# Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $514,858

## Abstract

ABSTRACT
Biliary epithelial cells (BECs; also called as cholangiocytes) that line the hepatic biliary tree control bile
composition and flow. Injury to the BECs leads to cholestasis, which can progress to fibrosis, cirrhosis and liver
failure. Cholestatic liver diseases are associated with high morbidity and mortality; however, few effective
therapies are available. In fact, liver transplantation is the only life-extending treatment for end-stage cholestatic
liver diseases, but the shortage of donor livers makes this therapy extremely limited. In the injured liver with
biliary damage, hepatocytes (HCs) can contribute to BECs to recover from the loss of BECs. Recent studies in
mice have shown that HC-derived BECs contribute to the intrahepatic bile ducts, thereby restoring appropriate
bile flow. Patients with biliary obstruction or cholangiopathies also exhibit biliary marker expression in HCs,
suggesting their reprogramming into BECs. Thus, augmenting innate HC-to-BEC reprogramming in cholestatic
liver diseases is an attractive therapeutic alternative to ameliorate cholestasis and subsequent cirrhosis. To
develop such a therapy, it is crucial to better understand the molecular mechanisms underlying HC-to-BEC
reprogramming. Furthermore, identifying small molecules that can augment the reprogramming should provide
promising therapeutic drugs for patients with cholestatic liver diseases. Our long-term goal is to completely
delineate the molecular mechanisms underlying HC-to-BEC reprogramming. As a first step in pursuit of that goal,
the objective of this proposal is to determine the cellular and molecular characteristics of HC-to-BEC
reprogramming-driven biliary regeneration in our two innovative zebrafish models and to elucidate how histone
deacetylase 1 (hdac1) regulates HC-to-BEC reprogramming. Based on our preliminary data obtained from
pharmacological and genetic studies, we hypothesize that Hdac1 inhibition promotes HC-to-BEC reprogramming
by derepressing the Notch receptor gene notch2 and the signal transducer and activator of transcription 3 gene
(stat3). We will test this hypothesis and accomplish the objective of this application by (1) elucidating the entire
process of HC-to-BEC reprogramming-driven biliary regeneration in the two zebrafish models, in which complete
absence of BECs is achieved and subsequently HCs convert to BECs. (Aim 1), (2) determining the effects of
Hdac1 inhibition on HC-to-BEC reprogramming in both zebrafish and mice (Aim 2), and (3) elucidating the
molecular mechanisms by which Hdac1 inhibition promotes the reprogramming (Aim 3). The successful
accomplishment of the proposed research will not only provide novel molecular mechanisms underlying HC-to-
BEC reprogramming but also suggest HDAC1/2 inhibitors as promising therapeutic drugs to promote the
reprogramming in patients with cholestatic liver diseases.

## Key facts

- **NIH application ID:** 10415302
- **Project number:** 1R01DK132014-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Donghun Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $514,858
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415302

## Citation

> US National Institutes of Health, RePORTER application 10415302, Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming (1R01DK132014-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10415302. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*