Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production

被引：215

作者：

Ito, Yukitaka ^{[1
,10
]}

Nakamura, Sou ^{[1
]}

Sugimoto, Naoshi ^{[1
]}

Shigemori, Tomohiro ^{[10
]}

Kato, Yoshikazu ^{[11
]}

Ohno, Mikiko ^{[4
]}

Sakuma, Shinya ^{[6
]}

Ito, Keitaro ^{[6
]}

Kumon, Hiroki ^{[6
]}

Hirose, Hidenori ^{[10
]}

Okamoto, Haruki ^{[10
]}

Nogawa, Masayuki ^{[5
]}

Iwasaki, Mio ^{[2
]}

Kihara, Shunsuke ^{[3
]}

Fujio, Kosuke ^{[1
]}

Matsumoto, Takuya ^{[1
,12
]}

Higashi, Natsumi ^{[1
]}

Hashimoto, Kazuya ^{[1
]}

Sawaguchi, Akira ^{[9
]}

Harimoto, Ken-ichi ^{[1
,13
]}

Nakagawa, Masato ^{[2
]}

Yamamoto, Takuya ^{[2
]}

Handa, Makoto ^{[5
]}

Watanabe, Naohide ^{[5
]}

Nishi, Eiichiro ^{[4
]}

Arai, Fumihito ^{[6
]}

Nishimura, Satoshi ^{[7
]}

Eto, Koji ^{[1
,8
]}

机构：

[1] Kyoto Univ, Ctr iPS Cell Res & Applicat CiRA, Dept Clin Applicat, Kyoto, Japan

[2] Kyoto Univ, Ctr iPS Cell Res & Applicat CiRA, Dept Life Sci Frontiers, Kyoto, Japan

[3] Kyoto Univ, Ctr iPS Cell Res & Applicat CiRA, Dept Fundamental Cell Technol, Kyoto, Japan

[4] Shiga Univ Med Sci, Dept Pharmacol, Otsu, Shiga, Japan

[5] Keio Univ, Ctr Transfus Med & Cell Therapy, Sch Med, Tokyo, Japan

[6] Nagoya Univ, Dept Micronano Syst Engn, Nagoya, Aichi, Japan

[7] Jichi Med Univ, Ctr Mol Med, Shimotsuke, Tochigi, Japan

[8] Chiba Univ, Sch Med, Dept Regenerat Med, Chiba, Japan

[9] Miyazaki Univ, Fac Med, Dept Anat, Miyazaki, Japan

[10] Megakaryon Corp, Kyoto Dev Ctr, Kyoto, Japan

[11] SATAKE Chem Equipment Mfg Ltd, Mixing Technol Lab, Saitama, Japan

[12] AMED, CREST, Tokyo, Japan

[13] Toray Industries Ltd, Med Devices & Mat Res Lab, Adv Mat Res Labs, Tokyo, Japan

来源：

CELL | 2018年 / 174卷 / 03期

基金：

日本学术振兴会;

关键词：

PLURIPOTENT STEM-CELLS; PROPLATELET FORMATION; BONE-MARROW; SELECTIVE-INHIBITION; ADAM PROTEASES; MEGAKARYOCYTES; GENERATION; BIOREACTOR; MEGAKARYOPOIESIS; NARDILYSIN;

D O I：

10.1016/j.cell.2018.06.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：636 / +

页数：31

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