Parsing the niche code: the molecular mechanisms governing hematopoietic stem cell adhesion and differentiation.

Hematopoietic stem cells (HSC) are responsible for maintaining a functional blood system throughout life. They fulfill this requirement by giving rise both to new HSC and to a cascade of increasingly mature cells, thereby balancing the processes of selfrenewal and multilineage differentiation. HSC also have a tremendous capability to respond to stress and rapidly restore hematopoietic homeostasis by giving rise to the appropriate cell types. The mechanisms governing HSC function have been intensely investigated and a long list of molecules has been found to influence the properties of HSC. However, more than 50 years after the first successful hematopoietic transplant and two decades after the prospective isolation of HSC, large gaps in knowledge hamper both our understanding of basic HSC biology and their clinical use in regenerative medicine. Here we review the prominent role that cell surface receptors play in integrating extrinsic and intrinsic cues to support effective hematopoiesis. HSC are believed to reside in a limited number of specialized niches within the bone marrow. An important role of these niches is to balance HSC self-renewal and differentiation, quiescence and proliferation. Intriguingly, HSC location changes during development, with hematopoiesis shifting from the yolk sac and aortagonad-mesonephros region to the placenta, fetal liver and bone marrow. In adult life, HSC remain in dynamic contact with bone marrow niches, and can also be found in extramedullary sites such as spleen, liver and blood at various levels in response to stress or experimental stimuli. The clinical use of bone marrow and HSC transplantation is well established and has made HSC a paradigm for stem cell therapy. Indeed, hematopoietic transplants are used to treat both hematopoietic and nonhematopoietic disorders and to reconstitute hematopoiesis after cancer therapies of a variety of solid tumors. A prerequisite for proper HSC function upon transplantation is the ability to travel through the blood stream and find these specialized bone marrow niches, a process referred to as homing. Homing and subsequent engraftment are likely accomplished by a combination of passive transport in the blood, active migration through the vascular endothelium, and adhesive interactions with cellular and extra-cellular components of the niche (Figure 1). Once engrafted in the niche, HSC fate decisions are influenced by a combination of cell intrinsic and extrinsic factors. Parsing the niche code: the molecular mechanisms governing hematopoietic stem cell adhesion and differentiation