Xiong Zhiyu, Chen Ping, Wang Zheng, Yao Lichao, Yuan Mengqin, Liu Pingji, Sun Muhua, Shu Kan, Jiang Yingan
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430060, China.
Free Radic Biol Med. 2025 Apr;231:163-177. doi: 10.1016/j.freeradbiomed.2025.02.045. Epub 2025 Feb 27.
Liver fibrosis is a reversible dynamic pathological process induced by chronic liver injury. Without intervention, liver fibrosis can progress to become cirrhosis, liver failure, or hepatocellular carcinoma, thus posing a high global health burden. Therefore, effective therapies for liver fibrosis are urgently required. Although transplantation of mesenchymal stem cells (MSCs) has significant value as a treatment strategy for liver damage, the underlying mechanisms remain unclear. Chronic liver injury progression is significantly influenced by hepatocyte ferroptosis, and targeting ferroptosis is emerging as a potential treatment strategy for liver fibrosis. Here, we showed that the infusion of human umbilical cord-derived MSCs (hUC-MSCs) alleviated TAA-induced liver fibrosis, improved liver functionality, and decreased ferroptosis in mice. hUC-MSCs inhibit ferroptosis-related mitochondrial damage and lipid peroxidation in AML12 cells in vitro. Mechanistically, under oxidative stress, hUC-MSCs transfer healthy mitochondria to damaged hepatocytes through tunneling nanotubes (TNTs). Cytochalasin D (CytoD), an inhibitor of TNT formation, abrogated the protective effects of hUC-MSCs against ferroptosis. This research emphasizes the ability of hUC-MSCs to serve as a promising treatment for liver fibrosis via mitochondrial transfer through TNTs.
肝纤维化是由慢性肝损伤引起的一种可逆的动态病理过程。若不进行干预，肝纤维化可进展为肝硬化、肝衰竭或肝细胞癌，从而在全球造成沉重的健康负担。因此，迫切需要有效的肝纤维化治疗方法。尽管间充质干细胞（MSCs）移植作为肝损伤的一种治疗策略具有重要价值，但其潜在机制仍不清楚。慢性肝损伤的进展受到肝细胞铁死亡的显著影响，靶向铁死亡正成为一种潜在的肝纤维化治疗策略。在此，我们表明输注人脐带间充质干细胞（hUC-MSCs）可减轻TAA诱导的小鼠肝纤维化，改善肝功能，并减少铁死亡。hUC-MSCs在体外可抑制AML12细胞中与铁死亡相关的线粒体损伤和脂质过氧化。机制上，在氧化应激下，hUC-MSCs通过隧道纳米管（TNTs）将健康的线粒体转移至受损的肝细胞。细胞松弛素D（CytoD）是一种TNT形成抑制剂，可消除hUC-MSCs对铁死亡的保护作用。本研究强调了hUC-MSCs通过TNTs进行线粒体转移从而有望治疗肝纤维化的能力。
