# Defining the mechanisms driving maturation and morphogenesis of the hepatocyte-derived biliary tree

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $41,670

## Abstract

The biliary tree is a hierarchically organized system of tubes that drain bile from the liver into the intestine.
Integral to the development of this structure is NOTCH signaling, which directs biliary differentiation and
tubulogenesis in embryonic liver development1-3. Disruption of this signaling pathway results in a paucity of
intrahepatic bile ducts, as observed in the human disease Alagille syndrome (ALGS)4-6. By extinguishing all
NOTCH signaling in the hepatic progenitor cells of mice, we observe complete biliary agenesis and extensive
cholestatic liver damage similar to human cases of ALGS. Uniquely, this mouse is able to generate a new
biliary system postnatally, derived entirely from transdifferentiated hepatocytes and dependent on TGFβ
signaling7. We observe that as cholestatic injury increases in the NOTCH-deficient liver, resident hepatocytes
acquire biliary characteristics and proliferate around and between portal veins to form areas of dense cellular
processes called ductular reactions (DRs). DRs appear as vascularized, homogenous ductular structures at
least partially contiguous with the common bile duct and involve a complex assortment of cell types. Overtime,
DRs will resolve into a hierarchical biliary tree equivalent in size and function to that of a wild-type mouse7 –
how this occurs is unclear, but involves a demonstrable reduction in ductule number, suggesting a
heterogeneous commitment among hepatocyte-derived ductular cells to a mature cholangiocyte fate. Our
preliminary evidence in combination with recently published studies suggests there are multiple signaling
modules, including TGF, WNT, and YAP, that operate in a dynamic fashion to orchestrate the
transdifferentiation, expansion, and reorganization of hepatocyte-derived ductular cells into the finalized biliary
network7-12. Understanding the transcriptional changes occurring in these cells as the hepatocyte-derived
biliary system progressively matures would provide direct insight into the signaling pathways driving both
transdifferentiation and morphogenesis, as well as reveal the resident cell types directing these processes.
 I aim to define the lineage trajectory of hepatocyte-derived ductular cells that successfully
transdifferentiate into cholangiocytes, the signals directing their assembly into a functional biliary tree, and the
cell populations in the DR microenvironment that are responsible. To accomplish this, I will first single-cell
sequence pure populations of hepatocyte-derived ductular cells from progressive stages of biliary tree
maturation. Second, I will single-cell sequence ductular and non-ductular cells isolated from the DR together to
elucidate the ligand-receptor relationships driving hepatocyte fate conversion and subsequent tubulogenesis.
Understanding the blueprint for the successful genesis of the hepatocyte-derived biliary tree, independent of
NOTCH signaling, has direct clinical ramifications for the treatment of diseases involving biliary...

## Key facts

- **NIH application ID:** 10069188
- **Project number:** 1F31DK126419-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Simone Natalya Thorson Kurial
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,670
- **Award type:** 1
- **Project period:** 2020-06-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069188

## Citation

> US National Institutes of Health, RePORTER application 10069188, Defining the mechanisms driving maturation and morphogenesis of the hepatocyte-derived biliary tree (1F31DK126419-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10069188. Licensed CC0.

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