Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Department of Plastic, Reconstructive and Burns Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Sci Rep. 2023 Aug 14;13(1):13183. doi: 10.1038/s41598-023-40531-9.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive respiratory disease. Arguably, the complex interplay between immune cell subsets, coupled with an incomplete understanding of disease pathophysiology, has hindered the development of successful therapies. Despite efforts to understand its pathophysiology and develop effective treatments, IPF remains a fatal disease, necessitating the exploration of new treatment options. Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of IPF, but further investigation is needed to understand its therapeutic effect. This study aimed to assess the therapeutic effect of adipose-derived mesenchymal stem cells in a bleomycin-induced pulmonary fibrosis model. First, MSC cells were obtained from mice and characterized using flow cytometry and cell differentiation culture methods. Then adult C57BL/6 mice were exposed to endotracheal instillation of bleomycin and concurrently treated with MSCs for reversal models on day 14. Experimental groups were evaluated on days 14, 21, or 28. Additionally, lung fibroblasts challenged with TGF-β1 were treated with MSCs supernatant or MSCs to explore the mechanisms underlying of pulmonary fibrosis reversal. Mesenchymal stem cells were successfully isolated from mouse adipose tissue and characterized based on their differentiation ability and cell phenotype. The presence of MSCs or their supernatant stimulated the proliferation and migration of lung fibrotic cells. MSCs supernatant reduced lung collagen deposition, improved the Ashcroft score and reduced the gene and protein expression of lung fibrosis-related substances. Bleomycin-challenged mice exhibited severe septal thickening and prominent fibrosis, which was effectively reversed by MSCs treatment. MSC supernatant could suppress the TGF-β1/Smad signaling pathway and supernatant promotes fibroblast autophagy. In summary, this study demonstrates that MSCs supernatant treatment is as effective as MSCs in revert the core features of bleomycin-induced pulmonary fibrosis. The current study has demonstrated that MSCs supernatant alleviates the BLM-induced pulmonary fibrosis in vivo. In vitro experiments further reveal that MSC supernatant could suppress the TGF-β1/Smad signaling pathway to inhibit the TGF-β1-induced fibroblast activation, and promotes fibroblast autophagy by Regulating p62 expression. These findings contribute to the growing body of evidence supporting the therapeutic application of MSCs in cell therapy medicine for IPF.
特发性肺纤维化（IPF）是一种慢性、进行性呼吸系统疾病。可以说，免疫细胞亚群之间的复杂相互作用，加上对疾病病理生理学的不完全了解，阻碍了成功治疗方法的发展。尽管人们努力了解其病理生理学并开发有效的治疗方法，但 IPF 仍然是一种致命的疾病，需要探索新的治疗选择。间充质基质/干细胞（MSC）治疗在 IPF 的实验模型中显示出了希望，但需要进一步研究以了解其治疗效果。本研究旨在评估脂肪来源的间充质干细胞在博莱霉素诱导的肺纤维化模型中的治疗效果。首先，从小鼠中获得 MSC 细胞，并通过流式细胞术和细胞分化培养方法对其进行表征。然后，将成年 C57BL/6 小鼠暴露于博莱霉素气管内滴注，并在第 14 天同时用 MSC 进行逆转模型治疗。在第 14、21 或 28 天评估实验组。此外，用 TGF-β1 刺激肺成纤维细胞，并分别用 MSC 上清液或 MSC 处理，以探讨肺纤维化逆转的潜在机制。间充质干细胞成功地从小鼠脂肪组织中分离出来，并根据其分化能力和细胞表型进行了特征描述。MSC 或其上清液的存在刺激了肺成纤维细胞的增殖和迁移。MSC 上清液减少了肺胶原沉积，改善了 Ashcroft 评分，并降低了与肺纤维化相关物质的基因和蛋白表达。博莱霉素处理的小鼠表现出严重的间隔增厚和明显的纤维化，MSC 治疗可有效逆转这一现象。MSC 上清液可以抑制 TGF-β1/Smad 信号通路，而上清液促进成纤维细胞自噬。总之，本研究表明，MSC 上清液治疗与 MSC 治疗一样有效，可以逆转博莱霉素诱导的肺纤维化的核心特征。本研究表明，MSC 上清液减轻了 BLM 诱导的体内肺纤维化。体外实验进一步表明，MSC 上清液可以通过调节 p62 表达抑制 TGF-β1/Smad 信号通路，从而抑制 TGF-β1 诱导的成纤维细胞激活，并促进成纤维细胞自噬。这些发现为间充质干细胞在 IPF 细胞治疗中的治疗应用提供了越来越多的证据支持。
