Mobilization Studies in Immunodeficient Mice Support a Role of Complement in Modulating the Trafficking of Hematopoietic Stem Cells (HSC) - A Pivotal Role of C3 Cleavage Fragments in Retention and C5 Fragments in Mobilization/Egress of HSC.
Bibliographic record
Abstract
Abstract We postulate that mobilization of hematopoietic stem cells (HSC) is part of a immune-response and to support this notion i) complement (C) cascade cleavage fragments modulate trafficking of HSC (Blood2003;101,3784; Blood2004;103,2071) and ii) patients suffering from severe combined immunodeficiency (SCID) are poor mobilizers (Blood1996;88, 1104). To shed more light on mechanisms involved in C-mediated trafficking of HSC we studied mobilization in several strains of immune-deficient mice mobilized by employing various mobilization protocols. We noticed that mobilization of HSC is always preceded by C activation - occuring by the classical (G-CSF, CY) or alternative (polysaccharides, chemokines) activation pathways. Accordingly, the classical pathway of C activation after G-CSF or CY administration is a result of proteolytic modification of the BM environment leading to the exposure of a neo-antigen in BM tissue, and binding of natural IgM antibodies to this neo-epitope triggers activation of the C cascade. In support of this, IgM-deficient mice (SCID, RAG2null and Jh) are poor mobilizers and G-CSF-induced mobilization in these mice was restored after supplementation with purified C-activating inmmunoglobulins. On the other hand the mobilization in these mice (SCID, RAG2null and Jh) was normal in response to polysaccharides or chemokines that activate complement by the alternative IgM-independent pathway. To further support an important role of C in HSC mobilization, we studied HSC mobilization in mice deficient for various C components (C3−/− and C5−/− mice). We noticed that C3−/− mice are easy mobilizers. In contrast mobilization was very poor in C5−/− mice. This suggests that C3 and C5 cleavage fragments differently control the mobilization of HSC. We will present evidence that C3 cleavage fragments directly interact with HSC and prevent their uncontrolled egress from BM during mobilization by increasing their SDF-1-dependent marrow retention. In contrast C5 cleavage fragments activate neutrophils and BM-endothelium and thus are crucial for the egress of HSC. Thus the mobilization of HSC is i) dependent on C activation by the classical or alternative pathway, ii) modified differently by C3 cleavage fragments which enhance retention and C5 cleavage fragments which promote egress of HSC. Thus modulation of C activation in BM may help to develop new more efficient strategies for both HSC mobilization and their homing/engraftment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".