# Epithelial progenitor cells for lung repair and regeneration

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $664,141

## Abstract

ABSTRACT
Small airway epithelial cell dysfunction and structural tissue remodeling are pathognomonic of chronic lung
diseases, but molecular mechanisms are poorly understood. Much evidence indicates that initiation and/or
progression of chronic lung disease is linked to progenitor cell dysfunction, hence suggesting that strategies
aimed at modulating the regenerative capacity of epithelial progenitor cells could provide therapeutic benefits
to patients. In preliminary studies we show that loss of alveolar type 2 (AT2) cells in lung tissue of patients with
end-stage IPF is associated with distal airway basal and secretory cell hyperplasia. The source of distal airway
basal cells and their contribution to repair vs remodeling in the setting of alveolar progenitor cell dysfunction is
unclear. Influenza (PR8) virus infection in mice leads to recruitment of basal-like epithelial cells that expand to
repopulate depleted epithelium. Our data suggest that the PR8-activated milieu of the infected lung leads to
expansion of progenitor cell potency and acquisition of basal stem cell-like characteristics. We also found that
the STAT3-dependent cytokine IL22 is induced early in the response to PR8 infection and was sufficient to
initiate a program of basal cell differentiation in the absence of PR8 infection. Interestingly, we find that
enhanced epithelial stemness by IL22/STAT3 signaling can be partially phenocopied by modulating p53 gene
dosage. Based upon these data we propose to test the hypothesis that ectopic basal cell differentiation
of distal airway progenitors enhances repair capacity in the face of severe injury and that these
changes in cell fate are regulated by local production of IL22 leading to STAT3 mediated expansion of
progenitor cell potency. Furthermore, we will test the related hypothesis that STAT3 effects of stem
cell potency are mediated through suppression of p53. These hypotheses will be tested in aims that will
take advantage of PR8 influenza virus infection in mice to understand roles for IL22/STAT3 innate immune
signaling in regulation of progenitor cell fate and tissue repair or remodeling. Specific Aims will define roles for
IL22/STAT3 signaling in regulation of airway progenitor cells (Aim 1), investigate mechanisms by which STAT3
regulates “stemness” (Aim 2) and roles for nascent basal stem cells in repair and/or remodeling (Aim 3).
Completion of these aims will provide new insights into cellular and molecular mechanisms of repair in acute
lung injury and how persistent activation of these repair pathways might contribute to tissue remodeling in the
setting of chronic lung disease. We anticipate identification of therapeutic targets that could lead to the
development of novel therapies to alter outcome in patients with acute and chronic lung disease.

## Key facts

- **NIH application ID:** 9837459
- **Project number:** 5R01HL135163-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Barry R Stripp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $664,141
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837459

## Citation

> US National Institutes of Health, RePORTER application 9837459, Epithelial progenitor cells for lung repair and regeneration (5R01HL135163-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837459. Licensed CC0.

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