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

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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.

Authors

Ziyu Chen, Soheila Ali Akbari Ghavimi, Mengfan Wu, John McNamara, Olga Barreiro, David Maridas, Radomir Kratchmarov, Ashley Siegel, Sarah Djeddi, Maria Gutierrez-Arcelus, Patrick J. Brennan, Timothy P. Padera, Ulrich von Andrian, Babak Mehrara, Arin K. Greene, C. Ronald Kahn, Dennis P. Orgill, Indranil Sinha, Vicki Rosen, Shailesh Agarwal