Identification of a New Genetic Determinant Controlling Human Hematopoietic Stem Cell Engraftment.
Bibliographic record
Abstract
Abstract Transplantation of human hematopoietic stem cells (HSC) has been the most important clinical application of stem cell biology. A key discovery enabling successful HSC transplantation was the recognition that HSC engraftment is controlled by human leukocyte antigen (HLA) polymorphism. Although HLA disparity plays a key role in graft rejection, graft failure can occur even in patients receiving an HLA-identical transplant, suggesting that additional, as yet uncharacterized, factors modulate engraftment. We have identified a new genetic determinant that controls the outcome of human HSC transplantation. Xenotransplantation in the non-obese diabetic/severe combine immune-deficient (NOD.SCID) mouse is the best functional assay for human HSC, based on their ability to repopulate recipient animals. We show that NOD.SCID mice provide significantly better support for human hematopoietic grafts than mice of different strain backgrounds carrying equivalent immunodeficiency mutations. To identify the molecular basis for this strain-specificity, we used positional genetics combined with in vitro and in vivo assays of human hematopoiesis. We generated reciprocal congenic strains between NOD and the related non-obese diabetes resistant (NOR) strain which is 88% identical to NOD, and found that support of human hematopoiesis is conferred by variation in a single gene, signal regulatory protein α (Sirpα) on chromosome 2. Human HSC were unable to engraft NOD.SCID mice carrying the NOR allele of Sirpα. NOD SIRPα displays 24 amino acid variations compared to NOR and C57BL/6, concentrated in the immunoglobulin IgV-like domain of this Ig-superfamily member. SIRPα is expressed on myeloid cells and mediates signals that modulate diverse macrophage functions. Indeed, lentiviral gene transfer of the NOD Sirpα variant into NOR macrophages restored their ability to support human hematopoiesis in long-term chimeric stroma-based assays. CD47, the only known cellular ligand of SIRPα, is ubiquitously expressed and modulates multiple cellular actions on hematopoietic cells including platelet activation and adhesion, and leukocyte adhesion and cytokine production. NOD SIRPα demonstrates enhanced binding to human CD47 compared to the NOR protein, suggesting that differential interaction with CD47 underlies the strong effect of Sirpα variation on support of human hematopoiesis in vitro and in vivo. Our findings reveal a novel SIRPα-dependent, macrophage-mediated mechanism critical in HSC transplantation. Future analysis of Sirpα variants within human populations could identify alleles associated with hematopoietic support in BM failure syndromes or correlated with outcomes in clinical transplantation.
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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) | 0.000 | 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) | 0.001 | 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 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".