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Characterization of the dynamics of hepatic stellate cell (HSC) turnover and their contribution to non-alcoholic steatohepatitis (NASH)

Grant number: 22/02175-1
Support Opportunities:Scholarships abroad - Research
Effective date (Start): October 01, 2022
Effective date (End): September 30, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Bruno Cogliati
Grantee:Bruno Cogliati
Host Investigator: Scott Friedman Md
Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Icahn School of Medicine at Mount Sinai, United States  


Non-alcoholic esteatohepatitis (NASH) is a rising public health threat that is increasingly complicated by hepatocellular carcinoma. NASH is characterized by steatosis, hepatocyte injury, inflammation, and fibrosis; and is associated with features of the metabolic syndrome, including type 2 diabetes, obesity, hypertension, and hyperlipidemia. Recently, we have developed a highly efficient model of hepatic stellate cells (HSC) depletion that can address critical gaps in understanding their role in NASH fibrosis, called JEDI ("Just eGFP death inducing") T-cells. In this model, CD8+ T cells engineered to kill cells that express green fluorescent protein (GFP) are administered to transgenic mice wherein GFP is driven by the ²-platelet-derived growth factor receptor (Pdgfr-²) receptor promoter, killing > 99% of HSCs. This model reinforces the relevant contribution of HSCs to fibrosis, and allow us to ask key unanswered questions in NASH pathogenesis: 1) How, and how quickly do HSCs repopulate the liver after depletion?; and 2) What are the molecular features of resident and repopulating HSCs in normal and NASH livers that contribute to disease? Then, the main aim of this proposal is to define the dynamics, origin and transcriptomic features of HSC before and after their depletion in normal and NASH mice. For this purpose, we will establish the rates of HSC turnover using a lineage tracing system in healthy mice and animals with NASH liver injury before or after JEDI T cell depletion model. Following depletion, the origin(s) of repopulated HSCs will be defined using quantitative morphometry with origin-specific cell markers, coupled with isolation of HSC subpopulations and single cell RNA sequencing. This question is novel and important, as there are no prior studies that have quantified the half-life, turnover, or dynamics of HSC repopulation. The findings are expected to create new knowledge that will change the direction of the field by uncovering mechanisms of HSC repopulation that will be vital in anticipating clinical strategies for HSC depletion and their impact on liver homeostasis. (AU)

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