Functional crosstalk of hepatic stellate cells and sinusoidal endothelial cells for liver homeostasis

肝星状细胞（hepatic stellate cells，HSC）在肝脏再生和体内平衡中起着重要作用。自噬和自我更新的病理性失调是保证肝再生能力的基础，可能导致肝变性和纤维化。在肝脏中，多种细胞表达精氨酸酶-1（Arg 1），已显示其在炎症过程和肝再生中发挥核心作用，包括肝细胞、窦状隙内皮细胞（SEC）和HSC。在不执行完整尿素循环的细胞（如HSC和SEC）中，Arg 1主要通过限制L-精氨酸作为两种酶的底物来控制iNOS的活性。此外，ARG 1有助于多胺合成，这反过来又控制多种生物过程，包括通过蛋白质翻译和基因表达调控调节自我更新、自噬和增殖。我们发现初步证据表明，ERAS，Arg 1和精氨酸转运蛋白（CAT）可能是共同定位和功能上连接的一个假定的Arg 1微域。我们推测，这种非典型的Arg 1微域控制的HSC的静止状态，通过调节自噬，协调相互控制NO的合成，和多胺的生产在串扰与SEC的空间中的Disse。为了证实这一假设，我们将结合联合收割机的知识和复杂的方法，从Ahmadian实验室的HSC的生化和细胞生理特性的知识/分析专业知识的Arg 1/NO途径和EC Arg 1基因敲除小鼠的可用性，从Cortese-Krott实验室研究以下目标：（1）分析的组成Arg 1非典型的HSC和SEC的微结构域。(2)研究Arg 1-多胺轴在维持HSC静止中的功能作用及其在自噬中的作用。(3)分析Arg 1-多胺轴在SEC和HSC之间的串扰中的作用。这项研究将为维持肝脏稳态的机制提供新的见解，也可能有助于确定可能影响慢性肝病HSC激活进展的新途径。

Hepatic stellate cells (HSCs) play a central role in liver regeneration and homeostasis. Pathological dysregulation of autophagy and self-renewal, which is fundamental to assure liver regeneration capacity, may lead to liver degeneration and fibrosis. In the liver, multiple cells express Arginase-1 (Arg1), which has been shown to play a central role in inflammatory processes and liver regeneration, including hepatocytes, sinusoidal endothelial cells (SECs), and HSCs. In cells that do not execute a full urea cycle (like HSCs and SECs), Arg1 mainly controls the activity of iNOS by limiting the availability of L-arginine as a substrate of both enzymes. Additionally, ARG1 contributes to polyamine synthesis, which in turn controls multiple biological processes, including modulation of self-renewal, autophagy, and proliferation via protein translation and gene expression regulation. We found preliminary evidence that ERAS, Arg1, and arginine transporters (CATs) may be co-localized and functionally connected on a putative Arg1 microdomain. We hypothesize that this non-canonical Arg1 microdomain controls the quiescent state of HSCs via regulating autophagy, coordinating the reciprocal control of NO synthesis, and the polyamine production in crosstalk with SECs in the space of Disse. To corroborate this hypothesis, we will combine the knowledge and sophisticated methods for biochemical and cell-physiological characterization of HSCs from the Ahmadian Lab with the knowledge/analytical expertise of the Arg1/NO pathway and the availability of EC Arg1 KO mice from the Cortese-Krott Lab to investigate the following objectives: (1) Analyze the composition of Arg1 non-canonical microdomains in HSCs and SECs. (2) Investigate the functional role of the Arg1-polyamine axis in maintaining HSC quiescence and its role in autophagy. (3) Analyze the role of the Arg1-polyamine axis in the crosstalk between SECs and HSCs. This study will provide new insights into mechanisms involved in sustaining liver homeostasis and may also help identify novel pathways that can potentially influence the progression of HSC activation in chronic liver diseases.