肝星状细胞通过r -应答控制肝脏的分区、大小和功能，这一成果由哥伦比亚大学Robert F. Schwabe研究小组经过不懈努力而取得。相关论文于2025年3月12日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组证明了造血干细胞的基因缺失改变了肝细胞的WNT活性和分区，导致肝再生、细胞色素P450代谢和损伤的显著改变。该研究团队确定了R-spondin 3 (RSPO3)，一种HSCs富集的WNT信号调节剂，负责HSCs的这些肝细胞调节作用。HSCs选择性缺失RSPO3表型显示了HSC缺失对肝细胞基因表达、分区、肝脏大小、再生和细胞色素p450介导的解毒的影响，并加剧了酒精相关和代谢功能障碍相关的脂肪变性肝病。在酒精相关和代谢功能障碍相关的脂肪变性肝病患者中，RSPO3表达随HSCs激活而降低，并与预后呈负相关。造血干细胞通过RSPO3发挥的这些保护和调节肝细胞的功能类似于其他器官中表达r -spondin的基质生态位，应该整合到当前的治疗概念中。

据悉，肝星状细胞（HSCs）在肝纤维化的发展中起着中心的发病作用。然而，它们与纤维化无关和体内平衡的功能仍然知之甚少。

附：英文原文

Title: Hepatic stellate cells control liver zonation, size and functions via R-spondin 3

Author: Sugimoto, Atsushi, Saito, Yoshinobu, Wang, Guanxiong, Sun, Qiuyan, Yin, Chuan, Lee, Ki Hong, Geng, Yana, Rajbhandari, Presha, Hernandez, Celine, Steffani, Marcella, Qie, Jingran, Savage, Thomas, Goyal, Dhruv M., Ray, Kevin C., Neelakantan, Taruna V., Yin, Deqi, Melms, Johannes, Lehrich, Brandon M., Yasaka, Tyler M., Liu, Silvia, Oertel, Michael, Lan, Tian, Guillot, Adrien, Peiseler, Moritz, Filliol, Aveline, Kanzaki, Hiroaki, Fujiwara, Naoto, Ravi, Samhita, Izar, Benjamin, Brosch, Mario, Hampe, Jochen, Remotti, Helen, Argemi, Josepmaria, Sun, Zhaoli, Kendall, Timothy J., Hoshida, Yujin, Tacke, Frank, Fallowfield, Jonathan A., Blockley-Powell, Storm K., Haeusler, Rebecca A., Steinman, Jonathan B., Pajvani, Utpal B., Monga, Satdarshan P., Bataller, Ramon, Masoodi, Mojgan, Arpaia, Nicholas, Lee, Youngmin A., Stockwell, Brent R., Augustin, Hellmut G., Schwabe, Robert F.

Issue&Volume: 2025-03-12

Abstract: Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1,2,3,4,5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of Rspo3 phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease. RSPO3 expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.

DOI: 10.1038/s41586-025-08677-w

Source: https://www.nature.com/articles/s41586-025-08677-w