# Pathogenic Role of Foxl1+ Hepatic Progenitor Cells in Fibrotic Liver Disease

> **NIH NIH R37** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $359,547

## Abstract

PROJECT SUMMARY/ABSTRACT
Progression of chronic liver disease to fibrosis, cirrhosis, and cancer is the common course of several liver
diseases, but treatments for the end-stage liver disease are limited highlighting the critical need to identify a
novel therapeutic target. Despite the numerous evidence indicating that accumulation of hepatic progenitor cells
(HPCs) - the epithelial compartment of ductular reactions - is associated with fibrosis, definitive evidence
supporting the causal role of HPCs in progression of fibrotic liver disease and cancer remains largely uncertain
mainly due the lack of a mouse model that allows conditional labeling and tracing of HPCs. Furthermore, although
increased angiogenesis in cirrhotic livers is a risk factor for tumorigenesis, whether and how HPCs signal to
endothelial cells remains as a knowledge gap. We have previously reported that the forkhead box L1 (Foxl1)-
Cre transgenic line can be used for specific labeling and isolation of HPCs. Using this new mouse model, we
generated preliminary data indicating that inhibition of Notch signaling in HPCs leads to decreased angiogenesis
and fibrosis in mice with chronic liver disease and increased differentiation of HPCs into cells with hepatocytic
morphology. Our data also indicate that HPCs secrete several paracrine factors to stimulate proliferation of
endothelial cells and angiogenic gene expression. This led to our central hypothesis that Foxl1+ HPCs promote
progression of liver disease by crosstalking with endothelial cells and hepatic stellate cells in a paracrine manner,
and modulation of the Notch signaling pathway is a valid strategy to promote differentiation of HPCs and inhibit
pathogenic mechanisms. We propose HPCs as a novel and unique cellular target that can be modulated to
simultaneously inhibit progression of fibrotic liver disease and tumorigenesis and promote liver regeneration. Our
overall objective for the proposed study is to establish the causal role of HPCs in pathogenesis using
experimental models that recapitulate progression of human fibrotic disease. We will test our hypothesis with the
following specific aims: Aim 1 will determine the role of the Notch signaling pathway in reprogramming of Foxl1+
HPCs into mature hepatocytes in vivo. Aim 2 will determine the cellular and molecular mechanism by which
Foxl1+ HPCs regulate disease progression. Aim 3 will determine the requirement for Foxl1+ HPCs in multiple
stages of tumorigenesis.

## Key facts

- **NIH application ID:** 10652008
- **Project number:** 4R37CA225807-06
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Soona Shin
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $359,547
- **Award type:** 4N
- **Project period:** 2023-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652008

## Citation

> US National Institutes of Health, RePORTER application 10652008, Pathogenic Role of Foxl1+ Hepatic Progenitor Cells in Fibrotic Liver Disease (4R37CA225807-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10652008. Licensed CC0.

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