近日，清华长庚医院王韫芳等研究人员合作揭示急性中央静脉区损伤后肝再生的区域特异性细胞和分子基础。相关论文于2024年2月22日在线发表在《细胞—干细胞》杂志上。

通过使用命运测绘品系Cyp2e1-DreER来阐明急性中央静脉区损伤后的肝脏再生，研究人员发现中央静脉区再生主要通过剩余中央静脉区肝细胞的扩增来代偿，其次是通过肝门周围肝细胞的扩增来代偿。通过单细胞RNA测序、空间转录组学、免疫染色和体内功能测试，研究人员证实肝细胞中mTOR/4E-BP1轴和乳酸脱氢酶A的表达上调有助于中央静脉区再生，而受损区域的转化生长因子β（TGF-β1）信号激活介导了纤维化反应并抑制了肝细胞增殖。

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的巨噬细胞在中央静脉区的聚集，可减轻这些细胞衍生的TGF-β1信号，从而改善中央静脉区的再生。这项研究提供了对中央静脉区再生的细胞和分子基础的综合、高分辨率时空洞察。

据介绍，肝脏损伤通常以分区的方式发生。然而，这种带状损伤在细胞和分子水平上的详细再生反应在很大程度上仍然难以捉摸。

附：英文原文

Title: Region-specific cellular and molecular basis of liver regeneration after acute pericentral injury

Author: Shuyong Wang, Xuan Wang, Yiran Shan, Zuolong Tan, Yuxin Su, Yannan Cao, Shuang Wang, Jiahong Dong, Jin Gu, Yunfang Wang

Issue&Volume: 2024-02-22

Abstract: Liver injuries often occur in a zonated manner. However, detailed regenerative responsesto such zonal injuries at cellular and molecular levels remain largely elusive. Byusing a fate-mapping strain, Cyp2e1-DreER, to elucidate liver regeneration after acute pericentral injury, we found that pericentralregeneration is primarily compensated by the expansion of remaining pericentral hepatocytes,and secondarily by expansion of periportal hepatocytes. Employing single-cell RNAsequencing, spatial transcriptomics, immunostaining, and in vivo functional assays, we demonstrated that the upregulated expression of the mTOR/4E-BP1axis and lactate dehydrogenase A in hepatocytes contributes to pericentral regeneration,while activation of transforming growth factor β (TGF-β1) signaling in the damagedarea mediates fibrotic responses and inhibits hepatocyte proliferation. Inhibitingthe pericentral accumulation of monocytes and monocyte-derived macrophages throughan Arg-Gly-Asp (RGD) peptide-based strategy attenuates these cell-derived TGF-β1 signalings,thus improving pericentral regeneration. Our study provides integrated and high-resolutionspatiotemporal insights into the cellular and molecular basis of pericentral regeneration.

DOI: 10.1016/j.stem.2024.01.013

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00043-2