Kupffer cells are essential for platelet-mediated thrombopoietin generation in the liver
Bibliographic record
Abstract
Thrombopoietin (TPO), predominantly produced by the liver, is the key regulator for platelet production and the hematopoietic stem cell niche. Our earlier report demonstrated that platelet GPIbα is required for hepatocellular TPO generation, which is the major resource of TPO in the blood circulation. However, how hepatocytes physically contact circulating sinusoidal platelets across the liver endothelium for this process is unknown. Kupffer cells reside in contact with both sinusoidal blood and underlying hepatocytes, and mediate senescent platelet clearance, but their role in TPO regulation has never been explored. Here, we found Kupffer cell depletion via either clodronate liposomes or specific transgenic models abrogated circulating TPO. Kupffer cell depletion also prevented TPO level increase in GPIbα-deficient mice following wild-type (GPIbα + ) platelet transfusion, signifying an interdependent mechanism for TPO regulation. Mice treated with arsenite had significantly decreased liver endothelial fenestrations and hepatocyte sinusoidal protrusions as well as TPO levels. This effect was exacerbated by Kupffer cell depletion, and Kupffer cells were identified to enhance liver endothelial fenestrations. Electron microscopy and immunofluorescence analysis of the liver revealed platelets arrested on Kupffer cell surface were in contact with hepatocyte protrusions. Thus, we elucidated that Kupffer cells promote endothelial fenestrae and hepatocyte protrusions, accumulate circulating platelets, and facilitate cellular interactions between hepatocytes and platelets, which drive TPO generation. This connection between platelet clearance and thrombopoiesis should have broad implications for hematology and pathologies such as Bernard–Soulier syndrome, thrombocytopenias, as well as liver diseases.
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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 | 0.001 |
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".