Liu Mingqi, Zhu Yan, Li Zhishuai, Yu Yong, Wang Duoxiang, Wang Yue, Jiang Xiaoqing, Li Bin
Department I of Biliary Tract, The Third Affiliated Hospital of Naval Medical University, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Cell Death Dis. 2025 Aug 12;16(1):609. doi: 10.1038/s41419-025-07925-1.
Studies have shown that extracellular vesicles play a crucial role in maintaining homeostasis in healthy individuals and influencing disease pathology in patients. However, the mechanisms by which exosomes facilitate liver regeneration following portal vein ligation (PVL) remain unclear. Our previous research highlighted the critical role of the Notch signaling pathway in liver regeneration after PVL. Nevertheless, the involvement of liver-derived exosomes in actively promoting regeneration through the YAP-Notch signaling pathway and their role in cell proliferation have not been fully explored. In this study, we demonstrate that exosomes from hypertrophic liver tissue can activate the YAP-Notch signaling pathway both in vitro and in vivo, thereby promoting liver regeneration after PVL. Specifically, we show that these exosomes carry JAG1, which activates Notch signaling in recipient cells, a process that is inhibited by JAG1 antibodies. Co-immunoprecipitation and mass spectrometry (Co-IP-MS) identified JAG1 interactors, confirming that ALG-2 plays a critical role in linking SEC31A and Alix to facilitate the intracellular transport and sorting of JAG1 onto exosomes. Additionally, we reveal that YAP induces hepatocyte reprogramming into Sox9 liver progenitor cells (LPCs) and promotes the release of JAG1 exosomes via the SEC31A/ALG-2/Alix axis, thereby activating Notch signaling in neighboring cells and enhancing liver regeneration. These findings suggest that YAPSox9 LPCs serve as a key source of JAG1 exosomes, playing a vital role in liver regeneration following PVL.
研究表明，细胞外囊泡在维持健康个体的内环境稳态以及影响患者疾病病理过程中发挥着关键作用。然而，外泌体促进门静脉结扎（PVL）后肝脏再生的机制仍不清楚。我们之前的研究强调了Notch信号通路在PVL后肝脏再生中的关键作用。尽管如此，肝脏来源的外泌体通过YAP-Notch信号通路积极促进再生及其在细胞增殖中的作用尚未得到充分探索。在本研究中，我们证明肥大肝脏组织来源的外泌体在体外和体内均可激活YAP-Notch信号通路，从而促进PVL后的肝脏再生。具体而言，我们发现这些外泌体携带JAG1，其可激活受体细胞中的Notch信号，这一过程可被JAG1抗体抑制。免疫共沉淀和质谱分析（Co-IP-MS）鉴定了JAG1相互作用蛋白，证实ALG-2在连接SEC31A和Alix以促进JAG1的细胞内运输和分选至外泌体上发挥关键作用。此外，我们发现YAP可诱导肝细胞重编程为Sox9肝脏祖细胞（LPCs），并通过SEC31A/ALG-2/Alix轴促进JAG1外泌体的释放，从而激活邻近细胞中的Notch信号并增强肝脏再生。这些发现表明YAP-Sox9 LPCs作为JAG1外泌体的关键来源，在PVL后的肝脏再生中发挥着至关重要的作用。
