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

肝星状细胞(HSCs)在肝脏再生和动态平衡中起着核心作用。自噬和自我更新的病理性失调是保证肝脏再生能力的基础，也可能导致肝脏变性和纤维化。在肝脏中，多个细胞表达精氨酸酶-1(Arg1)，已被证明在炎症过程和肝再生中发挥核心作用，包括肝细胞、肝窦内皮细胞(SECs)和肝干细胞。在不执行完整尿素循环的细胞中(如HSCs和SECs)，Arg1主要通过限制L-精氨酸作为这两种酶的底物来控制iNOS的活性。此外，ARG1参与多胺的合成，进而控制多种生物过程，包括通过蛋白质翻译和基因表达调节调节自我更新、自噬和增殖。我们发现初步证据表明，ERAS、Arg1和精氨酸转运体(CATS)可能在一个可能的Arg1微域上共定位并在功能上相连。我们推测，这个非规范的Arg1微域通过调节自噬、协调NO合成的相互控制以及与Disse空间中的Secs串扰中的多胺产生来控制HSCs的静止状态。为了证实这一假设，我们将结合Ahmadian实验室关于HSCs生化和细胞生理特性的知识和成熟的方法，以及Arg1/NO通路的知识/分析专业知识和Cortese-Krott实验室的EC Arg1 KO小鼠的可用性来研究以下目标：(1)分析HSCs和SEC中Arg1非规范微域的组成。(2)探讨Arg1-多胺轴在维持HSC静止中的作用及其在自噬中的作用。(3)分析Arg1-多胺轴在SECs和HSCs之间的串扰中的作用。这项研究将为维持肝脏内稳态的机制提供新的见解，并可能有助于识别可能影响慢性肝病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.