肝脏组织特化血管发育和重塑的细胞学基础和分子机制研究

Liver sinusoids are tissue specific capillaries. Several liver diseases are related to the change of liver sinusoids. It is significantly meaningful to.investigate the detailed mechanism involved in the sinusoid homeostasis and reconstruction. Liver sinusoids get specialized endothelial cells (Sinusoidal endothelial cells, SEC) and vascular pericyte (Hepatic stellate cells, HSC). These two subtypes of cells interacted with each other and further constitutes sinusoid homeostasis. Besides, Notch signaling pathway has been reported to strictly modulate vascular development, therefore it is indeed a good way to better observe the molecular network within liver sinusoid homeostasis and reconstruction. In this project, according to previous findings, using endothelium specific Notch gene modified mice, we would like to illustrate the detailed mechanism involved in SEC-HSC interaction during embryo development, adult homeostasis and injury induced sinusoid reconstruction. We would also detect the pathway crosstalk among Notch and eNOS and Angiopoietin-2, which may probably provide a brand new sinusoid based target of advanced biological therapy for liver diseases.

肝血窦是肝脏特化的毛细血管，诸多肝病的病理进程均涉及肝血窦病变。深入研究其发育和生理、病理重塑的调控机制，对于揭示肝病的发病机理，为其诊治提供科学依据具有重大意义。肝血窦具有其组织特化的血管内皮细胞（肝血窦内皮细胞，SEC）和血管周细胞（肝星型细胞，HSC），二者协同作用可能是维系肝血窦微环境稳态的重要细胞基础。Notch信号被证实广泛参与对血管发育、稳态的调控，从而为我们阐明肝血窦发育和重重塑调控的分子网络提供了很好的切入点。本项目，申请人拟在前期工作基础上，利用血管特异性的Notch基因修饰模型，深入研究在肝脏胚胎发育、生理和病理重塑过程中，肝血窦SEC-HSC协同作用机制，并以Notch信号通路为核心阐明其与eNOS、Angiopoietin-2等通路相互作用的分子网络，从而为肝病的诊治提供科学依据，为针对肝血窦的血管靶向药物的研发奠定理论基础。

全面地揭示了肝脏非实质细胞中星型细胞（HSC）、内皮细胞、巨噬细胞分别介导的Notch信号通路在加速肝纤维化进程、抑制肝纤维化消融中的重要作用。通过外泌体的包装和修饰，构建了肝纤维化干预、治疗的新载体；通过选择性阻断Notch信号，开辟了肝纤维化干预、治疗的新途径。深入解析了肝脏内皮细胞在肝再生过程中的空间和功能异质性。首次提出肝脏中“促增殖”内皮，即靠近中央静脉区的C-kit+LSEC可以通过分泌Wnt2 等旁分泌因子促进肝细胞的增殖和再生；而“抑增殖”内皮，即异常血流剪应力诱发的老化的LSEC可以破坏肝血窦的重塑，而阻碍肝再生进程。研究成果以通讯作者发表在Cell Metabolism（2021），Hepatology（2022；2021；2018），Cell Mol Gastroenterol Hepatol（2022），Theranostics (2022) 等期刊。