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<p>Hirschsprung’s disease (HSCR) is a congenital malformation of the enteric nervous system (ENS) caused by deficient enteric neural crest cell (ENCC) colonization. However, the mechanisms inducing impaired ENCC colonization remain unclear. This study investigates the involvement of extracellular vesicles (EVs), pivotal mediators of intercellular communication, in ENS development and HSCR pathogenesis. We find that treatment with plasma-derived EVs from children with HSCR (HSCR-EV) significantly inhibits ENCC proliferation and migration. <i>MIR22HG</i> is identified as the key mediator of the HSCR-EV-induced suppression of ENCC proliferation and migration. Schwann cells within the aganglionic colon of HSCR children derive EVs containing upregulated <i>MIR22HG</i>. In vitro, Schwann cell-derived EV-<i>MIR22HG</i> inhibits ENCC proliferation and migration. In vivo, it blocks ENCC colonization in the distal colon and disrupts ENS formation. <i>MPP3</i> is identified as a potential downstream target of <i>MIR22HG</i>, with <i>MIR22HG</i> downregulating its expression via the m<sup>6</sup>A-dependent ALKBH5/IGF2BP3 axis. Collectively, Schwann cell-derived EVs transfer <i>MIR22HG</i> to ENCCs, downregulating <i>MPP3</i> through the m<sup>6</sup>A/ALKBH5/IGF2BP3 pathway, and thereby disrupting ENCC colonization and impairing ENS formation.</p><p></p>

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Extracellular vesicle-mediated transfer of MIR22HG inhibits the colonization of enteric neural crest cells in the colon by decreasing MPP3 expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Zhengke Zhi,
  • Qiaochu Sun,
  • Chenglong Wang,
  • Yuanxiang Qiu,
  • Zichuan Gao,
  • Chunxia Du,
  • Jie Tang,
  • Hongxing Li,
  • Weibing Tang

摘要

Hirschsprung’s disease (HSCR) is a congenital malformation of the enteric nervous system (ENS) caused by deficient enteric neural crest cell (ENCC) colonization. However, the mechanisms inducing impaired ENCC colonization remain unclear. This study investigates the involvement of extracellular vesicles (EVs), pivotal mediators of intercellular communication, in ENS development and HSCR pathogenesis. We find that treatment with plasma-derived EVs from children with HSCR (HSCR-EV) significantly inhibits ENCC proliferation and migration. MIR22HG is identified as the key mediator of the HSCR-EV-induced suppression of ENCC proliferation and migration. Schwann cells within the aganglionic colon of HSCR children derive EVs containing upregulated MIR22HG. In vitro, Schwann cell-derived EV-MIR22HG inhibits ENCC proliferation and migration. In vivo, it blocks ENCC colonization in the distal colon and disrupts ENS formation. MPP3 is identified as a potential downstream target of MIR22HG, with MIR22HG downregulating its expression via the m6A-dependent ALKBH5/IGF2BP3 axis. Collectively, Schwann cell-derived EVs transfer MIR22HG to ENCCs, downregulating MPP3 through the m6A/ALKBH5/IGF2BP3 pathway, and thereby disrupting ENCC colonization and impairing ENS formation.