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<p>Post-hepatectomy liver failure (PHLF) is a serious complication after partial hepatectomy without approved therapies to safely enhance liver regeneration. This study investigated whether exosomes derived from human umbilical cord mesenchymal stem cells promote liver regeneration by regulating a macrophage-transforming growth factor-beta (TGF-β)-ZBP1-PANoptosis axis. Using a 70% partial hepatectomy mouse model and a macrophage-hepatocyte co-culture system, we found that exosome treatment preserved liver structure, reduced serum injury markers (ALT/AST), increased liver-to-body weight ratio by 32.4%, and elevated proliferating hepatocytes (Ki67-positive cells) by 2.8-fold. Exosomes shifted hepatic macrophages towards a reparative (CD206-positive) phenotype, increased anti-inflammatory cytokines (interleukin-10 and TGF-β), suppressed ZBP1 expression, and inhibited PANoptosis markers. Overexpression of ZBP1 in macrophages reversed the exosome-induced polarization and cytokine changes. Neutralizing TGF-β blocked the ability of exosome-exposed macrophages to suppress hepatocyte ZBP1 expression and PANoptosis. These results identify a key mechanism by which mesenchymal stem cell-derived exosomes enhance liver regeneration after partial hepatectomy by at least partially promoting TGF-β-dependent reparative macrophage polarization, which inhibits ZBP1-mediated PANoptosis in hepatocytes, suggesting a potential therapeutic strategy for preventing PHLF.</p>

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Human umbilical cord mesenchymal stem cell exosomes promote liver regeneration by inducing CD206+ macrophage polarization and suppressing ZBP1 PANoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Xiaojing Song,
  • Xiao Tang,
  • Yao Liu,
  • Songtian Liu,
  • Jian Ma,
  • Yi Shao

摘要

Post-hepatectomy liver failure (PHLF) is a serious complication after partial hepatectomy without approved therapies to safely enhance liver regeneration. This study investigated whether exosomes derived from human umbilical cord mesenchymal stem cells promote liver regeneration by regulating a macrophage-transforming growth factor-beta (TGF-β)-ZBP1-PANoptosis axis. Using a 70% partial hepatectomy mouse model and a macrophage-hepatocyte co-culture system, we found that exosome treatment preserved liver structure, reduced serum injury markers (ALT/AST), increased liver-to-body weight ratio by 32.4%, and elevated proliferating hepatocytes (Ki67-positive cells) by 2.8-fold. Exosomes shifted hepatic macrophages towards a reparative (CD206-positive) phenotype, increased anti-inflammatory cytokines (interleukin-10 and TGF-β), suppressed ZBP1 expression, and inhibited PANoptosis markers. Overexpression of ZBP1 in macrophages reversed the exosome-induced polarization and cytokine changes. Neutralizing TGF-β blocked the ability of exosome-exposed macrophages to suppress hepatocyte ZBP1 expression and PANoptosis. These results identify a key mechanism by which mesenchymal stem cell-derived exosomes enhance liver regeneration after partial hepatectomy by at least partially promoting TGF-β-dependent reparative macrophage polarization, which inhibits ZBP1-mediated PANoptosis in hepatocytes, suggesting a potential therapeutic strategy for preventing PHLF.