Enhanced Levels and Enhanced Clonogenic Capacity of Blood Progenitor Cells Following Administration of Stem Cell Factor Plus Granulocyte Colony-Stimulating Factor to Humans

Abstract

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.

Combination of stem cell factor and granulocyte colony‐stimulating factor mobilizes the highest number of primitive haemopoietic progenitors as shown by pre‐colony‐forming unit (pre‐CFU) assay

“…This study provides new functional data demonstrating that the increase in immunophenotypically primitive cells is associated with an increase in pre-CFUs. It also confirms the findings based on LTCICs (Weaver et al, 1996) and recloning of CFU-GM colonies (Begley et al, 1997) performed on SCF 1 G-CSF-mobilized cells. The synergy between SCF and G-CSF in mobilization could be related to the lower expression of c-kit (reviewed in Roberts et al, 1999).…”

The composition of leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen

“…Prognostic factor Short-term engraftment-associated variables WBC count* ANC* PLT count* >1 × 10 9 >0.1 × 10 9 >0.5 × 10 9 >1 × 10 9 >20 × 10 9 >50 × 10 9 Uni- † Multi- ‡ Uni- plus CCP was the most effective mobilization regimen, resulting in a total number of PB CD34+ HPC collected in the first LPs six times greater than that collected after G-CSF-and G-CSF plus CCP-based regimens. [30][31][32][33][34][35] These results would support the use of SCF in addition to CCP plus G-CSF to increase mobilization efficacy, both for patients in which a high number of CD34+ HPCs are required and for individuals who have received extensive chemotherapy in whom poor mobilization of CD34+ HPCs is expected. 31,32,36,37 Despite the value of the overall number of CD34+ HPCs, there is a significant proportion of patients who show delayed recovery of neutrophil and/or PLT counts, despite receiving greater than 2 ‫ן‬ 10 6 CD34+ HPCs per kg, while some individuals receiving lower numbers of CD34+ HPCs reach a prompt successful engraftment.…”

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

“…We have recently described the neuroprotective properties of both granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a murine model of FA, 16 two agents used in clinical practice to mobilize BM stem cells prior to a peripheral blood (PB) stem cell harvest. 17,18 In both healthy animals and animals with central nervous system (CNS) injury, the numbers of BM-derived cells detectable in the brain are increased following treatment with G-CSF and SCF. 19,20 This implies that migration of BM-derived cells into the nervous system has potential for therapeutic manipulation, and in addition to their neuroprotective effects in FA, 16 G-CSF and SCF may also aid the delivery of BM cells to sites of injury in the disease, stimulating neural repair.…”