G-CSF Induces Expression of Both Hepatocyte Growth Factor (HGF) and Its Receptor (c-Met) in Human Hematopoietic Stem/Progenitor Cells and Mature Myeloid Cells - Novel Evidence That during Mobilization the HGF-c-Met Axis Counterbalances G-CSF-Induced Attenuation of the SDF-1-CXCR4 Axis.
Bibliographic record
Abstract
Abstract The stromal-derived factor-1 (SDF-1)-CXCR4 axis plays an important role in stem cell trafficking, and G-CSF- induced mobilization decreases SDF-1 expression in the bone marrow (BM) microenvironment and CXCR4 expression by CD34+ hematopoietic stem/progenitor cells (HSPC). Alternatively, the tyrosine kinase c-Met receptor-HGF axis was recently postulated to play an important role in the trafficking of non-hematopoietic cells; however, our previous research demonstrated that while HGF is an important constituent of the BM microenvironment, c-Met is not expressed by BM-derived steady state HSPC (Br J Haem1997;99:228). Recently we observed that both c-Met and HGF are upregulated during tissue organ/injury in a hypoxia-inducible factor-1α-dependent manner (Circ Res2004;95:1191). To determine whether G-CSF-induced mobilization affects the c-Met-HGF axis in HSPC, we isolated human CD34+ cells from BM and mobilized peripheral blood (mPB), mature myeloid cells and stromal cells and evaluated expression of c-Met and HGF by hematopoietic and BM-derived stromal cells without and after exposure to G-CSF, and the chemotactic responses of steady state and mobilized hematopoietic cells to HGF. We confirmed using RT-PCR and FACS analysis that the c-Met receptor is not expressed by steady-state BM CD34+ cells and mature mononuclear cells (MNC), but to our surprise we found that c-Met is expressed in G-CSF-mobilized CD34+ cells and MNC obtained from leukapheresis products. Supporting this was our finding that mPB but not steady state CD34+ cells responded to HGF stimulation by phosphorylation of MAPKp42/44 and AKT. HGF was found to highly expressed in mPB CD34+ cells and MNC but in steady state BM MNC. Moreover, G-CSF stimulation induced HGF expression in steady state BM MNC and BM-derived fibroblastic and mesenchymal stem cells. Importantly, when we compared c-Met expression on circulating PB leukocytes from patients during early and late stages of G-CSF mobilization we found that it increases in the later stages. When we compared the expression of CXCR4 and c-Met on leukocytes from the leukapheresis product vs circulating PB from the same patient we found that CXCR4 expression is similar but expression of c-Met is higher in the leukapheresis product. HGF was also found to be a strong chemoattractant for mPB leukocytes, but not for steady state leukocytes, and the chemotactic activity of HGF was totally inhibited by a c-Met antagonist. Additionally, we demonstrated that c-Met is incorporated into lipid rafts as shown by confocal microscopy and that G-CSF stimulation increases the secretion of matrix metalloproteinase (MMP)-9 from BM MNC, which was inhibited by the c-Met antagonist. A combination of G-CSF and HGF also upregulated membrane-type (MT)-MMPs such as MT1-MMP and MT6-MMP on leukocytes. Thus we demonstrate for the first time that G-CSF induces expression of functional c-Met and HGF in HSPC and leukocytes, and that the HGF-c-Met axis could play an important role in their mobilization and maintenance of high expression of matrix-degrading enzymes, allowing egress of HSPC from the BM.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".