ADSC-Exs Suppresses the Fibrosis Process of Derma in Secondary Lymphedema

Abstract Background Mesenchymal stem cells (MSCs) and their exosomes, particularly adipose-derived stem cell exosomes (ADSC-Exs), have shown promise in treating secondary lymphedema (SLE), a condition characterized by fibrosis driven by the TGFβ-Smad signaling pathway. While ADSCs and ADSC-Exs have demonstrated antifibrotic effects, it is not yet clear whether these benefits stem from their ability to regulate this pathway. This study aimed to clarify the role of ADSCs and ADSC-Exs in reducing fibrosis in SLE by modulating the TGFβ-Smad pathway. Methods We established a secondary lymphedema model in C57BL/6 mice through surgical excision and localized radiation. Tissue staining was used to assess fibrosis progression at key time points, identifying the peak fibrosis stage. ADSCs and ADSC-Exs were injected into the affected areas to test their therapeutic effects, while TGFβ1 inhibitors were used as controls to block the TGFβ-Smad signaling pathway. This study compared the effects of ADSCs, ADSC-Exs, and the inhibitors on lymphedema and fibrosis markers, with a focus on their influence on the TGFβ-Smad pathway. Results Fibrosis in the SLE model peaked between the 4th and 5th weeks. Both ADSCs, ADSC-Exs, and the TGFβ inhibitor EW-7197 reduced edema and fibrosis, with ADSC-Exs having the most significant effect on skin fibrosis. This was evident by decreased levels of TGFβ1, Smad2/3, and phosphorylated Smad2/3, along with increased Smad7 levels, indicating that ADSC-Exs effectively regulate the TGFβ-Smad pathway to reduce fibrosis. Conclusions Our findings demonstrate that ADSCs and ADSC-Exs significantly alleviate edema and fibrosis in a secondary lymphedema mouse model. This therapeutic effect is largely mediated through the regulation of the TGFβ-Smad pathway, suggesting a promising approach for treating fibrosis in SLE.