TIMP-3 Inhibition of Angiopoietin-1 Signaling Recruits Hematopoietic Stem Cells from the Bone Marrow Niche.
Bibliographic record
Abstract
Abstract Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production in the adult bone marrow. Quiescent HSCs are rapidly recruited into the cell cycle when they face hematopoietic demands such as myelosuppression, returning to quiescence once they produce enough progenitors. It was previously shown that quiescent HSCs express Tie2 and that Tie2/angiopoietin-1 (Ang-1) signaling plays a critical role for maintaining HSC quiescence. However, molecular cues for recruiting HSCs from a quiescent state into cycle remain poorly understood. Extracellular signals are often regulated by the extracellular matrix environment, which is modulated by metalloproteinase (MMP) activities. TIMP-3 is an endogenous inhibitor of MMPs, and we have previously proposed that TIMP-3 may play a critical role in HSC physiology. In addition, TIMP-3 has been reported to suppress angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling. By analogy with VEGF inhibition, we reasoned that TIMP-3 might suppress Ang-1 signaling in HSC and act as a molecular cue for HSC recruitment. In order to investigate a role of TIMP-3 in the HSC recruitment, we first examined whether TIMP-3 is regulated in the BM upon myelosuppression. Analyses by reverse transcription polymerase chain reaction (RT-PCR) and immunostaining revealed that the injection of 5-fluorouracil (5-FU) or irradiation induced TIMP-3 at the endosteal surface of the BM after 3-days of treatment. We next tested the hypothesis that TIMP-3 might be regulating Ang-1 signals by using cell line models. This revealed that the pre-treatment of cells with TIMP-3 suppressed autophosphorylation of Tie-2 in response to Ang-1. BIAcore and in vitro binding assay revealed that TIMP-3 directly interacted with Ang-1 and Tie-2, indicating that TIMP-3 suppressed Ang-1 signaling through interfering ligand-receptor interaction. Next we examined the effect of TIMP-3 on HSC physiology. TIMP-3 promoted the proliferation of CD34-KSL cells in vitro by approximately 2–3 fold. This was mainly due to the enhanced production of multipotential progenitors from CD34-KSL cells, which was accomplished by an enhanced symmetrical cell division of multipotential progenitors as revealed by paired-daughter cell analysis. Bone marrow transplantation study of TIMP-3-treated CD34-KSL cells showed that they sustained long-term repopulating potential comparable to the control-treated cells. Furthermore, in vivo administration of TIMP-3 into mice accelerated recovery and protected mice from myelosuppression, and in turn, the bone marrow recovery after myelosuppression was delayed in TIMP-3-deficient animals. In summary, TIMP-3 is induced by myelosuppression in the BM niche, stimulates HSC proliferation by inhibiting Ang-1 signaling, and thereby promotes production of multipotential progenitors from HSCs. These results demonstrate that TIMP-3 acts as a molecular cue for recruiting quiescent HSCs from the BM 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".