Plasmin therapy enhances mobilization of HPCs after G-CSF.
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ABSTRACT:
SUBMITTER: Tjwa M
PROVIDER: S-EPMC2581978 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood by the cytokine granulocyte colony-stimulating factor (G-CSF) has become the preferred source of HSPCs for stem cell transplants. However, G-CSF fails to mobilize sufficient numbers of stem cells in up to 10% of donors, precluding autologous transplantation in those donors or substantially delaying transplant recovery time. Consequently, new regimens are needed to increase the number of stem cells in peripheral blood upon mobilization. Using a forward genetic approach in mice, we mapped the gene encoding the epidermal growth factor receptor (Egfr) to a genetic region modifying G-CSF-mediated HSPC mobilization. Amounts of EGFR in HSPCs inversely correlated with the cells' ability to be mobilized by G-CSF, implying a negative role for EGFR signaling in mobilization. In combination with G-CSF treatment, genetic reduction of EGFR activity in HSPCs (in waved-2 mutant mice) or treatment with the EGFR inhibitor erlotinib increased mobilization. Increased mobilization due to suppression of EGFR activity correlated with reduced activity of cell division control protein-42 (Cdc42), and genetic Cdc42 deficiency in vivo also enhanced G-CSF-induced mobilization. Our findings reveal a previously unknown signaling pathway regulating stem cell mobilization and provide a new pharmacological approach for improving HSPC mobilization and thereby transplantation outcomes.
| S-EPMC4464748 | biostudies-literature
Project description:BackgroundThis study was conducted to investigate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the mobilization of mesenchymal stem cells (MSCs) from the bone marrow (BM) into the peripheral blood (PB) in rats.MethodsGM-CSF was administered subcutaneously to rats at 50 μg/kg body weight for 5 consecutive days. The BM and PB of rats were collected at 1, 3, and 5 days during the administration for analysis.ResultsUpon GM-CSF administration, the number of mononuclear cells increased rapidly at day 1 both in the BM and PB. This number decreased gradually over time in the BM to below the initial amount by day 5, but was maintained at a high level in the PB until day 5. The colony-forming unit-fibroblasts were increased in the PB by 10.3-fold at day 5 of GM-CSF administration, but decreased in the BM. Compared to GM-CSF, granulocyte-colony stimulating factor (G-CSF) stimulated lower levels of MSC mobilization from the BM to the PB. Immunohistochemical analysis revealed that GM-CSF induced a hypoxic and proteolytic microenvironment and increased C-X-C chemokine receptor type 4 (CXCR4) expression in the BM. GM-CSF added to BM MSCs in vitro dose-dependently increased CXCR4 expression and cell migration. G-CSF and stromal cell derived factor-1 (SDF-1) showed similar results in these in vitro assays. Know-down of CXCR4 expression with siRNA significantly abolished GM-CSF- and G-CSF-induced MSC migration in vitro, indicating the involvement of the SDF-1-CXCR4 interaction in the mechanism.ConclusionThese results suggest that GM-CSF is a useful tool for mobilizing BM MSCs into the PB.
| S-EPMC6361095 | biostudies-literature
Project description:single cell RNA-seq/CITE-seq analysis of bone marrow cells from wild type and Kmt2c-deleted mice
2024-07-11 | GSE243869 | GEO
Project description:Hematopoietic stem-cell gene therapy is a promising treatment of X-linked severe combined immunodeficiency disease (SCID-X1), but currently, it requires recipient conditioning, extensive cell manipulation, and sophisticated facilities. With these limitations in mind, we explored a simpler therapeutic approach to SCID-X1 treatment by direct IV administration of foamy virus (FV) vectors in the canine model. FV vectors were used because they have a favorable integration site profile and are resistant to serum inactivation. Here, we show improved efficacy of our in vivo gene therapy platform by mobilization with granulocyte colony-stimulating factor (G-CSF) and AMD3100 before injection of an optimized FV vector incorporating the human phosphoglycerate kinase enhancerless promoter. G-CSF/AMD3100 mobilization before FV vector delivery accelerated kinetics of CD3+ lymphocyte recovery, promoted thymopoiesis, and increased immune clonal diversity. Gene-corrected T lymphocytes exhibited a normal CD4:CD8 ratio and a broad T-cell receptor repertoire and showed restored γC-dependent signaling function. Treated animals showed normal primary and secondary antibody responses to bacteriophage immunization and evidence for immunoglobulin class switching. These results demonstrate safety and efficacy of an accessible, portable, and translatable platform with no conditioning regimen for the treatment of SCID-X1 and other genetic diseases.
| S-EPMC5942001 | biostudies-literature
Project description:Recent studies suggest that tumor-associated CD11b(+)Gr1(+) myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b(+)Gr1(+) cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1alpha, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b(+)Gr1(+) cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.
| S-EPMC2665197 | biostudies-literature
Project description:Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10(6)?cells/kg on day 1 vs 2.92 × 10(6)?cells/kg, P=0.0231; myeloma: 4.16 × 10(6) vs 3.69 × 10(6)?cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10(6)?cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.
| S-EPMC3797171 | biostudies-literature
Project description:Previous studies suggest that diabetes impairs hematopoietic stem cell (HSC) mobilization in response to granulocyte colony-stimulating factor (G-CSF). In this study, we tested whether the CXCR4 antagonist plerixafor, differently from G-CSF, is effective in mobilizing HSCs in patients with diabetes. In a prospective study, individuals with and without diabetes (n = 10/group) were administered plerixafor to compare CD34(+) HSC mobilization; plerixafor was equally able to mobilize CD34(+) HSCs in the two groups, whereas in historical data, G-CSF was less effective in patients with diabetes. In a retrospective autologous transplantation study conducted on 706 patients, diabetes was associated with poorer mobilization in patients who received G-CSF with/without chemotherapy, whereas it was not in patients who received G-CSF plus plerixafor. Similarly in an allogeneic transplantation study (n = 335), diabetes was associated with poorer mobilization in patients who received G-CSF. Patients with diabetes who received G-CSF without plerixafor had a lower probability of reaching >50/?L CD34(+) HSCs, independent from confounding variables. In conclusion, diabetes negatively impacted HSC mobilization after G-CSF with or without chemotherapy but had no effect on mobilization induced by G-CSF with plerixafor. This finding has major implications for the care of patients with diabetes undergoing stem cell mobilization and transplantation and for the vascular regenerative potential of bone marrow stem cells.
| S-EPMC4512229 | biostudies-literature
Project description:Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.
| S-EPMC7884351 | biostudies-literature
Project description:Granulocyte-colony stimulating factor (G-CSF) is used to boost granulocyte counts in immunocompromised patients, but its effects on the immune system may be counter productive. We tested the hypothesis that G-CSF mobilized peripheral blood stem cell (PBSC) products are immunologically down regulated based on gene microarray analysis. Ten peripheral blood samples from normal donors for allogeneic PBSC transplantation were obtained before and after administration of G-CSF and tested on Affymetrix Human U133 Plus 2.0 GeneChip® microarrays. Significant changes in gene expression after G-CSF mobilization were reported by controlling the false discovery rate at 5%. Immune-related genes were isolated from the data set and categorized according to probe set annotations and a thorough, independent literature search. We found that G-CSF up-regulated inflammatory and neutrophil activation pathway gene expression; however, adaptive immune-related gene expression, such as antigen presentation, co-stimulation, T cell activation and cytolytic effector pathways, were generally down-regulated. Thus, despite significant increases in stem cells, lymphocytes and antigen presenting cells, G-CSF mobilized PBSC allografts exhibit a suppressive adaptive immune-related gene expression profile. Our data provides an explanation for the potentially immunosuppressive effects observed after G-CSF administration. Keywords: PBSCT, G-CSF, microarray, gene expression
2007-08-09 | GSE7400 | GEO
Project description:Successful gene therapy for β-thalassemia requires optimal numbers of autologous gene-transduced hematopoietic progenitors stem cells (HPSC) with high repopulating capacity and mobilization is the optimal approach for achieving this goal. We performed a clinical study to investigate safety and efficacy of G-CSF+AMD3100 mobilization in four adult with β-thalassemia to reach a cell dose of â¥8x106 CD34+cells/Kg and to characterize the CD34+cell populations mobilized before and after plerixafor administration. The procedure resulted well-tolerated in all patients. Three of the four patients reached the target cell dose or more in single-apheresis collections, even one patient where a significant dose reduction of G-CSF was imposed due to early hyperleukocytosis. A significant increase in the number of circulating CD34+ cells/µl (12.1± 8.2 fold), and in the frequency of the more primitive CD34+/CD133+/CD38- cells (1.7±0.7 fold) was unanimously observed after AMD3100 addiction. Intraindividual comparison of gene expression profile of CD34+ cells mobilized with G-CSF versus G-CSF+ AMD3100 highlighted a different expression pattern of genes involved in the processes of HSC/stroma adhesion, homing, cell motility and transcription regulation. Overall, the safety profile, the yield, and the expression of genes that potentially promote superior engraftment depict G-CSF+AMD3100 mobilized HSC as optimal graft source for β-thalassemia gene therapy One experiment performed on purified CD34+ PBPC of the same patient 1 after mobilization with G-CSF + Plerixafor , and after mobilization with G-CSF alone. Universal Human Reference RNA (Stratagene, La Jolla, CA), was used as reference.
2017-04-28 | E-GEOD-70219 | biostudies-arrayexpress