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<p>Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles. Here, we performed single-cell and spatial transcriptome analysis in human and mouse infarcted hearts to dissect the molecular basis of these interactions. We identified a unique fibroblast subset with high CD248 expression, strongly associated with extracellular matrix remodeling. Genetic <i>Cd248</i> deletion in fibroblasts mitigated cardiac fibrosis and dysfunction following ischemia/reperfusion. Mechanistically, CD248 stabilizes type I transforming growth factor beta receptor and thus upregulates fibroblast ACKR3 expression, leading to enhanced T cell retention. This CD248-mediated fibroblast–T cell interaction is required to sustain fibroblast activation and scar expansion. Disrupting this interaction using monoclonal antibody or chimeric antigen receptor T cell reduces T cell infiltration and consequently ameliorates cardiac fibrosis and dysfunction. Our findings reveal a CD248<sup>+</sup> fibroblast subpopulation as a key regulator of immune–fibroblast cross–talk and a potential therapy to treat tissue fibrosis.</p>

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Dynamic molecular atlas of cardiac fibrosis at single-cell resolution shows CD248 in cardiac fibroblasts orchestrates interactions with immune cells

  • 期刊论文

  • 发表日期：

    2025年3月27日

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  • Guohua Li,
  • Cheng Ni,
  • Jiacheng Wang,
  • Feimu Zhang,
  • Zaiyang Fu,
  • Lingjun Wang,
  • Biqing Wang,
  • Ye Liu,
  • Jing Zhao,
  • Mo Li,
  • Hao Lin,
  • Fei Liao,
  • Shuchang Ye,
  • Yu Zhang,
  • Jiayue Cai,
  • Shaohui Shi,
  • Zhiwei Zhong,
  • Yanna Shi,
  • Junhua He,
  • Xushen Xiong,
  • Yang Xu,
  • Jinghai Chen,
  • Wei Zhu,
  • Yibin Wang,
  • Jian’an Wang,
  • Xinyang Hu

摘要

Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles. Here, we performed single-cell and spatial transcriptome analysis in human and mouse infarcted hearts to dissect the molecular basis of these interactions. We identified a unique fibroblast subset with high CD248 expression, strongly associated with extracellular matrix remodeling. Genetic Cd248 deletion in fibroblasts mitigated cardiac fibrosis and dysfunction following ischemia/reperfusion. Mechanistically, CD248 stabilizes type I transforming growth factor beta receptor and thus upregulates fibroblast ACKR3 expression, leading to enhanced T cell retention. This CD248-mediated fibroblast–T cell interaction is required to sustain fibroblast activation and scar expansion. Disrupting this interaction using monoclonal antibody or chimeric antigen receptor T cell reduces T cell infiltration and consequently ameliorates cardiac fibrosis and dysfunction. Our findings reveal a CD248+ fibroblast subpopulation as a key regulator of immune–fibroblast cross–talk and a potential therapy to treat tissue fibrosis.