PMID- 34256837 OWN - NLM STAT- MEDLINE DCOM- 20210806 LR - 20220208 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 12 IP - 1 DP - 2021 Jul 13 TI - Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling. PG - 396 LID - 10.1186/s13287-021-02468-6 [doi] LID - 396 AB - BACKGROUND: Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models. METHODS: Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2x10(6) hUC-MSCs, 4x10(6) hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation. RESULTS: The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-gamma/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs. CONCLUSIONS: hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway. CI - (c) 2021. The Author(s). FAU - He, Yulin AU - He Y AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. FAU - Guo, Xingrong AU - Guo X AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. FAU - Lan, Tingyu AU - Lan T AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. AD - Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. FAU - Xia, Jianbo AU - Xia J AD - Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Wuhan, 430070, Hubei, China. FAU - Wang, Jinsong AU - Wang J AD - Shenzhen Beike Biotechnology Research Institute, Nanshan District, Shenzhen, 518057, China. FAU - Li, Bei AU - Li B AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. FAU - Peng, Chunyan AU - Peng C AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. FAU - Chen, Yue AU - Chen Y AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. AD - Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. FAU - Hu, Xiang AU - Hu X AD - Shenzhen Beike Biotechnology Research Institute, Nanshan District, Shenzhen, 518057, China. huxiang@beike.cc. FAU - Meng, Zhongji AU - Meng Z AUID- ORCID: 0000-0003-0401-535X AD - Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. zhongji.meng@163.com. AD - Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China. zhongji.meng@163.com. AD - Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. zhongji.meng@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210713 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (STAT1 Transcription Factor) RN - 0 (STAT1 protein, human) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - 0 (Stat1 protein, rat) SB - IM EIN - Stem Cell Res Ther. 2022 Feb 7;13(1):65. PMID: 35130963 MH - *Acute-On-Chronic Liver Failure/therapy MH - Animals MH - Humans MH - *Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells MH - Rats MH - Rats, Wistar MH - STAT1 Transcription Factor MH - STAT3 Transcription Factor/genetics MH - Swine MH - Umbilical Cord PMC - PMC8278604 OTO - NOTNLM OT - ACLF OT - Liver fibrosis OT - Liver injury OT - Notch OT - Paracrine OT - Stat1 OT - Stat3 OT - hUC-MSCs COIS- The authors declare that they have no competing interests. EDAT- 2021/07/15 06:00 MHDA- 2021/08/07 06:00 PMCR- 2021/07/13 CRDT- 2021/07/14 05:41 PHST- 2021/01/24 00:00 [received] PHST- 2021/06/21 00:00 [accepted] PHST- 2021/07/14 05:41 [entrez] PHST- 2021/07/15 06:00 [pubmed] PHST- 2021/08/07 06:00 [medline] PHST- 2021/07/13 00:00 [pmc-release] AID - 10.1186/s13287-021-02468-6 [pii] AID - 2468 [pii] AID - 10.1186/s13287-021-02468-6 [doi] PST - epublish SO - Stem Cell Res Ther. 2021 Jul 13;12(1):396. doi: 10.1186/s13287-021-02468-6.