Liu Jiang, Peng Danyi, You Jingyi, Zhou Ou, Qiu Huijun, Hao Chang, Chen Hong, Fu Zhou, Zou Lin
Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Respiratory, Children's Hospital of Chongqing Medical University, Chongqing, China.
Stem Cells Dev. 2021 Jul 1;30(13):660-670. doi: 10.1089/scd.2020.0208. Epub 2021 Jun 1.
Pulmonary fibrosis (PF) is a chronic, progressive, and lethal disease with little response to available therapies. One of the major mechanisms of PF is the repeated injury and inadequate regeneration of the alveolar epithelium. In this study, we induced human umbilical cord mesenchymal stem cells (hUC-MSCs) to differentiate into type 2 alveolar epithelial cells (AEC2s), and we provided evidence that intratracheal transplantation of hUC-MSC-derived AEC2s (MSC-AEC2s) could improve mortality and alleviate fibrosis in bleomycin-induced PF mice. Transplantation of MSC-AEC2s could increase the AEC2 cell count in these mice, and the results of the cell tracing experiment exhibited that the increased AEC2s originated from the self-renewal of mouse alveolar epithelium. The AEC2 survival was controlled by the apoptosis of AEC2s via the expression of β-catenin in PF mice. In in vitro experiments, MSC-AEC2s could alleviate the apoptosis of MLE-12 cells induced by transforming growth factor beta (TGF-β1), which could be eliminated by using PRI-724, a β-catenin inhibitor, suggesting β-catenin signaling involved in the protection against apoptosis provided by MSC-AEC2s. Our study demonstrated that MSC-AEC2s could protect PF mice through regulating apoptosis mediated by β-catenin, which provided a viable strategy for the treatment of PF.
肺纤维化（PF）是一种慢性、进行性且致命的疾病，对现有治疗方法反应甚微。PF的主要机制之一是肺泡上皮反复损伤且再生不足。在本研究中，我们诱导人脐带间充质干细胞（hUC-MSCs）分化为2型肺泡上皮细胞（AEC2s），并且我们提供了证据表明气管内移植hUC-MSC来源的AEC2s（MSC-AEC2s）可提高博来霉素诱导的PF小鼠的存活率并减轻纤维化。MSC-AEC2s移植可增加这些小鼠的AEC2细胞数量，细胞追踪实验结果显示增加的AEC2s源自小鼠肺泡上皮的自我更新。在PF小鼠中，AEC2的存活通过β-连环蛋白的表达来控制AEC2s的凋亡。在体外实验中，MSC-AEC2s可减轻转化生长因子β（TGF-β1）诱导的MLE-12细胞凋亡，而使用β-连环蛋白抑制剂PRI-724可消除这种作用，这表明β-连环蛋白信号通路参与了MSC-AEC2s提供的抗凋亡保护作用。我们的研究表明，MSC-AEC2s可通过调节β-连环蛋白介导的凋亡来保护PF小鼠，这为PF的治疗提供了一种可行的策略。
