PECAM‐1: a multi‐faceted regulator of megakaryocytopoiesis

Abstract

The differentiation of megakaryocytes from hematopoietic stem cells and their further maturation is a complex process. Abnormal megakaryocytopoiesis could lead to hematological diseases. PECAM-1 (CD31), a member of the Ig superfamily, has been demonstrated to function as a scaffolding protein in regulating, in part, vasculogenesis, angiogenesis and leukocyte migration. In this report, upon examination of the bone marrow of PECAM-1 null animals we observed that the marrow was hypercellular, with increased numbers and altered localizations of polyploidy megakaryocytes. Upon further examination we found that the Lin-, Sca+, c-kit+ (LSK) progenitor population was expanded in the PECAM-1 null animals (caused by a decreased apoptotic rate) and less PECAM-1 null LSK population was arrested in quiescent G0 phase. Although megakaryocyte-CFU colony formation potential of marrow progenitor cells was impaired, the colonies can undergo excessive clonal expansion associated with increased number of more committed progenitor cells and their progeny in PECAM-1 null marrow. We also observed that multiploidy of mature megakaryocytes was increased. In addition to these findings, we documented differences in PECAM-1 null megakaryocyte adhesion to fibronectin and endothelial cell monolayers as well as differences in transmigration through bone marrow derived stromal cell and endothelial cell monolayers in response to FGF-4 and SDF-1. Further, we attributed the altered localization and adhesive and migratory properties of the PECAM-1 null megakaryocytes to their inability to organize and maintain an actin filament organization because of their inability to appropriately tether, and localize SHP-1, SHP-2 and moesin, all known to interact with PECAM-1. # Supported, in part, by USPHS grants R37-HL28373 and PO1-DK55879 to JAM and a Reed Foundation Fellowship to YW.