# Hepatic stellate cells in NASH fibrosis and HCC

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $474,893

## Abstract

Non-alcoholic steatohepatitis (NASH) is a rising public health threat characterized by progression from steatosis,
to hepatocyte injury, inflammation, fibrosis and hepatocellular carcinoma (HCC). A key unanswered question is
how inflammation and hepatic fibrosis create a ‘pro-carcinogenic stroma’ that promotes the development of
hepatocellular carcinoma (HCC), even without co-existent cirrhosis. Central to these stromal changes is the
activation of hepatic stellate cells (HSCs), which are resident perisinusoidal, vitamin A-rich cells that
transdifferentiate into myofibroblasts (cancer-associated fibroblasts, or CAFs) to secrete a host of extracellular
matrix constituents, growth factors, and cytokines. The objective of this research is to clarify the role of hepatic
stellate cells in the pathogenesis of NASH and HCC. We and our collaborators have developed two highly
efficient, complementary models of HSC depletion that can address critical gaps in understanding their role in
NASH fibrosis and HCC: 1) JEDI (“Just EGFP death inducing”) T-cells, in which CD8+ T cells engineered to kill
cells that express green fluorescent protein (GFP) are administered to transgenic mice, in which GFP is driven
by the b-PDGF receptor promoter, killing 99% of HSCs; 2) CAR T cells targeting urokinase plasminogen
activated receptor (uPAR), which eliminate only senescent HSCs in murine liver. Concurrently, we have created
a highly reproducible murine NASH model that faithfully replicates the histology, fibrosis progression and HCCs
of human NASH. Our central hypothesis is that activated and senescent HSCs in NASH express unique drivers
that contribute to a tumor-prone stromal microenvironment. Thus, this proposal concurrently investigates the
dynamics and unique contributions of HSCs to NASH, and the stromal abnormalities they generate that give rise
to HCC. We will address this hypothesis in three interrelated, but distinct Specific Aims:1) To define the
dynamics, origin and cellular features of HSC repopulation before and after their depletion in normal and NASH
mice; 2) To establish the relative contributions of senescent and non-senescent HSCs to NASH fibrosis and
HCC; 3) To identify HSC-derived stromal drivers of HCC in murine and human NASH. This innovative approach
leveraging unique animal models is significant because it will yield fundamental new insights into HSC biology
in health and disease, define specific stromal drivers that they regulate, and link abnormalities from mouse
models to human NASH-HCC to establish their clinical relevance as potential therapeutic targets.

## Key facts

- **NIH application ID:** 10810679
- **Project number:** 5R01DK128289-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SCOTT L. FRIEDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,893
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810679

## Citation

> US National Institutes of Health, RePORTER application 10810679, Hepatic stellate cells in NASH fibrosis and HCC (5R01DK128289-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10810679. Licensed CC0.

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