Human umbilical cord-derived mesenchymal stem cells attenuate liver fibrosis by inhibiting hepatocyte ferroptosis through mitochondrial transfer
Zhiyu Xiong, Ping Chen, Zheng Wang, Lichao Yao, Mengqin Yuan, Pingji Liu, Moyi Sun, Kan Shu, Yingan Jiang
Abstract
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. The graphical abstract illustrates that ferroptosis and mitochondrial dysfunction in hepatocytes play a critical role in the development of liver fibrosis. Furthermore, mesenchymal stem cells (MSCs) have been shown to transfer mitochondria through tunneling nanotubes, restoring mitochondrial homeostasis in hepatocytes, alleviating ferroptosis, and thereby inhibiting the progression of liver fibrosis. • Ferroptosis and mitochondrial dysfunction in hepatocytes are crucial inliver fibrosis. • MSCs transfer mitochondria via tunneling nanotubes, alleviating hepatocytes ferroptosis, and thereby inhibiting liver fibrosis. • The transferred mitochondria restore hepatocytes ferroptosis by regulating the Nrf2/HO-1 signaling pathway.