Adhesion receptors as regulators of the hematopoietic process.

H EMATOPOIESIS IS A complex process in which pluripo-tent stem cells proliferate and differentiate to generate the full complement of mature blood cells. More than 30 hemopoietic cytokines and growth factors that increase or decrease progenitor proliferation and differentiation have been cloned and characterized. 1-3 Although the biological effects of these cytokines and growth factors on stem and progenitor cells has been extensively studied, we still do not understand how this extremely orderly hematopoietic process is regulated. Under steady-state conditions, hematopoiesis takes place within the bone marrow microenvironment. Stem cells and their progeny interact relatively specifically with cell and extracellu-lar matrix (ECM) ligands present in the marrow but not other microenvironments. 4-6 These adhesive interactions are responsible for the retention of hematopoietic cells in the marrow. Like hematopoietic cells, hematopoietic cytokines and growth factors bind to some specific extracellular matrix components 7,8 and stromal cells can express certain cytokines on their surface. 9 Selective adhesion of progenitors and cytokines to ECM components or stromal cells then results in the colocalization of progenitors at a specific stage of differentiation with a specific array of cytokines, in so-termed niches. 10,11 This provides one level of growth and differentiation regulation. There is also mounting evidence that contact interactions per se between progenitors and marrow stromal ligands play an important role in the regulation of the hematopoietic process. 12-14 Adhesive interactions themselves may serve as growth or survival signals or adhesion itself may modulate cytokine-or growth factor-dependent signals. These contact-mediated cues may be responsible for regulating the orderly progression of hematopoiesis. More than 20 different adhesion receptors have been identified on hematopoietic progenitors. 15,16 These include members of the integrin family responsible for adhesion to ECM components (fibronectin, collagen, laminin, or thrombospondin) 17 or cell surface-expressed cell adhesion molecules (CAM; vascular [VCAM] and intracellular [ICAM]). 18,19 Progenitors express CD44, 20 which supports adhesion to hyaluronate 20,21 and fibro-nectin. 22 Platelet-endothelial-(PE) CAM-1, a member of the Ig superfamily of cell adhesion molecules, and L-selectin are expressed on progenitors. 23,24 Finally, several sialomucins have been found on progenitors, including the stem cell antigen, CD34, 25 CD43, 26,27 CD45RA, 28 P-selectin glycoprotein li-gand-1 (PSGL-1), 29 and CD164, described by Zanettino et al 30 in this issue of BLOOD. 31 Other members from this family not expressed on hematopoietic cells include glycosylation-dependent cell-adhesion molecule-1 (Glycam-1) 32 and mucosal addressin cell adhesion molecule-1 (Madcam-1). 33 Which of these receptors …