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<p>Primary sclerosing cholangitis (PSC) pathogenesis involves immune dysregulation, genetic factors, and bile duct pathology; however, a comprehensive pathogenesis model and effective therapeutic strategies remain limited. Here, we develop a novel human liver multilineage organoid (Mulorg) model combined with Mdr2<sup>−/−</sup> mice to investigate the pro-fibrotic role of T helper 17 cells (Th17) and the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (EV<sup>MSC</sup>) for PSC, particularly periductal fibrosis. EV<sup>MSC</sup> alleviates interleukin-17A (IL-17A)-induced fibrotic Mulorgs (FibHOs) and mitigates periductal fibrosis in Mdr2<sup>−/−</sup> mice by inhibiting Th17 differentiation, decreasing Th17 numbers, and lowering intrahepatic IL-17A levels. Functional assays, miRNA array, and CUT &amp; Tag analyses reveal that EVs-derived hsa-miR-7977 targets <i>NFKBIZ</i>, repressing IκBζ translation to reduce IL-17A and its downstream targets involved in Th17 differentiation, IL-17 signaling, and bile secretion pathways. Moreover, miR-7977-enriched EV<sup>MSC</sup> efficiently reduces IL-17A<sup>+</sup> cell percentages in fibrotic areas and improves periductal fibrosis in Mdr2<sup>−/−</sup> mice. Co-culture of FibHOs with Th17 found miR-7977 inhibits Th17 migration to the periductal fibrosis area, with distinct morphological differences observed between patient- and healthy-derived FibHOs. These findings demonstrate that EV-derived miR-7977 mitigates the periductal fibrosis microenvironment by inhibiting Th17 differentiation and migration, the former by targeting <i>NFKBIZ</i>, regulating IL-17A and IκBζ-targeted gene expression. This study clarifies Th17’s role in the PSC fibrotic microenvironment, underscores the modeling contributions of Mulorgs, and highlights EV-derived miR-7977’s potential to ameliorate Th17-related periductal fibrosis, offering insights and novel therapeutic avenues for PSC.</p>

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Mesenchymal stem cell-derived extracellular vesicles attenuate periductal fibrosis by inhibiting Th17 differentiation in human liver multilineage organoids and Mdr2−/− mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • Wenyi Chen,
  • Xinyi Chen,
  • Feiqiong Gao,
  • Qigu Yao,
  • Sheng Cheng,
  • Qiaoling Pan,
  • Jiong Yu,
  • Jinfeng Yang,
  • Guanghua Ma,
  • Jintao Gong,
  • Qian Li,
  • Yunhua Chen,
  • Lee Wei Lim,
  • Ilia Stambler,
  • Georgina M. Ellison-Hughes,
  • Brun Ulfhake,
  • Robert Chunhua Zhao,
  • Hongcui Cao

摘要

Primary sclerosing cholangitis (PSC) pathogenesis involves immune dysregulation, genetic factors, and bile duct pathology; however, a comprehensive pathogenesis model and effective therapeutic strategies remain limited. Here, we develop a novel human liver multilineage organoid (Mulorg) model combined with Mdr2−/− mice to investigate the pro-fibrotic role of T helper 17 cells (Th17) and the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (EVMSC) for PSC, particularly periductal fibrosis. EVMSC alleviates interleukin-17A (IL-17A)-induced fibrotic Mulorgs (FibHOs) and mitigates periductal fibrosis in Mdr2−/− mice by inhibiting Th17 differentiation, decreasing Th17 numbers, and lowering intrahepatic IL-17A levels. Functional assays, miRNA array, and CUT & Tag analyses reveal that EVs-derived hsa-miR-7977 targets NFKBIZ, repressing IκBζ translation to reduce IL-17A and its downstream targets involved in Th17 differentiation, IL-17 signaling, and bile secretion pathways. Moreover, miR-7977-enriched EVMSC efficiently reduces IL-17A+ cell percentages in fibrotic areas and improves periductal fibrosis in Mdr2−/− mice. Co-culture of FibHOs with Th17 found miR-7977 inhibits Th17 migration to the periductal fibrosis area, with distinct morphological differences observed between patient- and healthy-derived FibHOs. These findings demonstrate that EV-derived miR-7977 mitigates the periductal fibrosis microenvironment by inhibiting Th17 differentiation and migration, the former by targeting NFKBIZ, regulating IL-17A and IκBζ-targeted gene expression. This study clarifies Th17’s role in the PSC fibrotic microenvironment, underscores the modeling contributions of Mulorgs, and highlights EV-derived miR-7977’s potential to ameliorate Th17-related periductal fibrosis, offering insights and novel therapeutic avenues for PSC.