# Mechanisms of Hepatocyte Polarization and Apical Tube Formation

> **NIH DK R01** · UNIVERSITY OF PENNSYLVANIA · 2026 · $697,454

## Abstract

Project Summary/Abstract:
The vital functions of the liver—detoxification, serum protein synthesis, and bile production—critically depend
on the establishment of a unique hepatic polarity and the formation of bile canaliculi (BC). Defects in these
processes contribute to serious liver diseases, including cholestasis and hepatocarcinoma. Using the rat
hepatocyte line Can 10, the only known cells that can proliferate and form “tubular” BCs in vitro resembling
those in vivo, we discovered that hepatocyte polarization and “primordial” BC formation are linked to
cytokinesis. Our collaborative work suggests that this division-linked mechanism underlies BC biogenesis in
mice during liver development and regeneration. However, it remains unclear how hepatic polarity is
established and maintained at the molecular level, and how a primordial BC, formed between daughter cells
at the division site, is remodeled into a tubular BC nestled between aligned hepatocytes produced by
oriented divisions.
We hypothesize that hepatocyte polarization and BC morphogenesis require the spatiotemporal coordination
of cytokinesis with adherens junction and tight junction assembly and remodeling, spindle orientation, and
polarized membrane trafficking. Within this conceptual framework, we address three interrelated questions,
each guided by a specific hypothesis involving key players identified from our genomic and proteomic
screens. In Aim 1, we will investigate the mechanisms underlying our surprising finding that knockdown of
Epithelial(E)-cadherin impairs BC elongation, whereas knockdown of Neural(N)-cadherin causes a switch
from hepatic polarity to columnar polarity. While both cadherins are required for establishing hepatic polarity
at the division site, E-cadherin promotes BC elongation via GEF-mediated Rho activation, whereas N-
cadherin maintains hepatic polarity via GAP-mediated Rho inactivation. In Aim 2, we will determine how the
actin-binding LIM domain proteins Ablim1 and Alblim3 f

## Key facts

- **NIH application ID:** 11364592
- **Project number:** 2R01DK128861-05A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erfei  Bi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DK
- **Fiscal year:** 2026
- **Award amount:** $697,454
- **Award type:** 2
- **Project period:** 2021-07-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11364592

## Citation

> US National Institutes of Health, RePORTER application 11364592, Mechanisms of Hepatocyte Polarization and Apical Tube Formation (2R01DK128861-05A1). Retrieved via AI Analytics 2026-07-03 from https://api.ai-analytics.org/grant/nih/11364592. Licensed CC0.

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