Adipose-derived stem cells alleviate radiation-induced muscle fibrosis by promoting muscle regeneration

Sha Li¹Mingjing Peng¹Xiang Ou²Zhijiao Zhou³Luyuan Xie⁴Yuxin Ge¹Xiao Zhou¹Chunmeng Shi⁵Xiaowu Sheng^1*

• ¹Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China, Changsha, China
• ²Department of Endocrinology,The Affiliated Changsha Central Hospital,Hengyang Medical School,University of South China, Changsha, China
• ³Department of Pathology, Third Xiangya Hospital,Central South University, Changsha, China
• ⁴Changsha Medical University, Changsha, China
• ⁵Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqin, China

Background: Radiation-induced muscle fibrosis (RIF) is a severe late-stage side effect of radiotherapy in adjacent normal tissues that significantly affects anticancer therapeutic efficacy and can even be life-threatening. Our previous studies have shown that satellite cells (SCs) become activated after ionizing radiation to facilitate muscle tissue repair. However, the acceleration and strengthening of this process have received little attention until recently. Adipose-derived stem cells (ADSCs), a type of mesenchymal stem cell, have emerged as an attractive therapeutic option in regenerative medicine due to their accessibility, abundance, and plasticity in adult organisms. In this study, we explored whether ADSCs could enhance SC proliferation and differentiation after radiation therapy. Methods: ADSCs were harvested, cultured, and passaged from male Sprague-Dawley rats and characterized in vitro. In vivo, rats were randomly assigned to control and ADSC-treated groups (n=6). ADSCs were transplanted into radiation-induced fibrosis (RIF) rat models at different time points (4, 12, and 24 w). Therapeutic effects of transplanted ADSCs were assessed via Masson's trichrome staining, electron microscopy, and hematoxylin-eosin (H&E) staining. SC activation, proliferation, and central nuclear immigration following ADSC transplantation therapy were evaluated via real-time polymerase chain reaction and H&E staining. Results: In vivo, fibrosis was markedly alleviated over time following ADSC treatment. In RIF rat model, ultrastructural histopathological changes, including mitochondrial edema and vacuolization, myofilament dissolution, vascular endothelial swelling, were notably attenuated by ADSC transplantation. Additionally, SCs exhibited a significant increase in activation and proliferation in the ADSC-treated groups, accompanied by a decrease in fibrotic symptoms. Conclusion: Our study provides evidence that ADSCs protect against RIF by promoting SC activation, proliferation and differentiation in vivo. ADSCs may represent a promising therapeutic candidate restoring muscle dysfunctions and abnormalities caused by RIF.