The Effect of Rhg-CSF on MDSC In Bone Marrow and Peripheral Blood Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4709-4709
Author(s):  
Yiwen Ling ◽  
Qifa Liu ◽  
Zhiping Fan ◽  
Xiuli Wu ◽  
Can Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
The Difference ◽  
The Relationship ◽  
Stimulating Factor

Abstract Abstract 4709 Objective: As granulocyte colony-stimulating factor, recombinant human granulocyte colony stimulating factor (rhG-CSF) is widely used in neutropenic patients. In addition to stimulating the growth of granulocyte, rhG-CSF can promote hematopoietic stem cells from bone marrow (BM) to peripheral blood (PB) and has the effect of immune regulation. Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous cells, derived from bone marrow progenitor cells and immature myeloid cells. Recently, MDSC is researched in the field of solid tumor, but not in the field of hematopoietic stem cell transplantation. Here, we investigate rhG-CSF's effect on MDSC in healthy donors’ BM, PB and the relationship between MDSC and graft-verse-host disease (GVHD). Methods: We obtained the BM and PB samples before mobilization and the BM APB and peripheral blood stem cell collection (PBSC) on the 5th day after the rhG-CSF mobilization from 12 healthy donors, respectively. Then we used the flow cytometry to check the absolute number of MDSC. Finally, we analyzed the relationship between the number of MDSC and the incidence of GVHD. Results: In normal physiological conditions, the MDSC could be detected in healthy donor's PB and BM. In PB, the proportion of MDSC in the mononuclear cells was 1.35 ± 0.35%. In BM, the proportion was 2.44 ± 1.11%. The proportion in BM is higher than that in PB, the difference was statistically significant (P=0.047). On the 5th day after the rhG-CSF mobilization, the MDSC ratio of mononuclear cell in PB were 4.01 ± 1.82%. In BM, the ratio was 4.38 ± 2.19%. The difference between the ratio of MDSC in BM and PB was no significant (P=0.076). The number of mobilized peripheral blood MDSC was significantly higher than that before mobilization (P=0.015), while the difference between the numbers of bone marrow MDSC cells before and after mobilization was not significant (P=0.083). The numbers of MDSC in collection and the incidence of GVHD had a significant negative correlation (P=0.048). Conclusion: MDSC could be detected in the healthy donors’ PB and BM, the numbers of MDSC in BM were higher than that in PB. The rhG-CSF could mobilize more MDSC from BM to the peripheral blood, and the increased s of MDSC in PB after rhG-CSF mobilization might be related to the low incidence of GVHD in hematopoietic stem cell transplantation. Supported by National Natural Science Foundation of China (30971300), Science and Technology Planning Project of Guangdong Province of China (2009A030200007) and China Postdoctoral Science Foundation (200902332, 20080440776). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficient retrovirus transduction of mouse pluripotent hematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1482-1491 ◽  
Author(s):  
DM Bodine ◽  
NE Seidel ◽  
MS Gale ◽  
AW Nienhuis ◽  
D Orlic
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Abstract Cytokine-mobilized peripheral blood cells have been shown to participate in hematopoietic recovery after bone marrow (BM) transplantation, and are proposed to be useful targets for retrovirus- mediated gene transfer protocols. We treated mice with granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) to mobilize hematopoietic progenitor cells into the peripheral blood. These cells were analyzed for the number and frequency of pluripotent hematopoietic stem cells (PHSC). We found that splenectomized animals treated for 5 days with G-CSF and SCF showed a threefold increase in the absolute number of PHSC over normal mice. The number of peripheral- blood PHSC increased 250-fold from 29 per untreated mouse to 7,200 in peripheral-blood PHSC in splenectomized animals treated for 5 days with G-CSF and SCF. Peripheral blood PHSC mobilized by treatment with G-CSF and SCF were analyzed for their ability to be transduced by retroviral vectors. Peripheral-blood PHSC from splenectomized animals G-CSF and SCF were transduced with a recombinant retrovirus containing the human MDR-1 gene. The frequency of gene transfer into peripheral blood PHSC from animals treated for 5 and 7 days was two-fold and threefold higher than gene transfer into PHSC from the BM of 5-fluorouracil-treated mice (P < .01). We conclude that peripheral blood stem cells mobilized by treatment with G-CSF and SCF are excellent targets for retrovirus- mediated gene transfer.

Successful Hematopoietic STEM CELL Mobilization with GRANULOCYTE Colony Stimulating FACTOR PLUS Plerixafor (MOZOBIL, AMD3100) IN POOR Mobilizers: A Single CENTER STUDY

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4444-4444
Author(s):  
Despina Mallouri ◽  
Ioanna Sakellari ◽  
Chrisa Apostolou ◽  
Panayotis Baliakas ◽  
Apostolia Papalexandri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Peripheral Blood ◽  
Median Number ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Cd 34 ◽  
Healthy Donors ◽  
Stimulating Factor ◽  
Poor Mobilizers

Abstract Abstract 4444 Background: According to published data mobilization of sufficient number of CD 34+ cells with cytokines alone or with chemo-mobilization fails in 5–30% of patients. Plerixafor is a novel chemokine receptor 4 antagonist (CXCR4) that reversibly inhibits the interaction with its ligand SDF-1 (Stromal Derived Factor 1). Phase III studies have demonstrated that plerixafor combined with granulocyte-colony stimulating factor (GCSF) improves CD 34+ cell collection in patients with Multiple Myeloma (MM) or Non Hodgkin Lymphoma (NHL). It has been shown to be efficacious in combination with GCSF to mobilize adequate number of CD 34+ cells in patients proven to be poor mobilizers yielding a success rate of 60–100% in several reports. Plerixafor is currently approved for administration in combination with GCSF to enhance mobilization of hematopoietic stem cells in patients with lymphoma and MM whose cells mobilize poorly. Patients/methods: We administered plerixafor in combination with GCSF in 14 patients (in 4/14 as part of compassionate use protocol) and 2 sibling donors after an informed consent was obtained. Individuals were defined as poor mobilizers either due to unsuccessful collection of CD34+ >2×106/kg or due to peripheral blood CD34+ peak <20/μ l in spite of adequate mobilization treatment. Data of the individuals were collected retrospectively. Eight patients suffered from MM, 3 of NHL, 3 of H°dgkin Lymphoma (HL). Marrow involvement was present in 1 patient suffering from MM. The median number of previous chemotherapy regimens was 4(1-8). Two patients had a history of previous autologous hematopoietic cell transplantation (autoHCT) and 4 patients had received multiple radiotherapy courses. Patients had a median of 2 (1-3) previous unsuccessful attempts of mobilization before plerixafor plus GCSF administration. Nine patients had received GCSF alone and 5 patients chemotherapy plus GCSF. Patients received GCSF for 4 consecutive days and plerixafor was administered at the evening of the forth day, 10–11 hours before the scheduled aphaeresis procedure. In case of not sufficient or suboptimal number of CD34+ cells collection the procedure was repeated for maximum of 3 days plerixafor administration (7 days of GCSF). Results: Mobilization with plerixafor plus GCSF and collection of adequate number of CD 34+ cells was successful in 12/14 patients. The median number of CD 34+ cells collected was 2.5×106/kg in a median of 2 (1-4) apheresis days. Two of 14 patients proceeded to a second mobilization with plerixafor plus GCSF, eventually succeeding a sufficient cell dose graft collection. In 2 sibling female donors, aged 47 and 54 years, after administration of GCSF 10μ g/kg/day for 5 consecutive days mobilization was poor and collection of a graft with an acceptable CD 34+ cell dose was not possible. Administration of plerixafor improved mobilization and eventually grafts consisting of 2.55 ×106 and 5.34×106 CD34+/kg were collected by apheresis. Patients reported a grade ≤ II according to WHO scale toxicity following plerixafor administration. Most common side effects were hyperhidrosis, facial numbness and abdominal pain. None of the two healthy donors reported any adverse side effect. Engraftment was uneventfully in predictive time according to our historical data. Discussion: In our experience mobilization with either cytokines alone or cytokines following chemotherapy fails in a number of otherwise eligible for transplantation patients, mostly heavily pretreated or with advanced disease. In addition a small minority of healthy donors with no identifiable risk factors for poor mobilization, also fail mobilization with GCSF. The combination of plerixafor and GCSF seems to augment peripheral blood stem cells mobilization in poor mobilizers and offers a new treatment to collect sufficient CD 34+ cells and benefit from the transplantation procedure Disclosures: Off Label Use: Plerixafor was used for the mobilization of two healthy sibling donors after a signed concept was optained, due to poor mobilization with GCSF and failure of addequate graft collection.

Interleukin-1β Promotes the Expression of CD34 and Granulocyte Colony-Stimulating Factor-Receptor in Adult Dermal Fibroblasts

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4815-4815
Author(s):  
Haruko Tashiro ◽  
Ryosuke Shirasaki ◽  
Yoko Oka ◽  
Tadashi Yamamoto ◽  
Nobu Akiyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Myelogenous Leukemia ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Single Clone ◽  
Normal Human ◽  
Stimulating Factor

Abstract Abstract 4815 Background and Aims: We reported that acute myelogenous leukemia blasts and chronic myelogenous leukemia cells converted to stromal myofibroblasts to create an environment for the proliferation of leukemic cells in vitro and also in a non-obese diabetes/ severe combined immunodeficiency (NOD/SCID) murine bone-marrow in vivo. In normal hematopoiesis, hematopoietic stem cell (HSC) and stromal immature mesenchymal stem cell (MSC) are speculated to have a cross-talk, and some reports indicate that the HSC generates MSC, and also a specific fraction of MSC shares similar molecular expressions to that of HSC. We made a hypothesis that HSC might be generated from MSC. To make clear this issue, expression cloning was performed to isolate a molecule that stimulated bone-marrow stromal myofibroblasts to express hematopoietic stem cell marker, CD34. And, we also observed the effect of the isolated molecule to an adult human dermal fibroblast (HDF). Materials and Methods: cDNA-expression library was constructed using PHA-P-stimulated normal human blood lymphocytes, and the prepared plasmids were transfected to COS7 cells. After 3 days of culture, supernatants were added to the normal human bone-marrow-derived myofibroblasts (final 10%), and cells were further cultured for one week. RNA was extracted from the cultured myofibroblasts, and cDNA was synthesized. Positive clones were selected on CD34-expression with reverse transcription-polymerase chain reaction, and a single clone was isolated. The purified protein from the isolated single clone was added to HDF-culture, and the morphological changes and the expression of specific hematopoiesis-related proteins were analyzed. Results and Discussion: Isolated single clone was human interleukin 1β (IL-1β). When the purified IL-1β protein was added to the bone-marrow-derived myofibroblast cultures, cell growth was increased, and up-regulation of the expression of several hematopoietic specific proteins, including cytokine receptors and transcription factor SCL, was observed. Based on these observations, we determined the effect of IL-1β to HDF. When HDFs were cultured with human IL-1β for 3 weeks, the expression of granulocyte colony-stimulating factor (G-CSF)-receptor, and SCL was increased. When these IL-1β-stimulated cells were cultured in a non-coated dish, cells were floating, and budding of the cells was also observed. When HDF were cultured with IL-1β for 3 weeks, and then G-CSF and erythropoietin were added to the cultures, expression of transcription factor GATA-1 and CEBPA was significantly increased after one week. These observations indicate that IL-1β can stimulate to induce HDF toward hematopoietic cells. Now we determine the precise actions of human IL-1β to HDF using NOD/SCID transplantation model in vivo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficient retrovirus transduction of mouse pluripotent hematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1482-1491 ◽  
Author(s):  
DM Bodine ◽  
NE Seidel ◽  
MS Gale ◽  
AW Nienhuis ◽  
D Orlic
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Cytokine-mobilized peripheral blood cells have been shown to participate in hematopoietic recovery after bone marrow (BM) transplantation, and are proposed to be useful targets for retrovirus- mediated gene transfer protocols. We treated mice with granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) to mobilize hematopoietic progenitor cells into the peripheral blood. These cells were analyzed for the number and frequency of pluripotent hematopoietic stem cells (PHSC). We found that splenectomized animals treated for 5 days with G-CSF and SCF showed a threefold increase in the absolute number of PHSC over normal mice. The number of peripheral- blood PHSC increased 250-fold from 29 per untreated mouse to 7,200 in peripheral-blood PHSC in splenectomized animals treated for 5 days with G-CSF and SCF. Peripheral blood PHSC mobilized by treatment with G-CSF and SCF were analyzed for their ability to be transduced by retroviral vectors. Peripheral-blood PHSC from splenectomized animals G-CSF and SCF were transduced with a recombinant retrovirus containing the human MDR-1 gene. The frequency of gene transfer into peripheral blood PHSC from animals treated for 5 and 7 days was two-fold and threefold higher than gene transfer into PHSC from the BM of 5-fluorouracil-treated mice (P < .01). We conclude that peripheral blood stem cells mobilized by treatment with G-CSF and SCF are excellent targets for retrovirus- mediated gene transfer.

scholarly journals The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow–derived endothelial cells in brains of mice following cerebral ischemia

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5544-5552 ◽  
Author(s):  
Zsuzsanna E. Toth ◽  
Ronen R. Leker ◽  
Tal Shahar ◽  
Sandra Pastorino ◽  
Ildiko Szalayova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Fluorescent Protein ◽  
Fold Increase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow–derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)–expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow–derived angiogenesis, thus improving neuronal survival and functional outcome.

Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2071-2078 ◽  
Author(s):  
Janina Ratajczak ◽  
Ryan Reca ◽  
Magda Kucia ◽  
Marcin Majka ◽  
Daniel J. Allendorf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Complement C3 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Chimeric Mice ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Abstract The mechanisms regulating the homing/mobilization of hematopoietic stem/progenitor cells (HSPCs) are not fully understood. In our previous studies we showed that the complement C3 activation peptide, C3a, sensitizes responses of HSPCs to stromal-derived factor 1 (SDF-1). In this study, mobilization was induced with granulocyte colony-stimulating factor (G-CSF) in both C3-deficient (C3–/–) and C3a receptor–deficient (C3aR–/–) mice as well as in wild-type (wt) mice in the presence or absence of a C3aR antagonist, SB 290157. The data indicated (1) significantly increased G-CSF–induced mobilization in C3–/– and C3aR–/– mice compared with wt mice, (2) significantly accelerated and enhanced G-CSF–induced mobilization in wt, but not in C3–/– or C3aR–/–, mice treated with SB 290157, and (3) deposition of C3b/iC3b fragments onto the viable bone marrow (BM) cells of G-CSF–treated animals. Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR–/– BM cells, but not C3aR–/– mice reconstituted with wt BM cells, are more sensitive to G-CSF–induced mobilization, suggesting that C3aR deficiency on graft-derived cells is responsible for this increased mobilization. Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-1, the concentration of which is reduced in BM during mobilization. The C3a-C3aR axis may prevent an uncontrolled release of HSPCs into peripheral blood. These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation.

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