Lymphedema-Associated Fibroblasts Are Related to Fibrosis and Stage Progression in Patients and a Murine Microsurgical Model
Bibliographic record
Abstract
BACKGROUND: The driver of secondary lymphedema (SL) progression is chronic inflammation, which promotes fibrosis. Despite advances in preclinical research, a specific effector cell subpopulation as a biomarker for therapy response or stage progression is still missing for SL. METHODS: Whole skin samples of 35 murine subjects of a microsurgically induced SL model and 12 patients with SL were collected and their fibroblasts were isolated. These lymphedema-associated fibroblasts (LAFs) were cultured in a collagen I-poly-D-lysine 3-dimensional hydrogel to mimic skin conditions. Fibroblasts from nonlymphedema skin were used as negative control and transforming growth factor β (TGF-β)-stimulated fibroblasts were used to recreate profibrotic myofibroblasts. Quantitative immunocytofluorescence confocal microscopy analysis and invasion functional assays were performed in all subpopulations and statistically compared. RESULTS: In contrast to normal skin fibroblasts, LAFs exhibit α-smooth muscle actin-positive stress fibers and a reduced number of tight junctions in 3-dimensional hydrogel conditions. The switch from normal E-cadherin high phenotype to an N-cadherin high -E-cadherin low morphology suggests epithelial-to-mesenchymal transition for expansion and proliferation. This pathologic behavior of LAF was confirmed by live cell imaging analysis of invasion assays. The significant activation of markers of the TGF-β receptor 2-Smad pathway and collagen synthesis (HSP-47 [heat shock protein 47]) in LAFs supports epithelial-to-mesenchymal transition phenotypic changes and previous findings relating to TGF-β1 and fibrosis with lymphedema. CONCLUSIONS: A characteristic SL myofibroblast subpopulation was identified and translationally related to fibrosis and TGF-β1-associated stage progression. This SL-related subpopulation was termed LAFs. A comprehensive stage-related characterization is required to validate LAFs as a reliable biomarker for SL disease progression. CLINICAL RELEVANCE STATEMENT: The authors identify a cellular effector for fibrosis and stage progression of secondary lymphedema as a possible biomarker for surgical indication and therapy response.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 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 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".