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Blood, 18 June 2009, Vol. 113, No. 25, pp. 6428-6439.
Prepublished online as a Blood First Edition Paper on March 3, 2009; DOI 10.1182/blood-2008-08-175356.
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Submitted August 21, 2008
Accepted February 17, 2009
Negative regulation of activated  2 integrins during thrombopoiesis
Zhiying Zou, Alec A. Schmaier, Lan Cheng, Patricia Mericko, S. Kent Dickeson, Thomas P. Stricker, Samuel A. Santoro, and Mark L. Kahn*
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, United States
Department of Pathology, Vanderbilt University, Nashville, TN, United States
* Corresponding author; email: markkahn{at}mail.med.upenn.edu.
Circulating platelets exhibit rapid signaling and adhesive responses to collagen that facilitate hemostasis at sites of vessel injury. Since platelets are anuclear, their collagen receptors must be expressed by megakaryocytes, platelet precursors that arise in the collagen-rich environment of the bone marrow. Whether and how megakaryocytes regulate collagen adhesion during their development in the bone marrow is unknown. We find that surface expression of activated, but not wild-type,  2 integrins in hematopoietic cells in vivo results in the generation of platelets that lack surface 2 receptors. Culture of hematopoietic progenitor cells ex vivo reveals that surface levels of activated, but not wild-type, 2 integrin receptors are rapidly down-regulated during cell growth on collagen but reach wild-type levels when cells are grown in the absence of collagen. Progenitor cells that express activated 2 integrins are normally distributed in the bone marrow in vivo and exhibit normal migration across a collagen-coated membrane ex vivo. This migration is accompanied by rapid down-regulation of activated surface integrins. These studies identify ligand-dependent removal of activated 2 receptors from the cell surface as a mechanism by which integrin function can be negatively regulated in hematopoietic cells during migration between the adhesive environment of the bone marrow and the non-adhesive environment of the circulating blood.
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