Scholarlink

<p>Liver regeneration following partial hepatectomy (PHx) is a complex process. While cellular senescence and chemokine signaling have been implicated in tissue repair, their cell type–specific roles in liver regeneration remain poorly understood. We analyzed single-cell RNA sequencing (scRNA-seq) data from a PHx-induced mouse liver regeneration model at day 0 and day 7. The senescence-associated gene enrichment was assessed using single-sample gene set enrichment analysis (ssGSEA), while functional differences were evaluated by gene set enrichment analysis (GSEA) and pseudotime trajectory analysis. Cell–cell communication was inferred with the CellChat framework. To validate computational findings, in vivo experiments were performed using wild-type (WT) and CCL3 knockout (CCL3⁻/⁻) mice subjected to 70% PHx, followed by RT-qPCR, Western blot, immunohistochemistry (IHC), and serum biochemical assays. Endothelial cells exhibited the most pronounced alterations in senescence-associated gene expression during liver regeneration. Functional enrichment revealed activation of the chemokine and NF-κB signaling pathways at day 7, while pseudotime analysis indicated dynamic state transitions of endothelial cells. Cell–cell communication analysis highlighted markedly enhanced crosstalk between Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), predominantly mediated by the CCL signaling pathway. Among ligands, CCL3 was significantly upregulated in LSECs, while its receptor CCR5 was elevated in KCs, accompanied by an increased proportion of KCs at day 7. In vivo validation confirmed that CCL3 expression was prominently increased in LSECs after PHx. Functionally, CCL3 deficiency accelerated liver regeneration, as evidenced by higher liver-to-body weight ratios, reduced serum ALT/AST levels, and increased hepatocyte proliferation markers (Ki-67 and PCNA). Our study identifies CCL3 as a key endothelial-derived chemokine mediating endothelial–Kupffer cell interactions during liver regeneration. CCL3 deficiency enhances hepatocyte proliferation and accelerates liver regrowth, suggesting that modulation of the CCL3–CCR5 axis may represent a novel therapeutic strategy for improving liver regeneration.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cellular senescence and chemokine signaling in liver regeneration: insights from single-cell RNA sequencing

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月6日

查看全文
  • Zhipeng Bao,
  • Longfu Xi,
  • Xiaoyue Han,
  • Guangpeng Jia,
  • Peng Wang,
  • Shi Wang,
  • Saqirilatu,
  • Xiaodong Wang

摘要

Liver regeneration following partial hepatectomy (PHx) is a complex process. While cellular senescence and chemokine signaling have been implicated in tissue repair, their cell type–specific roles in liver regeneration remain poorly understood. We analyzed single-cell RNA sequencing (scRNA-seq) data from a PHx-induced mouse liver regeneration model at day 0 and day 7. The senescence-associated gene enrichment was assessed using single-sample gene set enrichment analysis (ssGSEA), while functional differences were evaluated by gene set enrichment analysis (GSEA) and pseudotime trajectory analysis. Cell–cell communication was inferred with the CellChat framework. To validate computational findings, in vivo experiments were performed using wild-type (WT) and CCL3 knockout (CCL3⁻/⁻) mice subjected to 70% PHx, followed by RT-qPCR, Western blot, immunohistochemistry (IHC), and serum biochemical assays. Endothelial cells exhibited the most pronounced alterations in senescence-associated gene expression during liver regeneration. Functional enrichment revealed activation of the chemokine and NF-κB signaling pathways at day 7, while pseudotime analysis indicated dynamic state transitions of endothelial cells. Cell–cell communication analysis highlighted markedly enhanced crosstalk between Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), predominantly mediated by the CCL signaling pathway. Among ligands, CCL3 was significantly upregulated in LSECs, while its receptor CCR5 was elevated in KCs, accompanied by an increased proportion of KCs at day 7. In vivo validation confirmed that CCL3 expression was prominently increased in LSECs after PHx. Functionally, CCL3 deficiency accelerated liver regeneration, as evidenced by higher liver-to-body weight ratios, reduced serum ALT/AST levels, and increased hepatocyte proliferation markers (Ki-67 and PCNA). Our study identifies CCL3 as a key endothelial-derived chemokine mediating endothelial–Kupffer cell interactions during liver regeneration. CCL3 deficiency enhances hepatocyte proliferation and accelerates liver regrowth, suggesting that modulation of the CCL3–CCR5 axis may represent a novel therapeutic strategy for improving liver regeneration.