Negative regulation of activated α2 integrins during thrombopoiesis

Circulating platelets exhibit rapid signaling and adhesive responses to collagen that facilitate hemostasis at sites of vessel injury. Because 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 are unknown. We find that surface expression of activated, but not wild-type, alpha 2 integrins in hematopoietic cells in vivo results in the generation of platelets that lack surface alpha 2 receptors. Culture of hematopoietic progenitor cells ex vivo reveals that surface levels of activated, but not wild- type, alpha 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 alpha 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 alpha 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 nonadhesive environment of the circulating blood. (Blood. 2009; 113: 6428-6439)