Egress and Mobilization of Hematopoietic Stem and Progenitor Cells: A Dynamic Multi-facet Process

Excerpt

Hematopoietic stem and progenitor cells (HSPCs) continuously egress out of the bone marrow (BM) to the circulation under homeostatic conditions. Their enhanced recruitment to the periphery in response to exogenous stimulation is a process, termed mobilization. HSPC mobilization is induced clinically or experimentally in animal models by a wide variety of agents, such as cytokines (e.g. G-CSF), chemotherapeutic agents (e.g. cyclophosphamide) and small molecules (e.g. the CXCR4 antagonist AMD3100). The major source for clinical transplantation protocols is via peripheral blood (PB) mobilization of BM derived HSPCs. Thus, deciphering mechanisms that regulate HSPC motility can be utilized for the development of improved mobilization regimens.

The chemokine stromal derived factor-1 (SDF-1, also termed CXCL12) and its major receptor CXCR4 are crucial in mediating both retention and mobilization of HSPCs, and this chapter will emphasize its recently revealed roles in directing steady state egress and rapid mobilization. Loss of retention is mediated by disruption of adhesion interactions, such as those mediated by integrins and CD44, and intrinsic signaling pathways such as Rho GTPases dependent signaling. Pivotal roles for the hemostatic fibrinolytic and stress-induced proteolytic enzymatic machineries in regulating HSPC recruitment are also discussed. Nevertheless, breakdown of adhesion interactions and activity of proteases are only part of the story, as accumulating evidences present the BM microenvironment, not only as maintaining HSPC quiescence and proliferation, but also as controlling HSPC retention and motility. Differentiating myeloid cells, bone remodeling by osteoblasts and osteoclasts, stimuli of the innate immunity as well as of the nervous system, including signals emanating the circadian clock, highly regulate various aspects of HSPC function, including egress, recruitment and mobilization. This review aims at presenting up to-date results concerning the dynamic interplay between the BM microenvironment and the HSPCs, focusing on molecular mechanisms that lead eventually to mobilization of HSPCs from the BM into the circulation.