State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Disease, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
J Nanobiotechnology. 2024 Aug 30;22(1):521. doi: 10.1186/s12951-024-02790-0.
Tissue-derived extracellular vesicles (EVs) are emerging as pivotal players to maintain organ homeostasis, which show promise as a next-generation candidate for medical use with extensive source. However, the detailed function and therapeutic potential of tissue EVs remain insufficiently studied. Here, through bulk and single-cell RNA sequencing analyses combined with ultrastructural tissue examinations, we first reveal that in situ liver tissue EVs (LT-EVs) contribute to the intricate liver regenerative process after partial hepatectomy (PHx), and that hepatocytes are the primary source of tissue EVs in the regenerating liver. Nanoscale and proteomic profiling further identify that the hepatocyte-specific tissue EVs (Hep-EVs) are strengthened to release with carrying proliferative messages after PHx. Moreover, targeted inhibition of Hep-EV release via AAV-shRab27a in vivo confirms that Hep-EVs are required to orchestrate liver regeneration. Mechanistically, Hep-EVs from the regenerating liver reciprocally stimulate hepatocyte proliferation by promoting cell cycle progression through Cyclin-dependent kinase 1 (Cdk1) activity. Notably, supplementing with Hep-EVs from the regenerating liver demonstrates translational potential and ameliorates insufficient liver regeneration. This study provides a functional and mechanistic framework showing that the release of regenerative Hep-EVs governs rapid liver regeneration, thereby enriching our understanding of physiological and endogenous tissue EVs in organ regeneration and therapy.
组织衍生的细胞外囊泡（EVs）作为维持器官内稳态的关键分子而备受关注，它们作为新一代医学应用的候选物具有广泛的来源。然而，组织 EVs 的详细功能和治疗潜力仍研究不足。在这里，我们通过批量和单细胞 RNA 测序分析结合超微结构组织检查，首次揭示了原位肝组织 EVs（LT-EVs）在部分肝切除（PHx）后参与复杂的肝再生过程，并且肝细胞是再生肝中组织 EVs 的主要来源。纳米尺度和蛋白质组学分析进一步鉴定出，在 PHx 后，具有增殖信号的肝细胞特异性组织 EVs（Hep-EVs）被强化释放。此外，通过体内 AAV-shRab27a 靶向抑制 Hep-EV 的释放，证实了 Hep-EVs 对于协调肝再生是必需的。在机制上，来自再生肝脏的 Hep-EVs 通过促进细胞周期进程来促进细胞周期蛋白依赖性激酶 1（Cdk1）活性，从而相互刺激肝细胞增殖。值得注意的是，补充来自再生肝脏的 Hep-EVs 具有转化潜力，并改善了肝再生不足的情况。本研究提供了一个功能和机制框架，表明再生 Hep-EVs 的释放可控制快速的肝再生，从而丰富了我们对器官再生和治疗中生理和内源性组织 EVs 的理解。
