Lymphedema-associated fibroblasts are related to fibrosis and stage progression in patients and a murine microsurgical model
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...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
October 2024
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| In: |
Plastic and reconstructive surgery
Year: 2024, Jahrgang: 154, Heft: 4, Pages: 688e-700e |
| ISSN: | 1529-4242 |
| DOI: | 10.1097/PRS.0000000000011141 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1097/PRS.0000000000011141 Verlag, lizenzpflichtig, Volltext: https://journals.lww.com/plasreconsurg/fulltext/2024/10000/lymphedema_associated_fibroblasts_are_related_to.19.aspx 
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| Verfasserangaben: | Patrick A. Will, Msc, Katja Kilian, MD, Karen Bieback, PhD, Fabia Fricke, PhD, Juan Enrique Berner, FRCS, Ulrich Kneser, MD, Christoph Hirche, MD |
| Zusammenfassung: | 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-cadherinhigh phenotype to an N-cadherinhigh-E-cadherinlow 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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| Beschreibung: | Gesehen am 24.03.2025 |
| Beschreibung: | Online Resource |
| ISSN: | 1529-4242 |
| DOI: | 10.1097/PRS.0000000000011141 |