HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

  • Cell Death Dis. 2022 Apr 8;13(4):319. doi: 10.1038/s41419-022-04764-2.
Youwen Tan   #  1 ,  Yan Huang   #  2  3 ,  Rong Mei  2 ,  Fei Mao  2 ,  Dakai Yang  2 ,  Jinwen Liu  2 ,  Wenrong Xu  2 ,  Hui Qian  4 ,  Yongmin Yan  5  6
Affiliations
  • 1. The Third Hospital of Zhenjiang Affiliated Jiangsu University, School of Medicine, Jiangsu University, 212003, Zhenjiang, PR China.
  • 2. Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
  • 3. The Second Affiliated Hospital of Soochow University, 215004, Suzhou, Jiangsu, PR China.
  • 4. Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China. [email protected].
  • 5. The Third Hospital of Zhenjiang Affiliated Jiangsu University, School of Medicine, Jiangsu University, 212003, Zhenjiang, PR China. [email protected].
  • 6. Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China. [email protected].
  • # Contributed equally.
PMID: 35395830 DOI: 10.1038/s41419-022-04764-2
Abstract

Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated Ferroptosis regulation. Results: MSC-ex could trigger HSCs Ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione Peroxidase 4 (GPX4) is a crucial regulator of Ferroptosis. We found that intravenous injection of MSC-ex significantly decreased Glutathione Peroxidase 4 (GPX4) expression in activated HSCs and Collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs Ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and Necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs Ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.

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