Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 125, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2023.111134
Keywords
Liver fibrosis; Human umbilical cord mesenchymal stem cells; Hepatic stellate cell; microRNA-148a-5p; SLIT3
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hUC-MSCs inhibit HSC activation through the miR-148a-5p/SLIT3 pathway, thus alleviating LF. High-throughput RNA-Seq analysis identified potential genes involved in the therapeutic effects of hUC-MSCs. miR-148a-5p delivered by hUC-MSCs via exosomes suppressed the activated phenotype of LX2 cells.
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 (CCl4) 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 CCl4-induced mice. Highthroughput 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.
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