# Regeneration of distal lung epithelium via epithelial-mesenchymal co-culture and modulation of Wnt signaling

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $48,243

## Abstract

PROJECT SUMMARY/ABSTRACT
The only curative treatment option for end-stage lung disease is transplantation, however, this therapy is
plagued by limitations: those who are fortunate enough to receive a donor lung face a lifetime of
immunosuppression and a ten-year survival rate of less than 30%. Nevertheless, evidence is accumulating for
the innate potential of numerous epithelial and mesenchymal cell types in the lung to promote repair and
regeneration after injury, even at the whole tissue level. This project proposes to use whole lung engineering
strategies to investigate the role of epithelial-mesenchymal interactions, along with a key developmental
signaling pathway, in promoting alveolar epithelial differentiation and alveolar unit formation. Specifically, the
overarching goal of this proposal is to investigate whether alveolar epithelial type II cell-fibroblast interactions
and canonical Wnt-β-catenin soluble effectors can be modulated in vitro in a 3-dimensional (3-D) biomimetic
rat lung model to engineer a distal lung epithelium with improved surfactant production and epithelial barrier
function. The first Aim of this project focuses on characterizing the pattern of canonical Wnt signaling in the
native lung, as well as in isolated type II cells (here RTII+ cells, selected for by the rat type II marker RTII-70)
and fibroblasts (FBs), during alveologenesis. Patterns of Wnt signaling during this late stage of lung
development, during which mature type II cells produce surfactant, differentiate into type I cell progeny, and
become part of the functional alveolus, will likely inform alveolar repair processes. The second Aim focuses on
evaluating the effects of canonical Wnt soluble effectors on the phenotype and differentiation of RTII+ cells,
with and without FB co-culture, using standard 2-D and 3-D organoid culture systems. It seeks to determine
whether temporal modulation of these effectors, according to a timescale determined in Aim 1, might be
utilized to promote maturation of alveolar epithelium in vitro. Finally, the third aim looks at the incremental
effect of decellularized lung extracellular matrix on the maturation of RTII+ cells, with or without FB co-culture.
In this last Aim, RTII+ cells and FBs will be seeded into an acellular rat lung scaffold and mounted into a
biomimetic bioreactor. This system allows for assessment of RTII+ cell function at the whole tissue level, in
terms of lung compliance and epithelial barrier function. Overall, this project has important implications, both
for understanding the factors that promote the formation of a mature alveolar epithelium capable of gas
exchange, as well as for the development of strategies to promote lung regeneration endogenously in patients
suffering from chronic lung disease.

## Key facts

- **NIH application ID:** 9998024
- **Project number:** 5F30HL143880-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Katherine Leiby
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,243
- **Award type:** 5
- **Project period:** 2018-09-16 → 2021-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998024

## Citation

> US National Institutes of Health, RePORTER application 9998024, Regeneration of distal lung epithelium via epithelial-mesenchymal co-culture and modulation of Wnt signaling (5F30HL143880-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9998024. Licensed CC0.

---

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