Many mechanisms mediating mobilization: an alliterative review

Abstract

Purpose of review: Blood cell production is maintained by hematopoietic stem cells (HSCs) that reside in specialized niches within bone marrow. Treatment with granulocyte-colony stimulating factor (G-CSF) causes HSC egress from bone marrow niches and trafficking to the peripheral blood, a process termed 'mobilization'. Although the mobilization phenomenon has been known for some time and is utilized clinically to acquire HSC for transplant, the mechanisms mediating HSC release are not completely understood. We discuss recent advances and controversies in defining the mechanisms responsible for G-CSF-induced mobilization.

Recent findings: New reports define a role for resident monocytes/macrophages in maintaining niche cells, which is diminished after G-CSF treatment, suggesting a new mechanism for mobilization. Although osteoblasts have been reported to be a primary component of the HSC niche, new results suggest a unique niche composed of innervated mesenchymal stem cells. Modulating bioactive lipid signaling also facilitates mobilization, and may define a future therapeutic strategy.

Summary: Hematopoietic mobilization by G-CSF is primarily mediated by alterations to the bone marrow niche by both direct and indirect mechanisms, rather than directly altering HSC function. Further understanding of the processes mediating mobilization will advance our understanding on the cellular and molecular components of the HSC niche.

Figure 1

Schematic representation of HSC niche retention and G-CSF induced mobilization. At steady state (left panel), HSC reside in bone marrow niches, closely associated with cells such as osteoblasts or nestin⁺ MSC that express SDF-1α and other supportive factors. Resident macrophages provide a positive supporting factor maintaining osteoblast and MSC activity. During G-CSF mobilization (right panel) G-CSF acts directly on the resident macrophages, causing them to transit away from the endosteal niche and reduces their number, and alters SNS signaling. This results in an attenuation of osteoblast function and a characteristic flattening, and reduction of supportive factors like SDF-1α in the marrow, with an increase in plasma SDF-1α. The role of both activated osteoclasts and neutrophils still remains unclear.