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
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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 <em>in vitro</em> 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. <em>In vitro</em> 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 <em>in vitro</em> VM, reinforcing the previous evidence of the importance of TGFβR activity in this process. Taken together, the present study highlighted a new <em>in vitro</em> 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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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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 it