:
30017246
DOI:
10.1016/j.cell.2018.06.011

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