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

• Applicant: Professorin Dr. Miriam Margherita Cortese-Krott
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521638178

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.

• DFG Programme: Research Grants