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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4044-4051.
Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-06-1773.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Production of functional platelets by differentiated embryonic stem (ES) cells in vitro
Tetsuro-Takahiro Fujimoto,
Satoshi Kohata,
Hidenori Suzuki,
Hiroshi Miyazaki, and
Kingo Fujimura
From the Department of Hematology and Oncology, Division of Clinical Pharmacotherapeutics, Program for Applied Biomedicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Medical Research and Development Center, The Tokyo Metropolitan Institute, Tokyo, Japan; and Pharmaceutical Research Laboratory, Kirin Brewery Co, Takasaki, Japan.
Megakaryocytes and functional platelets were generated in vitro from murine embryonic stem (ES) cells with the use of a coculture system with stromal cells. Two morphologically distinctive megakaryocytes were observed sequentially. Small megakaryocytes rapidly produced proplatelets on day 8 of the differentiation, and large hyperploid megakaryocytes developed after day 12, suggesting primitive and definitive megakaryopoiesis. Two waves of platelet production were consistently observed in the culture medium. A larger number of platelets was produced in the second wave; 104 ES cells produced up to 108 platelets. By transmission electron microscopy, platelets from the first wave were relatively rounder with a limited number of granules, but platelets from the second wave were discoid shaped with well-developed granules that were indistinguishable from peripheral blood platelets. ES-derived platelets were functional since they bound fibrinogen, formed aggregates, expressed P-selectin upon stimulation, and fully spread on immobilized fibrinogen. These results show the potential utility of ES-derived platelets for clinical applications. Furthermore, production of gene-transferred platelets was achieved by differentiating ES cells that were transfected with genes of interest. Overexpression of the cytoplasmic domain of integrin  3 in the ES-derived platelets prevented the activation of  IIb3, demonstrating that this system will facilitate functional platelet studies. (Blood. 2003;102:4044-4051)
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