PMID- 37918086
OWN - NLM
STAT- MEDLINE
DCOM- 20231120
LR  - 20231227
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 125
IP  - Pt A
DP  - 2023 Dec
TI  - Human umbilical cord mesenchymal stem cells inhibit liver fibrosis via the 
      microRNA-148a-5p/SLIT3 axis.
PG  - 111134
LID - S1567-5769(23)01460-1 [pii]
LID - 10.1016/j.intimp.2023.111134 [doi]
AB  - BACKGROUND: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have 
      garnered considerable attention as prospective modalities of treatment for liver 
      fibrosis (LF). The inhibition of hepatic stellate cell (HSC) activation underlies 
      the anti-fibrotic effects of hUC-MSCs. However, the precise mechanism by which 
      hUC-MSCs impede HSC activation remains unclarified. We aimed to elucidate the 
      intrinsic mechanisms underlying the therapeutic effects of hUC-MSCs in LF 
      patients. METHODS: Mice with liver cirrhosis induced by carbon tetrachloride 
      (CCl(4)) were used as experimental models and administered hUC-MSCs via tail-vein 
      injection. The alterations in inflammation and fibrosis were evaluated through 
      histopathological examinations. RNA sequencing (RNA-seq) and bioinformatics 
      analysis were then conducted to investigate the therapeutic mechanism of 
      hUC-MSCs. Finally, an in-vitro experiment involving the co-cultivation of 
      hUC-MSCs or hUC-MSC-derived exosomes (MSC-Exos) with LX2 cells was performed to 
      validate the potential mechanism underlying the hepatoprotective effects of 
      hUC-MSCs in LF patients. RESULTS: hUC-MSC therapy significantly improved liver 
      function and alleviated LF in CCl(4)-induced mice. High-throughput RNA-Seq 
      analysis identified 1142 differentially expressed genes that were potentially 
      involved in mediating the therapeutic effects of hUC-MSCs. These genes play an 
      important role in regulating the extracellular matrix. miRNA expression data 
      (GSE151098) indicated that the miR-148a-5p level was downregulated in LF samples, 
      but restored following hUC-MSC treatment. miR-148a-5p was delivered to LX2 cells 
      by hUC-MSCs via the exosome pathway, and the upregulated expression of 
      miR-148a-5p significantly suppressed the expression of the activated phenotype of 
      LX2 cells. SLIT3 was identified within the pool of potential target genes 
      regulated by miR-148a-5p. Furthermore, hUC-MSC administration upregulated the 
      expression of miR-148a-5p, which played a crucial role in suppressing the 
      expression of SLIT3, thereby palliating fibrosis. CONCLUSIONS: hUC-MSCs inhibit 
      the activation of HSCs through the miR-148a-5p/SLIT3 pathway and are thus capable 
      of alleviating LF.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Yuan, Mengqin
AU  - Yuan M
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Yao, Lichao
AU  - Yao L
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Chen, Ping
AU  - Chen P
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Wang, Zheng
AU  - Wang Z
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Liu, Pingji
AU  - Liu P
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Xiong, Zhiyu
AU  - Xiong Z
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Hu, Xue
AU  - Hu X
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China.
FAU - Li, Lanjuan
AU  - Li L
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China; State Key Laboratory for Diagnosis and Treatment of Infectious 
      Diseases, National Clinical Research Centre for Infectious Diseases, 
      Collaborative Innovation Centre for Diagnosis and Treatment of Infectious 
      Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 
      Hangzhou 310053, China. Electronic address: ljli@zju.edu.cn.
FAU - Jiang, Yingan
AU  - Jiang Y
AD  - Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 
      430060, China. Electronic address: jiangya_cn@aliyun.com.
LA  - eng
PT  - Journal Article
DEP - 20231031
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (MicroRNAs)
RN  - 0 (SLIT3 protein, human)
RN  - 0 (Membrane Proteins)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Prospective Studies
MH  - Liver Cirrhosis/chemically induced/genetics/therapy
MH  - *MicroRNAs/genetics/metabolism
MH  - Fibrosis
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Umbilical Cord
MH  - Membrane Proteins/metabolism
OTO - NOTNLM
OT  - Hepatic stellate cell
OT  - Human umbilical cord mesenchymal stem cells
OT  - Liver fibrosis
OT  - SLIT3
OT  - microRNA-148a-5p
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/03 00:42
MHDA- 2023/11/20 06:55
CRDT- 2023/11/02 19:02
PHST- 2023/07/20 00:00 [received]
PHST- 2023/10/08 00:00 [revised]
PHST- 2023/10/23 00:00 [accepted]
PHST- 2023/11/20 06:55 [medline]
PHST- 2023/11/03 00:42 [pubmed]
PHST- 2023/11/02 19:02 [entrez]
AID - S1567-5769(23)01460-1 [pii]
AID - 10.1016/j.intimp.2023.111134 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2023 Dec;125(Pt A):111134. doi: 
      10.1016/j.intimp.2023.111134. Epub 2023 Oct 31.