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Background <p>Biliary atresia (BA) is a nongenetic cholangiopathy characterized by biliary obliteration. However, the underlying pathological mechanism remains unclear. We aimed to explore the epigenetic BA pathology by using BA-specific deciduous dental pulp stem cells (BA-SHED), which develop in parallel with cholangiocyte progenitor cells in human embryos.</p> Methods <p>BA-SHED were isolated from human exfoliated deciduous teeth of patients with BA using the colony-forming unit fibroblast method. After sequential stimulation with cytokines and chemicals in cultured BA-SHED, the in vitro bile duct-forming capacity was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence. Expression of hepatocyte nuclear factor 6 (HNF6) and transforming growth factor beta receptor 2 (TGFBR2) was analyzed using immunoblotting and RT-qPCR. The regulation of chromatin architecture at the <i>HNF6</i> promoter was analyzed using nuclease-accessible chromatin-qPCR and chromatin immunoprecipitation-qPCR.</p> Results <p>BA-SHED showed an inheritable increase in HNF6 levels, resulting in TGFBR2 suppression and deficiency in bile duct formation. BA-SHED also accumulated Brahma and P65 complexes around the <i>HNF6</i> promoter with chromatin architecture remodeling. Tumor necrosis factor-alpha and interferon-gamma co-stimulation mimicked the epigenetic signatures of BA-SHED.</p> Conclusion <p>The present epigenetic memory in BA-SHED implies that BA-SHED imprint bile duct deficiency through TGFBR2 dysregulated by the <i>HNF6</i> promoter activation epigenetically. Thus, BA-SHED are a potential model for expanding our knowledge in BA research.</p>

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Dental pulp stem cells maintain epigenetic chromatin architecture remodeling primed by the etiological stimulus of biliary atresia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Soichiro Sonoda,
  • Liting Yu,
  • Lisha Dai,
  • Yukari Kyumoto-Nakamura,
  • Koichiro Yoshimaru,
  • Ratih Yuniartha,
  • Ying Liu,
  • M. Majd Sharifa,
  • Sara Murata,
  • Mohammed Fouad Zakaria,
  • Hiroki Kato,
  • Norihisa Uehara,
  • Satoshi Fukumoto,
  • Haruyoshi Yamaza,
  • Toshiharu Matsuura,
  • Tomoaki Taguchi,
  • Tatsuro Tajiri,
  • Takayoshi Yamaza

摘要

Background

Biliary atresia (BA) is a nongenetic cholangiopathy characterized by biliary obliteration. However, the underlying pathological mechanism remains unclear. We aimed to explore the epigenetic BA pathology by using BA-specific deciduous dental pulp stem cells (BA-SHED), which develop in parallel with cholangiocyte progenitor cells in human embryos.

Methods

BA-SHED were isolated from human exfoliated deciduous teeth of patients with BA using the colony-forming unit fibroblast method. After sequential stimulation with cytokines and chemicals in cultured BA-SHED, the in vitro bile duct-forming capacity was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence. Expression of hepatocyte nuclear factor 6 (HNF6) and transforming growth factor beta receptor 2 (TGFBR2) was analyzed using immunoblotting and RT-qPCR. The regulation of chromatin architecture at the HNF6 promoter was analyzed using nuclease-accessible chromatin-qPCR and chromatin immunoprecipitation-qPCR.

Results

BA-SHED showed an inheritable increase in HNF6 levels, resulting in TGFBR2 suppression and deficiency in bile duct formation. BA-SHED also accumulated Brahma and P65 complexes around the HNF6 promoter with chromatin architecture remodeling. Tumor necrosis factor-alpha and interferon-gamma co-stimulation mimicked the epigenetic signatures of BA-SHED.

Conclusion

The present epigenetic memory in BA-SHED implies that BA-SHED imprint bile duct deficiency through TGFBR2 dysregulated by the HNF6 promoter activation epigenetically. Thus, BA-SHED are a potential model for expanding our knowledge in BA research.