Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Stem Cells Transl Med. 2017 Mar;6(3):1006-1017. doi: 10.5966/sctm.2016-0054. Epub 2016 Oct 18.
Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti-inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM-preconditioned MSCs. OSM-preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM-preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor-β1- or OSM-induced extracellular matrix production in MRC-5 fibroblasts through paracrine effects. In bleomycin-induced lung fibrotic mice, transplantation of OSM-preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ-tagged MSCs were detected in the lung tissues of the OSM-preconditioned MSC-treated mice 18 days after post-transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM-preconditioned MSCs in alleviating lung fibrosis in the mice. Stem Cells Translational Medicine 2017;6:1006-1017.
间充质干细胞（MSCs）因其具有抗炎、抗纤维化、抗凋亡和再生特性而被广泛用于治疗肺纤维化。最近，在肺纤维化动物模型和患者的支气管肺泡灌洗液中报告了较高水平的抑瘤素 M（OSM）。在这项工作中，我们旨在通过使用 OSM 预处理的 MSC 延长植入 MSC 的存活时间并增强肺纤维化移植治疗的效果。结果表明，OSM 预处理的 MSC 过度表达 2 型 OSM 受体（gp130/OSMRβ），并对 OSM 表现出高敏感性，导致旁分泌因子肝细胞生长因子（HGF）上调。此外，OSM 预处理的 MSC 通过旁分泌作用增强了 MRC-5 成纤维细胞的细胞增殖和迁移，并减弱了转化生长因子-β1 或 OSM 诱导的细胞外基质产生。在博来霉素诱导的肺纤维化小鼠中，移植 OSM 预处理的 MSC 可显著改善肺呼吸功能，并下调肺组织中炎症因子和纤维化因子的表达。组织病理学检查表明肺纤维化有明显改善。在移植后 18 天，在 OSM 预处理的 MSC 治疗小鼠的肺组织中检测到 LacZ 标记的 MSC。总之，我们的数据进一步表明，HGF 的上调在介导移植的 OSM 预处理的 MSC 缓解小鼠肺纤维化的治疗作用中发挥了重要作用。《干细胞转化医学》2017；6：1006-1017。
