Liver injuries often occur in a zonated manner. However, detailed regenerative responses to such zonal injuries at cellular and molecular levels remain largely elusive. By using a fate-mapping strain, , to elucidate liver regeneration after acute pericentral injury, we found that pericentral regeneration is primarily compensated by the expansion of remaining pericentral hepatocytes, and secondarily by expansion of periportal hepatocytes. Employing single-cell RNA sequencing, spatial transcriptomics, immunostaining, and functional assays, we demonstrated that the upregulated expression of the mTOR/4E-BP1 axis and lactate dehydrogenase A in hepatocytes contributes to pericentral regeneration, while activation of transforming growth factor β (TGF-β1) signaling in the damaged area mediates fibrotic responses and inhibits hepatocyte proliferation. Inhibiting the pericentral accumulation of monocytes and monocyte-derived macrophages through an Arg-Gly-Asp (RGD) peptide-based strategy attenuates these cell-derived TGF-β1 signalings, thus improving pericentral regeneration. Our study provides integrated and high-resolution spatiotemporal insights into the cellular and molecular basis of pericentral regeneration.

中文翻译：

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急性中枢损伤后肝再生的区域特异性细胞和分子基础

肝损伤通常以分区方式发生。然而，在细胞和分子水平上对这种区域性损伤的详细再生反应在很大程度上仍然难以捉摸。通过使用命运图谱菌株来阐明急性中枢周围损伤后的肝脏再生，我们发现中枢周围再生主要是通过剩余中枢周围肝细胞的扩张来补偿的，其次是通过门静脉周围肝细胞的扩张来补偿。采用单细胞 RNA 测序、空间转录组学、免疫染色和功能测定，我们证明肝细胞中 mTOR/4E-BP1 轴和乳酸脱氢酶 A 的表达上调有助于中枢周围再生，同时激活转化生长因子 β (TGF) -β1) 受损区域的信号介导纤维化反应并抑制肝细胞增殖。通过基于 Arg-Gly-Asp (RGD) 肽的策略抑制单核细胞和单核细胞衍生巨噬细胞的中央周围积聚，减弱这些细胞衍生的 TGF-β1 信号传导，从而改善中央周围再生。我们的研究为中枢周围再生的细胞和分子基础提供了综合且高分辨率的时空见解。