PMID- 31973730 OWN - NLM STAT- MEDLINE DCOM- 20210311 LR - 20210311 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 11 IP - 1 DP - 2020 Jan 23 TI - Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p. PG - 37 LID - 10.1186/s13287-020-1550-0 [doi] LID - 37 AB - BACKGROUND: Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. MSCs are considered to play a therapeutic role under different stresses by adaptively producing specific factors, prompting us to investigate the factors that hUC-MSCs produce in response to high serum levels of IL-6, which plays a critical role in initiating and accelerating ALF. METHODS: We stimulated hUC-MSCs with IL-6, and the hUC-MSC-derived exosomes were deeply sequenced. The miRNAs in the exosomes that have potential to suppress IL-6-associated signaling pathway were screened, and the role of one of the most possible miRNAs was tested in the mouse model of inflammatory liver injury. RESULT: We determined that miR-455-3p, which is secreted through exosomes and potentially targets PI3K signaling, was highly produced by hUC-MSCs with IL-6 stimulation. The miR-455-3p-enriched exosomes could inhibit the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro. In a chemical liver injury mouse model, enforced expression of miR-455-3p could attenuate macrophage infiltration and local liver damage and reduce the serum levels of inflammatory factors, thereby improving liver histology and systemic disorder. CONCLUSIONS: miR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury. FAU - Shao, Mingyang AU - Shao M AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Xu, Qing AU - Xu Q AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Wu, Zhenru AU - Wu Z AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Chen, Yuwei AU - Chen Y AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Shu, Yuke AU - Shu Y AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Cao, Xiaoyue AU - Cao X AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Chen, Menglin AU - Chen M AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Zhang, Bo AU - Zhang B AD - Sichuan Stem Cell Bank & Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, 610037, China. FAU - Zhou, Yongjie AU - Zhou Y AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. FAU - Yao, Rong AU - Yao R AD - The Emergency Department, West China Hospital, Sichuan University, Chengdu, 610041, China. yaorong@wchscu.cn. FAU - Shi, Yujun AU - Shi Y AUID- ORCID: 0000-0003-0494-6023 AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. shiyujun@scu.edu.cn. AD - Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China. shiyujun@scu.edu.cn. FAU - Bu, Hong AU - Bu H AD - Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. AD - Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200123 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Interleukin-6) RN - 0 (MIRN455 microRNA, human) RN - 0 (MicroRNAs) SB - IM MH - Animals MH - Chemical and Drug Induced Liver Injury/*therapy MH - Cord Blood Stem Cell Transplantation/*methods MH - Disease Models, Animal MH - Exosomes/*metabolism/*transplantation MH - Female MH - Humans MH - Interleukin-6/pharmacology MH - Male MH - Mesenchymal Stem Cells/drug effects/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/*metabolism MH - Umbilical Cord/cytology PMC - PMC6979401 OTO - NOTNLM OT - Acute liver injury OT - Exosome OT - Inflammation OT - hUC-MSCs OT - microRNA-455-3p COIS- The authors declare that they have no competing interests. EDAT- 2020/01/25 06:00 MHDA- 2021/03/12 06:00 PMCR- 2020/01/23 CRDT- 2020/01/25 06:00 PHST- 2019/10/14 00:00 [received] PHST- 2019/12/10 00:00 [accepted] PHST- 2019/12/08 00:00 [revised] PHST- 2020/01/25 06:00 [entrez] PHST- 2020/01/25 06:00 [pubmed] PHST- 2021/03/12 06:00 [medline] PHST- 2020/01/23 00:00 [pmc-release] AID - 10.1186/s13287-020-1550-0 [pii] AID - 1550 [pii] AID - 10.1186/s13287-020-1550-0 [doi] PST - epublish SO - Stem Cell Res Ther. 2020 Jan 23;11(1):37. doi: 10.1186/s13287-020-1550-0.