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<p>Portal fibrosis, a determinant of progression in virtually all chronic liver diseases, prototypically develops in biliary diseases. Using single-cell RNA sequencing and genetic cell fate tracing in mouse models, we identify <i>Clec3b</i>⁺ fibroblasts as a distinct subset of portal fibroblasts, which rapidly expand after biliary injury and give rise to the bulk of portal myofibroblasts. Mechanistic analyses reveal that <i>Clec3b</i>⁺ portal fibroblasts activation is governed by a Krüppel-like factor 4 (KLF4)/periostin (POSTN) axis, <i>i.e</i>., KLF4 directly binds to the <i>Postn</i> promoter and represses its transcription&#xa0;in&#xa0;quiescent fibroblasts, whereas after injury, KLF4 is downregulated, which allows POSTN, acting via αvβ5 integrin, to&#xa0;drive portal fibroblast activation and portal fibrosis. Our findings identify <i>Clec3b</i><sup>+</sup> portal fibroblasts as the primary effectors of portal fibrosis and demonstrate that the KLF4/POSTN signaling axis regulates their activation, offering potential therapeutic targets for inhibiting fibrosis in biliary diseases.</p>

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Clec3b⁺ fibroblasts are the primary effectors of portal fibrosis following activation via a KLF4/periostin axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Lin Lei,
  • Chenchen Zhao,
  • Wenwen Gao,
  • Guowen Liu,
  • Menglin Liu,
  • Guoyue Lv,
  • Zhongqi Fan,
  • Yongkang Cheng,
  • Jinxia Li,
  • Fanrong Kong,
  • Haoping Wang,
  • Xiliang Du,
  • Yuxiang Song,
  • Sara Lemoinne,
  • Axelle Cadoret,
  • Chantal Housset,
  • Xinwei Li

摘要

Portal fibrosis, a determinant of progression in virtually all chronic liver diseases, prototypically develops in biliary diseases. Using single-cell RNA sequencing and genetic cell fate tracing in mouse models, we identify Clec3b⁺ fibroblasts as a distinct subset of portal fibroblasts, which rapidly expand after biliary injury and give rise to the bulk of portal myofibroblasts. Mechanistic analyses reveal that Clec3b⁺ portal fibroblasts activation is governed by a Krüppel-like factor 4 (KLF4)/periostin (POSTN) axis, i.e., KLF4 directly binds to the Postn promoter and represses its transcription in quiescent fibroblasts, whereas after injury, KLF4 is downregulated, which allows POSTN, acting via αvβ5 integrin, to drive portal fibroblast activation and portal fibrosis. Our findings identify Clec3b+ portal fibroblasts as the primary effectors of portal fibrosis and demonstrate that the KLF4/POSTN signaling axis regulates their activation, offering potential therapeutic targets for inhibiting fibrosis in biliary diseases.