The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071482
The Journal of Experimental Medicine, Vol. 205, No. 8, 1917-1927
The Rockefeller University Press, 0022-1007 $30.00
© Nishikii et al.
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ARTICLE

 Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells

Hidekazu Nishikii1, Koji Eto1, Noriko Tamura2, Koichi Hattori1, Beate Heissig1, Taisuke Kanaji3, Akira Sawaguchi4, Shinya Goto2, Jerry Ware5, and Hiromitsu Nakauchi1

1 Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
2 Department of Medicine, Division of Cardiology, Tokai University School of Medicine, Isehara 259-1193, Japan
3 Department of Medicine, Division of Hematology/Oncology, Kurume University School of Medicine, Fukuoka 830-0011, Japan
4 Department of Anatomy, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan
5 Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205

CORRESPONDENCE Koji Eto: keto{at}ims.u-tokyo.ac.jp OR Hiromitsu Nakauchi: nakauchi{at}ims.u-tokyo.ac.jp

Embryonic stem cells (ESCs) could potentially compensate for the lack of blood platelets available for use in transfusions. Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodies on day 6 demonstrated that c-Kit+ integrin {alpha}IIb ({alpha}IIb)+ cells, but not CD31+ cells or vascular endothelial cadherin+ cells, are capable of megakaryopoiesis and the release of platelet-like structures by day 12. {alpha}IIbβ3-expressing ESPs exhibited ectodomain shedding of glycoprotein (GP)Ib{alpha}, GPV, and GPVI, but not {alpha}IIbβ3 or GPIbβ. ESPs showed impaired {alpha}IIbβ3 activation and integrin-mediated actin reorganization, critical events for normal platelet function. However, the administration of metalloproteinase inhibitors GM6001 or TAPI-1 during differentiation increased the expression of GPIb{alpha}, improving both thrombogenesis in vitro and posttransfusion recovery in vivo. Thus, the regulation of metalloproteinases in culture could be useful for obtaining high-quality, efficacious ESPs as an alternative platelet source for transfusions.

Abbreviations used: ADAM, a disintegrin and metalloproteinase; EB, embryoid body; ESC, embryonic stem cell; ESP, ESC-derived platelet; Flk, fetal liver kinase; GC, glycocalicin; GP, glycoprotein; HSC, hematopoietic stem cell; MMP, matrix metalloproteinase; PC, platelet concentrate; TEM, transmission electron microscopy; TIMP, tissue inhibitors of metalloproteinase; TPO, thrombopoietin; VE, vascular endothelial; VWF, von Willebrand factor.

© 2008 Nishikii et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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