Novel Mechanisms of Thrombopoietin Generation: The Essential Role of Kupffer Cells
Bibliographic record
Abstract
Abstract Thrombopoietin (TPO) is the physiological regulator of hemopoietic stem cell niche and megakaryocyte differentiation, and therefore platelet production. Prevailing theory posits that TPO is constitutively expressed by hepatocytes, and levels are fine-tuned through platelet and megakaryocyte internalization/clearance via the c-Mpl receptor. Our lab has previously shown that platelet glycoprotein (GP) Ibα is indispensable for platelet-mediated TPO generation (Blood 2018), and recent reports have demonstrated that Kupffer cells, the tissue resident macrophages of the liver, contribute to the clearance of desialylated platelets. However, whether Kupffer cells may contribute to TPO generation has never been explored. To determine the possible role of Kupffer cells in TPO production, clodronate liposome was intravenously administered to deplete Kupffer cells in wild-type mice. Wild-type, Kupffer cell depleted mice showed a TPO decrease of 43.6% (±16%) 2 days post depletion, with only a gradual insignificant increase in TPO levels to day 6. Interestingly, TPO levels could not be significantly increased in wild-type Kupffer cell depleted mice even when transfused 2x10 8 wild-type or desialylated platelets, or 50mU neuraminidase. Kupffer cell depletion in IL4Rα/GPIbα-transgenic mice, which lack platelet-mediated TPO generation, showed a TPO decrease of 22.5% (±5%) from baseline 2 days post depletion, with only a gradual increase in levels to day 6, suggesting that Kupffer cells are required for constitutive in addition to platelet-mediated TPO production. As our lab has previously shown that platelet GPIbα drives platelet-mediated TPO generation, and that Kupffer cells now required, WT and GPIbα -/- platelets were co-cultured with Kupffer cells to assess interaction. Desialylated WT platelets interacted significantly more with Kupffer cells as analyzed by flow cytometry than GPIbα -/- platelets. Interestingly, desialylation of GPIbα -/- platelets did not increase binding to Kupffer cells, consolidating that desialylated GPIbα is required for Kupffer cell interaction, and subsequent TPO generation. This data demonstrates the novel and unexpected finding that Kupffer cells are required for both platelet-mediated and baseline hepatocellular TPO generation. Elucidation of the role of Kupffer cells in this crucial mechanism will provide a better understanding of why thrombocytopenias may occur in pathological states, as well as contribute to the development of TPO mimetic therapies. Disclosures No relevant conflicts of interest to declare.
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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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".