# Hepatic stellate cell plasticity and maladaptive fibrogenic memory in chronic liver disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $568,494

## Abstract

PROJECT SUMMARY
Hepatic stellate cell plasticity and maladaptive fibrogenic memory in chronic liver disease
Fibrosis associated with chronic liver disease affects hundreds of millions of patients worldwide. Hepatic stellate
cells (HSCs), in turn, represent the main cellular driver of hepatic fibrosis. A key unanswered question is why
HSCs activate to facilitate tissue repair in response to acute liver injury but hyperactivate to produce exuberant
extracellular matrix in response to repeated liver injury, leading to fibrosis. Central to this behavior switch is a
mechanism for HSCs to remember previous injury episodes in order to respond differently, i.e. hyperactivate,
when exposed to re-injury. Recent studies, including ours (Wang et al. Dev Cell 2019), strongly support the
epigenome and in particular DNA methylation patterns as the carrier of cell memory in development and in tissue
injury. The objective of this research is to clarify how the epigenome and specifically DNA methylation patterns
encode this maladaptive cell memory and amplify HSC’s fibrogenic response following re-injury. This proposal
builds upon recent advances in single cell technology and low-input chromatin profiling which we optimized
extensively to measure HSC gene expression and epigenomic changes in vivo in a novel mouse model of
fibrogenic memory. In our fibrogenic memory model, HSCs completely deactivate following fibrosis regression,
with their transcriptome indistinguishable from uninjured HSCs, however epigenomic changes persist in the form
of chromatin accessibility changes. In response to re-injury, HSCs from regressed liver hyperactivate and are
driven by unique transcriptional networks (WT1, TEAD1, TBX20, and PBX1) not found in HSCs undergoing initial
injury. Using the Uhrf1 floxed mice generated previously in our Dev Cell paper to specifically remove Uhrf1, a
critical component of the DNA methylation machinery, in HSCs, we found that these mice display augmented
fibrogenic memory in response to re-injury. Our central hypothesis is that memory of previous injury through
epigenetic changes modify HSC plasticity and amplify their activation in response to re-injury. We will address
this hypothesis in three interrelated, but distinct specific aims:1) Define the regulatory elements controlling
fibrogenic memory in HSCs; 2) Determine how UHRF1 and the DNA methylome control fibrogenic memory in
HSCs; 3) Uncover novel regulatory nodes driving HSC’s maladaptive response in re-injury. This innovative
approach leveraging cutting-edge genomics technology and unique animal models is significant because it will
yield fundamental new insights into stellate cell biology by uncovering the epigenetic basis of fibrogenic memory,
the contribution of specific genes and transcriptional networks to fibrogenic memory and hepatic fibrosis, and
conserved fibrogenic drivers in liver disease patients that can lead to potential therapeutic targets.

## Key facts

- **NIH application ID:** 10814951
- **Project number:** 5R01DK136016-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Shuang Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,494
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814951

## Citation

> US National Institutes of Health, RePORTER application 10814951, Hepatic stellate cell plasticity and maladaptive fibrogenic memory in chronic liver disease (5R01DK136016-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10814951. Licensed CC0.

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