TGF-β–mediated epithelial–mesenchymal transition of keratinocytes promotes fibrosis in secondary lymphedema
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PROVIDER: PRJNA1288784 | ENA |
REPOSITORIES: ENA
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Project description:Secondary lymphedema is characterized by fibrosis and impaired lymphatic function. Although TGF-β is a key regulator of fibrosis in this disease, the cellular mechanisms regulating this process remain unknown. Epithelial-mesenchymal transition(EMT), a mechanism by which TGF-β induces fibrosis in other skin diseases, is characterized by loss of epithelial cell markers and cellular polarity, upregulation of fibrotic gene expression, and gain of migratory capacity. Using clinical lymphedema biopsy specimens and animal models, we show that keratinocytes in the basal layer of epidermis undergo EMT in lymphedematous skin, migrate into the dermis, and contribute to dermal fibrosis. In vitro studies using cultured primary human keratinocytes treated with lymphatic fluid from the affected limbs of patients with secondary lymphedema resulted in a TGF-β-mediated increased expression of EMT markers. We show for the first time that EMT is activated by TGF-β in secondary lymphedema and that this process plays an important role in regulating skin fibrosis in this disease.
2025-07-09 | GSE302118 | GEO
Project description:Secondary lymphedema is a debilitating chronic tissue swelling in a limb caused by inadequate interstitial fluid drainage due to dysfunctional lymphatic vessels. Pathological enlargement of small lymphatics contributes to lymphatic dysfunction in secondary lymphedema, but the molecular mechanisms driving this remodelling are unclear. Here, using a surgical mouse model of secondary lymphedema and whole-genome microarray, we identified the transcript for insulin-like growth factor binding protein 5 (IGFBP5), a negative regulator of IGF signaling, as the most profoundly down-regulated mRNA in lymphedematous tissue. Notably, IGF signalling via IGF1 receptor (IGF1R) was previously shown to promote lymphatic remodelling. We therefore targeted IGF1R in the mouse model using the small molecule IGF1R inhibitor linsitinib. Linsitinib was effective in restricting enlargement of small lymphatics and tissue swelling during lymphedema development. Importantly, linsitinib profoundly reduced tissue swelling in mice with chronic lymphedema suggesting that IGF signalling could be a therapeutic target in clinical secondary lymphedema.
2025-02-19 | GSE256205 | GEO
Project description:Secondary lymphedema, a progressive disorder characterized by pathological fibroadipose tissue accumulation, is a common problem after cancer treatment and orthopedic surgery. It remains a therapeutic enigma due to its self-perpetuating fibrotic cascade and lack of disease-modifying therapies.Human skin tissue was collected from lymphedema patients and normal controls. Histological/immunofluorescence staining and RNA sequencing were performed. Fibrous tissue was observed in lymphedema samples. RNA sequencing and gene set enrichment analysis (GSEA) revealed significant downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling in lymphedema tissue.
2025-07-19 | GSE302563 | GEO
Project description:We isolated adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with malignancy-related extremity lymphedema, and we used adipose tissue from the normal upper abdomen of the same patients as control tissue. We compared the proliferation and adipogenic differentiation capacity between the two kinds of ASCs, and we explored the transcriptomic differences between them. We found that lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 inhibitors could return the abnormal biological characteristics of these cells to normal phenotype, suggesting that CDK1 is a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema, indicating the CDK1 may be a potential target for lymphedema therapy. On the other hand, our finding showed that ASCs from lymphedema adipose tissues have higher immunosuppressive effect, and the inhibition of up-regulated cytokine CHI3L1 may be clinically beneficial. In summary, explore the underlying mechanisms of fat deposition in lymphedema may provide powerful strategies for the treatment of lymphedema.
2019-06-19 | GSE132936 | GEO
Project description:Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in lymphedematous arm compared to normal arm in patients. The role of APLN in LD was confirmed in APLN-knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of non-integrative RNA-delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.
2023-10-20 | E-MTAB-13381 | biostudies-arrayexpress
Project description:Mouse surgical model of acute lymphedema induction. We performed three sets of microarrays with three replicates each for a total of 9 arrays. Each array was run using pooled RNA from three animals. The three conditions were Normal tail skin (no intervention), Lymphedema tail skin(due to surgical lymphatic vessel blockage), and Surgical Sham control tail skin(surgical incision with no lymphatic vessel blockage). 15ug of test and reference (e17.5 mouse whole embryo) RNA was used for labeling. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2006-03-04 | GSE4333 | GEO
Project description:BackgroundSecondary lymphedema is a common complication of cancer treatment, and previous studies have shown that the expression of transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic and anti-lymphangiogenic growth factor, is increased in this disease. Inhibition of TGF-β1 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown.MethodsExpression of TGF-β1 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL). The effects of TGF-β1 inhibition using neutralizing antibodies or a topical formulation of pirfenidone (PFD) were analyzed in mouse models of lymphedema. We also assessed the direct effects of TGF-β1 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant-negative TGF-β receptor selectively on LECs (LECDN-RII ).ResultsThe expression of TGF-β1 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF-β1 in mouse models of lymphedema using neutralizing antibodies or with topical PFD decreased ECM deposition, increased the formation of collateral lymphatics, and inhibited infiltration of T cells. In vitro studies showed that TGF-β1 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF-β1 responsiveness in LECDN-RII resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls.ConclusionsOur results show that TGF-β1 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema.
| S-EPMC9160979 | biostudies-literature
Project description:Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema
| PRJEB66475 | ENA
Project description:Transcriptome Analysis and Functional Identification of Adipose-Derived Mesenchymal Stem Cells in Secondary Lymphedema
| PRJNA549491 | ENA
Project description:Epigenetic reprogramming via EZH2 inhibition rescues fibroadipose pathogenesis in secondary lymphedema through activating PPARγ signaling
| PRJNA1291192 | ENA