Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells
Bibliographic record
Abstract
Hematopoietic stem cells preserve their ability to self-renew and differentiate to different lineages in the bone marrow (BM) niche, which is composed in large part by BM stromal cells. Studies have shown that altered signaling in the BM niche results in leukemia initiation or progression. Fanconi anemia (FA) is an inherited BM failure syndrome associated with extremely high risk of leukemic transformation. By using two FA mouse models, here we have investigated the hematopoiesis-supportive function of FA BM mesenchymal stroma cells (MSCs). We found that MSCs deficient for Fanca or Fancc gene are defective in proliferation and prone to undergo senescence in vitro. Mechanistically, we show that the activity of cell division control protein 42 (Cdc42), a Rho GTPase known to be a critical regulator for cytoskeleton organization, is significantly reduced in FA MSCs. Furthermore, we demonstrate that this reduction in Cdc42 activity plays a causal role in defective hematopoiesis-supportive function of the FA MSCs. The progenies of wild-type hematopoietic stem and progenitor cells cocultured on FA MSCs exhibit compromised self-renewal capacity both in vitro and in vivo. Genetic correction of FA deficiency restores Cdc42 activity and improves the hematopoiesis-supportive capacity of FA MSC. Finally, ectopic expression of a constitutively active Cdc42 mutant, Cdc42F28L, or pretreatment with Wnt5a, increases the active Cdc42 level and rescues the hematopoietic supportive defects of FA MSCs. Taken together, our results identify a novel link between Cdc42 activity and the hematopoiesis-supportive function of MSCs and suggest that a niche-specific increase of Cdc42 activity may be beneficial for FA therapy. Stem Cells 2018;36:785-795.
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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".