PMID- 35395830
OWN - NLM
STAT- MEDLINE
DCOM- 20220412
LR  - 20221211
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 4
DP  - 2022 Apr 8
TI  - HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate 
      cells via regulating the xCT/GPX4 axis.
PG  - 319
LID - 10.1038/s41419-022-04764-2 [doi]
LID - 319
AB  - 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, Fe(2)(+) 
      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.
CI  - (c) 2022. The Author(s).
FAU - Tan, Youwen
AU  - Tan Y
AD  - The Third Hospital of Zhenjiang Affiliated Jiangsu University, School of 
      Medicine, Jiangsu University, 212003, Zhenjiang, PR China.
FAU - Huang, Yan
AU  - Huang Y
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
AD  - The Second Affiliated Hospital of Soochow University, 215004, Suzhou, Jiangsu, PR 
      China.
FAU - Mei, Rong
AU  - Mei R
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
FAU - Mao, Fei
AU  - Mao F
AUID- ORCID: 0000-0001-5840-4436
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
FAU - Yang, Dakai
AU  - Yang D
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
FAU - Liu, Jinwen
AU  - Liu J
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
FAU - Xu, Wenrong
AU  - Xu W
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China.
FAU - Qian, Hui
AU  - Qian H
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China. lstmmmlst@163.com.
FAU - Yan, Yongmin
AU  - Yan Y
AUID- ORCID: 0000-0002-1990-1170
AD  - The Third Hospital of Zhenjiang Affiliated Jiangsu University, School of 
      Medicine, Jiangsu University, 212003, Zhenjiang, PR China. yym@ujs.edu.cn.
AD  - Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, 
      Jiangsu University, 212013, Zhenjiang, Jiangsu, PR China. yym@ujs.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220408
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
RN  - EC 1.11.1.9 (glutathione peroxidase 4, mouse)
SB  - IM
MH  - Animals
MH  - *Beclin-1/genetics/metabolism
MH  - *Exosomes/metabolism
MH  - *Ferroptosis
MH  - *Hepatic Stellate Cells/cytology
MH  - Humans
MH  - Liver Cirrhosis/genetics
MH  - Mesenchymal Stem Cells
MH  - Mice
MH  - *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
PMC - PMC8993870
COIS- The authors declare no competing interests.
EDAT- 2022/04/10 06:00
MHDA- 2022/04/13 06:00
PMCR- 2022/04/08
CRDT- 2022/04/09 05:10
PHST- 2021/10/18 00:00 [received]
PHST- 2022/03/25 00:00 [accepted]
PHST- 2022/03/11 00:00 [revised]
PHST- 2022/04/09 05:10 [entrez]
PHST- 2022/04/10 06:00 [pubmed]
PHST- 2022/04/13 06:00 [medline]
PHST- 2022/04/08 00:00 [pmc-release]
AID - 10.1038/s41419-022-04764-2 [pii]
AID - 4764 [pii]
AID - 10.1038/s41419-022-04764-2 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Apr 8;13(4):319. doi: 10.1038/s41419-022-04764-2.