Single Cell-Resolution Analysis of HSC Dysfunction in <i>Mir-146a</i> knockout Mice
Bibliographic record
Abstract
Abstract MicroRNA miR-146a is frequently depleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Loss of miR-146a may be an initiating event in tumorigenesis, as miR-146a loss in mouse models is sufficient to cause features of MDS and eventual progression to AML. To define how miR-146a loss initiates tumorigenesis, we analyzed hematopoietic stem cell (HSC) function from miR-146a knockout (KO) mice prior to onset of an overt malignant phenotype. Tracking cell division kinetics, proliferation, and differentiation of single long-term HSC (LT-HSC; EPCR+CD45+CD48-CD150+) in culture, we found evidence that miR-146a KOreduces HSC quiescence and promotes differentiating cell divisions. Our data show that miR-146a KO HSC dysfunction may stem from loss of a CD150-bright EPCR-bright sub-population, which has previously been associated with robust HSC activity. In line with this, single cell DNA methylation profiling revealed a reduction in a primitive sub-population of LT-HSCs in miR-146a KO animals. In addition, single cell LT-HSC transplants revealed a myeloid repopulation bias. As reduced HSC cell cycle quiescence has been linked to impaired HSC self-renewal upon hematopoietic stress, such as serial transplantation, we assessed the frequency of serially transplantable HSCs by performing secondary transplants with limiting dilution. Serially transplantable HSC frequency was reduced in miR-146a KO compared to wild type, suggesting impaired HSC self-renewal. Transcriptome profiling of miR-146a KO hematopoietic stem and progenitor cells identified tumor necrosis factor (TNF) signaling activation as a potential driver of HSC dysfunction. LT-HSC cell cycle quiescence and the CD150-bright EPCR-bright LT-HSC sub-population were restored in miR-146a/TNF double KO mice, suggesting that aberrant TNF signaling activation drives HSC dysfunction upon loss of miR-146a. Gene expression levels in the TNF signaling network are inversely correlated with miR-146a levels in human AML, implying that TNF signaling may similarly disrupt HSC function in miR-146a- depleted myeloid malignancies. Overall, our findings suggest that miR-146a promotes HSC cell cycle quiescence and inhibits differentiation by antagonizing TNF signaling, in order to maintain a primitive sub-population of long-term self-renewing HSCs. Disclosures Eaves: Experimental Hematology: Other: Editor of journal; StemCell Technologies Inc: Other: Wife of owner.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".