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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5298-5306.
Prepublished online as a Blood First Edition Paper on April 3, 2008; DOI 10.1182/blood-2007-10-117622.
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Submitted October 10, 2007
Accepted February 24, 2008
Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors
Naoya Takayama, Hidekazu Nishikii, Joichi Usui, Hiroko Tsukui, Akira Sawaguchi, Takashi Hiroyama, Koji Eto*, and Hiromitsu Nakauchi
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Department of Anatomy, University of Miyazaki Faculty of Medicine, Miyazaki, Japan
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan
* Corresponding author; email: keto{at}ims.u-tokyo.ac.jp.
Human embryonic stem cells (hESCs) could potentially represent an alternative source for blood transfusion therapies and a promising tool for studying the ontogeny of hematopoiesis. When we cultured hESCs on either C3H10T1/2 or OP-9 cells, we found that exogenous administration of vascular endothelial growth factor promoted, whereas basic fibroblast growth factor inhibited, the emergence of sac-like structures, which we named "embryonic stem cell-derived sacs" (ES-sacs). These ES-sacs consisted of multiple cysts demarcated by cellular monolayers that retained some of the properties of endothelial cells. The spherical cells inside ES-sacs expressed primarily CD34, along with VE-cadherin, CD31, CD41a and CD45, and were able to form hematopoietic colonies in semisolid culture and to differentiate into mature megakaryocytes by day 24 in the presence of thrombopoietin. Apparently, ES-sacs provide a suitable environment for hematopoietic progenitors. Relatively large numbers of mature megakaryocytes could be induced from the hematopoietic progenitors within ES-sacs, which were then able to release platelets that displayed integrin  IIB 3 activation and spreading in response to ADP or thrombin. This novel protocol thus provides a means of generating platelets from hESCs, which could serve as the basis for efficient production of platelets for clinical transfusion and studies of thrombopoiesis.
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