Loss of peroxisome function promotes oxidative stress-induced hematopoiesis
Bibliographic record
Abstract
The role of peroxisomes in hematopoiesis remains poorly understood. The PEX1-Gly844Asp knock-in mouse lacks peroxisome formation and is peroxisome deficient. We observed that peroxisome-deficient animals had up to 50% greater numbers of peripheral lymphocytes, neutrophils, and platelets which contained 2-fold greater reactive oxygen species (ROS, P = .0002). The marrow contained 2-fold greater numbers of cells and colony forming unit (P = .0009 and <.0001, respectively). We found expansion (up to 3-fold) in the hematopoietic stem and progenitor cell (HSPC) compartment compared to that of wild-type (WT) animals demonstrated by: in vivo enumeration of Lin-SCA1+c-KIT+ (LSK) (P < .0001). Importantly through competitive bone marrow transplant experiments (primary and secondary), we show that peroxisome-deficient cells outcompete WT. We further demonstrate that peroxisome-deficient HSPC harbor very high levels of intrinsic ROS which are attenuated after repopulation. Isolation of mesenchymal stem cells (MSC) isolated from peroxisome-deficient mice also showed elevated levels of ROS. Finally, we found elevated levels of stem cell factor (SCF) in the plasma of peroxisome-deficient mice, and peroxisome-deficient MSC expressed 2-fold more SCF compared to WT. Chemical induction of ROS also increased SCF expression by MSC. Lin-SCA1+c-KIT+ expanded 10-fold greater in the absence of SCF on peroxisome-deficient MSC than that on WT MSC. In conclusion, the increase in HSPC numbers is, in part, driven by response to ROS in the microenvironment leading to increased SCF. These data add new insight into the role of peroxisomes in the bone marrow niche.
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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 | 0.000 | 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) | 0.000 | 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".