Evidence of a functional Smad2/3 signaling axis and TGFβ‑mediated autocrine transcriptional regulation of <i>in vitro</i> vasculogenic mimicry in mesenchymal stem/stromal cells
Bibliographic record
Abstract
Transforming growth factor β (TGFβ) serves a key physiological role in regulating the mobilization of mesenchymal stem/stromal cells (MSCs) to peripheral blood and injured tissues during ischemic and inflammatory processes. However, it has been suggested that in pathological settings circulating MSCs in peripheral blood contribute to tumor angiogenesis in response to immunosuppressive cytokines, such as TGFβ. The fact that MSCs are unable to fully differentiate into an endothelial angiogenic phenotype suggests that alternative mechanisms, including vasculogenic mimicry (VM), may be involved. The present study aimed to assess the impact of TGFβ signaling on the in vitro formation of 3D capillary‑like structures that recapitulate VM, and to elucidate the underlying signal transduction and molecular mechanisms involved in the vasculogenic function of MSCs. In vitro VM of MSCs was induced on a Cultrex matrix and gene expression was measured by reverse transcription‑quantitative PCR. Protein expression in total lysates or in cytosolic/nuclear fractions was measured by western blotting. Transient gene suppression was performed using small interfering RNA. Cell chemotaxis was assessed using the xCELLigence system. Notably, treatment of MSCs with TGFβ induced the expression of Snail, a key transcription factor regulating epithelial‑to‑mesenchymal transition, as well as its translocation into the nucleus alongside phosphorylated Smad2/3. Similarly, the formation of 3D structures resulted in the upregulation of Snail, FOXC2 and TGFβ expression. Treatment with Galunisertib, a TGFβ receptor (TGFβR) kinase inhibitor, prevented the formation of 3D structures, demonstrating that TGFβR signaling is required for the vasculogenic activity of MSCs. Furthermore, transient silencing of Smad2/3 impaired TGFβ‑mediated cell chemotaxis, which is critical for in vitro VM, reinforcing the previous evidence of the importance of TGFβR activity in this process. Taken together, the present study highlighted a new in vitro alternative mechanism involving VM that allows MSCs to adopt a vasculogenic phenotype. The involvement of TGFβ‑mediated autocrine signaling in VM could represent a new target to modulate the angiogenic activity of MSCs in future anticancer strategies.
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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 | 0.001 |
| 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".