Bibliographic record
Abstract
Extracellular matrix (ECM) homeostasis is essential for normal tissue function. Disruption of homeostasis by iatrogenic injury, trauma, or disease can lead to fibrosis. Skin ECM homeostasis is maintained by a complex process involving an integration of cytokine and environmental mediators. It is currently unclear, in both normal and disease states, as to how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. In this study, an interplay between fatty acid oxidation (FAO) and glycolysis was observed to be a key convergence point governing ECM homeostasis in skin. A consistent shift from FAO to glycolysis was observed in human and murine skin with ECM accumulation, and in dermal fibroblasts induced to upregulate ECM production by multiple mediators (TGF-Β1, PDGF-BB, hypoxia). Pharmacologic inhibition and genetic knockdown of key FAO and glycolysis pathway enzymes in dermal fibroblasts confirmed that FAO and glycolysis have opposing roles in ECM regulation. Specifically, glycolysis induced an anabolic fibroblast that upregulated ECM production. This was counteracted by shifting fibroblasts to FAO, which induced a catabolic phenotype inhibiting both transcription of components of the ECM, as well as enhancing ECM internalization and lysosomal degradation. CD36, a multifunctional fatty acid transporter, was discovered to be a critical mediator connecting the metabolic state of fibroblasts with their capacity for ECM regulation. CD36 promoted the catabolic effect of a FAO fibroblast, as its knockdown abrogated the internalization and degradation of collagen-1. Restoring FAO and upregulating CD36, either through pharmacotherapy or by autologous transplantation of CD36high fibroblasts, reduced ECM accumulation in murine radiation fibrosis. Our data demonstrate that metabolic regulation may be an integration point downstream of molecular signaling pathways that govern ECM homeostasis by shifting fibroblasts between anabolism and catabolism. These results have broad implications for therapies aimed at ECM reduction, such as fibrosis, or ECM buildup, such as regenerative medicine and aging.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 | 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".