# Epithelial stem cell hippo signaling in pulmonary fibrosis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $174,049

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) resulting in alveolar
remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of
diagnosis. IPF pathogenesis encompasses fibrotic remodeling, inflammation, and loss of lung architecture.
Although the underlying causes of the disease remain elusive, genetic and experimental evidence support the
concept that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF
disease pathogenesis. Histologically, respiratory epithelial cells in the lung parenchyma express atypical
proximal airway epithelial and indeterminate cell type markers, including goblet and basal cell (BC)
characteristics that are normally restricted to conducting airways. Fibrotic lesions and honeycomb structures
replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Genome-wide
transcriptomic analyses of lung tissue and isolated epithelial cells from IPF patients demonstrate dramatic
changes in ciliated, basal, and goblet cell–associated gene expression and loss of normal alveolar epithelial
cells, reflecting profound changes in epithelial cell differentiation and function in IPF. One strategy to attenuate
or reverse the manifestations of IPF is to trigger proper alveolar regeneration by endogenous lung stem cells.
Changes in cell density and matrix stiffness as a result of injury are sensed by the Hippo pathway, which
controls stem cell quiescence. Recent reports also indicate increased YAP activity in respiratory epithelial cells
in lungs of patients with IPF. Individual IPF epithelial cells that feature aberrant YAP activation in bronchiolized
honeycomb regions frequently co-expressed AT1, AT2, conducting airway selective markers and even
mesenchymal or EMT markers, demonstrating "indeterminate" states of differentiation not seen in normal lung
development. Our preliminary findings indicate that inactivation of the Hippo pathway impairs alveolar epithelial
regeneration, whereas inactivation of Yap promotes the resolution of pulmonary fibrosis. Using the new
techniques and tools we have generated we will define the molecular pathways and mechanism by which the
Hippo pathway controls alveolar epithelial regeneration after bleomycin injury.

## Key facts

- **NIH application ID:** 10147147
- **Project number:** 5R01HL146461-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Stijn Piet Johan De Langhe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $174,049
- **Award type:** 5
- **Project period:** 2019-04-23 → 2021-10-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147147

## Citation

> US National Institutes of Health, RePORTER application 10147147, Epithelial stem cell hippo signaling in pulmonary fibrosis (5R01HL146461-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10147147. Licensed CC0.

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