A25 THE “UPSIDE-DOWN OR OUTSIDE-IN”: UNDERSTANDING HOW FOXL1+ TELOCYTES GOVERN THE EPITHELIAL-MESENCHYMAL CROSSTALK IMPACTING CELL BEHAVIOR BY USING PROTEOMICS STRATEGIES
Bibliographic record
Abstract
Abstract Background The mechanical information contained in the basement membrane (BM) is translated into intracellular signals via a process called mechanotransduction. The integrin-mediated cellular adhesions are found at the center of this outside-in mechanism connecting specific extracellular matrix (ECM) proteins with intracellular adaptors proteins that relay the signal via F-actin cytoskeleton turnover, Rho GTPase activity and eventually down to the nucleus. Dysregulation in any step of this tightly controlled process is a major contributor of disease development. Mesenchymal Foxl1+-telocytes (TCs) are known as a communication hub between stromal and epithelial cells from their proximity to the BM and from their potential roles in epithelial mechanical support and cell signaling. We have shown that BMPR1A signaling deletion in TCs (TCΔBmpr1a) induces stem cell niche defects, stromagenesis and colonic dysplasia in mouse model of GI diseases. Thus far, no study explored TCs relevance in microenvironment biomechanics and its subsequent impact in epithelial mechanotransduction. Aims Understand how TCΔBmpr1a can modulate mechanotransduction to induce early dysplastic changes in mouse colon. Methods Matrisomics was performed to determine the inventory of ECM proteins expressed solely in the GI stromal compartment following tissue deconstruction of control and TCΔBmpr1a mice colons. Collagen fibers analysis, histological and biochemical methods were used to further characterize the matrix biodynamics. Proteomics of the associated epithelial compartment was also done to expose mechanosensors and signaling cascades affecting cell behaviour. Results Matrisomics indicate modulations in fiber assembly proteins (collagens (CL), Decorin, Biglycan), ECM remodelling enzymes (LOXL1, TGM2), growth factors (LTBP1, WNT2B) and cell adhesion mediators (Periostin). This is associated with a reorganization in CL fiber alignment, cellular delocalization of TGM2 and increased unfolded CL content. TCΔBmpr1a leads to shortcomings in matrix assembly, hence variations in the ECM architecture and a novel epithelial mechanotransduction potential. Deregulations in matrix-to-cell communication were shown by proteomic analysis of the epithelial-enriched compartment of colonic dysplastic areas, with modulations of mechanosensors such as focal adhesion components (integrins, paxillin), F-actin cytoskeleton (gelsolin, RhoA) and nuclear lamina (Prelamin A/C, nesprin). Conclusions Taken together, these results suggest that TCΔBmpr1a can reprogram epithelial cells by impacting on matrix biodynamics and epithelial mechanotransduction. Modulation in this fine regulated sequence of communication from TCs to the epithelial nucleus via ECM could lead to the etiology of GI pathologies. Funding Agencies CIHR
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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) | 0.002 | 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".