Wang Ziyu, Shi Mengqi, Liu Zonghao, Chen Yahui, Shi Xiangguang, Wang Jiucun
State Key Laboratory of Genetics and Development of Complex Phenotypes, Fudan University, Shanghai, China.
Human Phenome Institute, Fudan University, Shanghai, China.
Stem Cell Res Ther. 2025 Jul 1;16(1):328. doi: 10.1186/s13287-025-04470-8.
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs, leading to significant morbidity and reduced quality of life. Despite ongoing research, the underlying pathogenesis of SSc remains unclear, and treatment options are limited. Stromal vascular fraction (SVF), a naturally occurring cell population that includes mesenchymal stem cells (MSCs), has emerged as a potential therapeutic agent for various fibrotic diseases. This study aimed to investigate the therapeutic effects and underlying mechanisms of SVF in a bleomycin-induced mouse model of skin fibrosis.
SVF was isolated from the inguinal adipose tissue of C57BL/6 mice and administered subcutaneously or intradermally at different disease stages to assess its impact on skin fibrosis. Histological analyses were performed to evaluate dermal thickness and collagen deposition. In vivo imaging and immunofluorescence were used to track the retention of SVF within fibrotic tissue over time, particularly in the subcutaneous layer. Flow cytometry and immunofluorescence were employed to examine cutaneous vascular pathology and the secretion of antifibrotic factors, such as hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF-2). Finally, we investigated the contribution of major SVF subsets to cutaneous fibrosis and the mechanisms by which these subsets mediate therapeutic effects.
SVF significantly attenuated skin fibrosis in both early and late stages of disease, as evidenced by reduced dermal thickness and collagen deposition. Notably, SVF showed prolonged retention in fibrotic tissues-especially in the subcutaneous layer-for at least 18 days post-injection, with antifibrotic effects primarily mediated through paracrine mechanisms. In early-stage fibrosis, SVF inhibited endothelial-mesenchymal transition and mitigated skin vascular damage. In late-stage fibrosis, SVF continued to secrete antifibrotic factors, including HGF and FGF-2. Subsequent analyses identified the CD45-negative subset of SVF as a key regulator of skin fibrosis.
SVF, particularly its CD45-negative subset, holds considerable promise for the treatment of SSc-associated skin fibrosis. These findings suggest that SVF-based therapies could be effective in managing fibrosis-related diseases and offer valuable insights for future clinical applications.
系统性硬化症（SSc）是一种慢性自身免疫性疾病，其特征为皮肤和内脏器官纤维化，导致严重发病并降低生活质量。尽管研究不断，但SSc的潜在发病机制仍不清楚，治疗选择有限。基质血管成分（SVF）是一种天然存在的细胞群体，包括间充质干细胞（MSC），已成为各种纤维化疾病的潜在治疗剂。本研究旨在探讨SVF在博来霉素诱导的皮肤纤维化小鼠模型中的治疗作用及潜在机制。
从C57BL/6小鼠腹股沟脂肪组织中分离SVF，并在不同疾病阶段皮下或皮内给药，以评估其对皮肤纤维化的影响。进行组织学分析以评估真皮厚度和胶原沉积。采用体内成像和免疫荧光技术追踪SVF随时间在纤维化组织中的滞留情况，特别是在皮下层。运用流式细胞术和免疫荧光技术检测皮肤血管病理以及抗纤维化因子如肝细胞生长因子（HGF）和碱性成纤维细胞生长因子（FGF-2）的分泌。最后，我们研究了主要SVF亚群对皮肤纤维化的作用以及这些亚群介导治疗效果的机制。
SVF在疾病的早期和晚期均显著减轻皮肤纤维化，表现为真皮厚度和胶原沉积减少。值得注意的是，SVF在纤维化组织中，尤其是皮下层，注射后至少18天内保留时间延长，抗纤维化作用主要通过旁分泌机制介导。在早期纤维化阶段，SVF抑制内皮-间充质转化并减轻皮肤血管损伤。在晚期纤维化阶段，SVF继续分泌抗纤维化因子，包括HGF和FGF-2。后续分析确定SVF的CD45阴性亚群是皮肤纤维化的关键调节因子。
SVF，特别是其CD45阴性亚群，在治疗SSc相关皮肤纤维化方面具有很大潜力。这些发现表明基于SVF的疗法可能对治疗纤维化相关疾病有效，并为未来临床应用提供有价值的见解。
