Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production

• Published in: Cell Vol. 174; no. 3; pp. 636 - 648.e18
• Main Authors: Ito, Yukitaka, Nakamura, Sou, Sugimoto, Naoshi, Shigemori, Tomohiro, Kato, Yoshikazu, Ohno, Mikiko, Sakuma, Shinya, Ito, Keitaro, Kumon, Hiroki, Hirose, Hidenori, Okamoto, Haruki, Nogawa, Masayuki, Iwasaki, Mio, Kihara, Shunsuke, Fujio, Kosuke, Matsumoto, Takuya, Higashi, Natsumi, Hashimoto, Kazuya, Sawaguchi, Akira, Harimoto, Ken-ichi, Nakagawa, Masato, Yamamoto, Takuya, Handa, Makoto, Watanabe, Naohide, Nishi, Eiichiro, Arai, Fumihito, Nishimura, Satoshi, Eto, Koji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.07.2018
• Subjects: bioreactor; Bioreactors; Blood Platelets - metabolism; Cell Culture Techniques - instrumentation; Cell Culture Techniques - methods; Humans; Hydrodynamics; IGFBP2; Induced Pluripotent Stem Cells - metabolism; iPSC; megakaryocyte; Megakaryocytes - metabolism; Megakaryocytes - physiology; MIF; Nardilysin; platelet; regenerative medicine; shear stress; Thrombopoiesis - physiology; turbulence; shear stress; regenerative medicine; iPSC; IGFBP2; megakaryocyte; platelet; MIF; bioreactor; turbulence; Nardilysin
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.06.011

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. [Display omitted] •In vivo imaging revealed turbulence activates platelet biogenesis in mice•Turbulent flow-based bioreactors enabled thrombopoiesis with high yield and quality•Optimized turbulent energy along with shear stress are key parameters for scaling up•Detection of cell-autonomous mechanism by the soluble factors IGFBP2, MIF, and NRDC 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.