Hematopoiesis is the best-studied stem cell system; the progenitor hierarchy has been defined along with the cytokine requirements and transcriptional regulators. The lymphohematopoietic stem cell also has been characterized morphologically, and cell surface antigens have been identified. Hematopoietic stem cell transplantation is one of the major advances in cancer therapy that gave rise to a Nobel prize. The article by Frenette et al.(1) represents an important step in defining the homing of hematopoietic stem cells to recipient marrow. Stem cell motility, directed movement, and homing represent the most important new frontier in hematopoietic stem cell biology. Although the hematopoietic stem cell homing field is still in its infancy, its basis was created by studies defining a wide variety of adhesion receptors and other ligands that mediate cell-to-matrix and cell-to-cell interactions. These include the selectins, the integrins, the Ig family, and a grab bag of ‘‘others.’’In seminal studies investigating lymphocyte trafficking, scanning electron micrography was used to demonstrate lymphocyte binding to the high endothelial venules of lymph nodes (2, 3). From this important visual research, phenomenology at its best, the understanding of the roles of various adhesion receptors and cellular homing has evolved (4, 5). L-selectin was defined as the major homing receptor for naive T cells for entry into lymphoid organs (6), and subsequent work revealed a family of selectins (L, P, and E) that function as lectin and adhesion molecules; all mediate leukocyte adhesion to endothelial cells, along with other activities. L-selectin is expressed by leukocytes, E-selectin is expressed by endothelial cells, and P-selectin is found in intracellular granules in platelets (α granules) and endothelial cells (Weibel–Palade bodies)(7, 8). L-selectin gained its notoriety as the receptor responsible for the initial tethering and ‘‘rolling’’function of lymphocytes on endothelium before engagement of the integrins. It later was shown that α4ß7 also could mediate such attachment and rolling under physiologic flow (9). All of the different classes of cell adhesion receptors appear to play a role in anchoring of hematopoietic cells within the marrow or the promotion of differentiation (5, 10). Intercellular adhesion molecule (ICAM-1) in the Ig family, very late antigen 4 (VLA-4), an integrin, L-selectin, and CD44 (other) are examples of receptors that play a role in the adhesion of marrow cells.

The integrin class of adhesion receptors are heterodimers of the noncovalently associated α and ß chains. There are at least 18 different α and 8 different ß chain types (4). The integrins are grouped according to the ß chain types. The system is complex, in that several α chains can associate with more than one ß chain type and vice versa, integrins may associate with more than one ligand and vice versa, and several subunits have alternatively spliced cytoplasmic domains, including ß1, α3, and α6. The integrins have specific binding sites on the extracellular matrix (ECM) ligands. Activation and inactivation of integrin function occur, possibly by conformational changes or phosphorylation. The ß1 chain associates with α1 through α6 to form the VLA antigens (VLA-1 through VLA-6). α5ß1 is the