G-CSF was among the first growth factors to be identified and rapidly transitioned into clinical medicine. Initially used to promote the production of neutrophils in patients with chemotherapy-induced neutropenia it helped to revolutionize the delivery of cancer therapy. Its ability to mobilize hematopoietic stem cells from the bone marrow into the blood was subsequently exploited, changing the face of hematopoietic stem cell transplantation. Today the knowledge gained in unraveling the mechanisms of stem cell mobilization by G-CSF is being explored as a means to increase chemosensitivity in hematological malignancies.
Traditionally, hematopoietic cells for both autologous and allogeneic transplantation were obtained by collecting large volumes of bone marrow, aspirated from the pelvic crests under general anesthesia. However, pre-clinical data showed that G-CSF could mobilize hematopoietic cells in large numbers from the marrow into the circulation with increased progenitor cells of all lineages detected in the spleens of G-CSF treated mice. The following year Duhrsen et al. confirmed the mobilizing activity of G-CSF in cancer patients . Subsequent clinical trials demonstrated that adequate numbers of these cells could be collected from cancer patients or normal donors to allow successful autologous and allogeneic hematopoietic cell transplantation (HCT) respectively. The use of G-CSF mobilization had the advantage of increasing the number of hematopoietic cells collected, with consequent reductions in the time taken post-transplant to restore neutrophil and platelet numbers to clinically safe levels, and improvements in transplant safety. In addition, despite common side effects of G-CSF such as bone pain, experience in randomized clinical trials was that normal donors preferred donation of hematopoietic cells collected from blood, rather than from pelvic marrow. These clinical trials have led to the widespread use of G-CSF-mobilized hematopoietic cells collected by leucapheresis in the majority of autologous and allogeneic transplants.
The biology underlying the process of hematopoietic stem cell mobilization has been extensively studied but our understanding of the process is still incomplete. Perhaps surprisingly G-CSF does not mobilize hematopoietic stem cell and progenitors by a direct influence on these cells. This was demonstrated using mice that were chimeric for expression of the G-CSFR on hematopoietic cells. In these animals hematopoietic progenitors lacking the G-CSFR were mobilized with equivalent efficiency as those expressing the receptor. However, mice where all hematopoietic cells lack the G-CSFR completely fail to mobilize. Together this suggests that while the response of hematopoietic cells to G-CSF is essential for hematopoietic stem cell mobilization, the effect is indirect and a specific response of individual HSC to G-CSF not required.
Overall at a cellular level it appears that G-CSF triggers a number of potentially parallel events including expansion of neutrophils and their precursors, stimulation of CD169+ bone marrow macrophages, the peripheral sympathetic nervous, osteocytes and osteomacs. The latter three either directly or indirectly suppress osteoblasts and the production of bone marrow supportive factors, notably CXCL12. The stimulation of CD169+ macrophages, potentially via the sympathetic nervous system, suppresses CXCL12 production by N+MSC. The granulocyte expansion provides a proteolytic environment that can degrade retentive factors. Together this results in alteration to the hematopoietic stem cell niche making it less attractive for hematopoietic stem cell, permitting their egress into the peripheral circulation potentially under the influence of a S1P gradient.
Bendall L J, et al. G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent[J]. Cytokine & growth factor reviews, 2014, 25(4): 355-367.
Petit I, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4[J]. Nature immunology, 2002, 3(7): 687-694.