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<p>Tissue-resident mesenchymal stromal cells (MSC) instruct immune cell activation at injury sites, a key event in tissue repair. However, the full array of immunomodulatory mechanisms driving injury-responsive immune-stromal cell interactions is underexplored. Here, using an endovascular injury mouse model, we demonstrate that perivascular MSCs enhance arterial immune response by facilitating recruitment of ST2-expressing reparative macrophages in male mice. Time-resolved single-cell sequencing reveals an MSC-mediated, macrophage phenotypic switch, essential for vascular regeneration. Mechanistically, injury activates NFκB-dependent IL-33 production in MSCs, which acts as a paracrine signal that drives Osteopontin (OPN/SPP1) production in ST2+ macrophages and stimulates vascular smooth muscle cell (VSMC) proliferation and neointima formation. Local hydrogel-mediated delivery of siRNAs targeting <i>Il33</i> or <i>Spp1</i> effectively alleviates injury-induced neointimal hyperplasia, suggesting a potential therapeutic strategy to prevent restenosis and other vascular diseases. Our findings define an IL33-ST2-OPN axis that mediates functional crosstalk between perivascular MSCs and reparative macrophages, orchestrating immune-mediated reparative responses.</p>

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Perivascular mesenchymal cells instruct ST2+ reparative macrophages to promote endovascular injury-induced neointimal hyperplasia in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月7日

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  • Yan Ping,
  • Zhewen Qin,
  • Xingxiao Huang,
  • Qiuli Sun,
  • Tao Yao,
  • Siqi Li,
  • Xin Tian,
  • Xintong Xia,
  • Bowen Diao,
  • Lin Zhao,
  • Xinyuan Zhang,
  • Danni Wei,
  • Long Wang,
  • Mengle Shao,
  • Ying Wu,
  • Jinyu Huang,
  • Bo Shan

摘要

Tissue-resident mesenchymal stromal cells (MSC) instruct immune cell activation at injury sites, a key event in tissue repair. However, the full array of immunomodulatory mechanisms driving injury-responsive immune-stromal cell interactions is underexplored. Here, using an endovascular injury mouse model, we demonstrate that perivascular MSCs enhance arterial immune response by facilitating recruitment of ST2-expressing reparative macrophages in male mice. Time-resolved single-cell sequencing reveals an MSC-mediated, macrophage phenotypic switch, essential for vascular regeneration. Mechanistically, injury activates NFκB-dependent IL-33 production in MSCs, which acts as a paracrine signal that drives Osteopontin (OPN/SPP1) production in ST2+ macrophages and stimulates vascular smooth muscle cell (VSMC) proliferation and neointima formation. Local hydrogel-mediated delivery of siRNAs targeting Il33 or Spp1 effectively alleviates injury-induced neointimal hyperplasia, suggesting a potential therapeutic strategy to prevent restenosis and other vascular diseases. Our findings define an IL33-ST2-OPN axis that mediates functional crosstalk between perivascular MSCs and reparative macrophages, orchestrating immune-mediated reparative responses.