PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα(+) mesenchymal cells Journal Article


Authors: Chen, Z.; Ghavimi, S. A. A.; Wu, M.; McNamara, J.; Barreiro, O.; Maridas, D.; Kratchmarov, R.; Siegel, A.; Djeddi, S.; Gutierrez-Arcelus, M.; Brennan, P. J.; Padera, T. P.; von Andrian, U.; Mehrara, B.; Greene, A. K.; Kahn, C. R.; Orgill, D. P.; Sinha, I.; Rosen, V.; Agarwal, S.
Article Title: PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα(+) mesenchymal cells
Abstract: Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-β1-treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue deposition. Single-cell RNA-Seq data obtained from human tissues and flow cytometric and histological evaluation of mouse tissues demonstrated increased presence of PDGFRα+ cells in lymphedema; human tissue analysis verified these cells have the capacity for adipogenic and fibrogenic differentiation. Upon treatment with rosiglitazone, we noted a reduction in the overall quantity of PDGFRα+ cells and LipidTOX+ cells. Our findings provide a framework for treating secondary lymphedema as a condition of fibrosis and adipose tissue deposition, both of which, paradoxically, can be prevented with a pro-adipogenic agent.
Keywords: mouse; animal; animals; mice; platelet derived growth factor alpha receptor; receptor, platelet-derived growth factor alpha; lymphedema; fibrosis; peroxisome proliferator activated receptor gamma; ppar gamma; rosiglitazone; adipose tissue; cell biology; humans; human; male; female
Journal Title: JCI Insight
Volume: 8
Issue: 24
ISSN: 2379-3708
Publisher: Amer Soc Clinical Investigation Inc  
Date Published: 2023-12-22
Start Page: e165324
Language: English
DOI: 10.1172/jci.insight.165324
PUBMED: 38131378
PROVIDER: scopus
PMCID: PMC10807713
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Babak Mehrara
    451 Mehrara