# Extracellular Matrix Regulation of Airway Epithelial Homeostasis

> **NIH NIH R21** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2024 · $203,974

## Abstract

Project Summary
Airway basal epithelial cells (BCs) play critical roles in lung homeostasis particularly in repair from injury
reflecting their ability to differentiate into and replenish a range of mature epithelial cell types. Increasing
knowledge of cell signaling and other transcriptional pathways regulating these behaviors has emerged over
recent years. However, less information is available about the effects of the physical environment, particularly
the lung extracellular matrix (ECM) on BC behaviors. The ECM is increasingly recognized as affecting cell
growth, differentiation, and other actions, reflecting ECM properties including protein content as well as
stiffness all of which can affect cell behaviors. Notably both BCs and ECM composition and structure can be
altered in diseases, for example COPD. However, the mechanistic links between altered ECM and
dysregulated BC self-renewal and differentiation is poorly understood. Better understanding will provide new
insights into normal lung epithelial homeostasis and disruption in disease and provide potential new
therapeutics.
To address this, we have developed novel tools and exciting preliminary data. Co-PI Dr. Ren has developed
novel “inside-out” spheroid BC cultures in which the apical cell surfaces are exterior (apical-out airway
organoids, AOAO), a reverse polarity compared to traditional spheroid cultures of airway epithelial cells, and
one that better reflects how the native airway interfaces with the exterior environment. In parallel, co-PI Dr.
Weiss has developed a novel series of hydrogels derived from ECM of decellularized human lungs (dECM)
including those produced from airway, vascular, and alveolar-enriched compartments of both normal and
diseased (COPD, IPF) human lungs. These techniques, individually and in combination, are powerful new tools
that have provided novel and exciting preliminary data utilizing both normal and COPD lung-derived hydrogel
to influence lung epithelial cell growth and differentiation.
The goal of the current proposal is to utilize these tools to systematically assess the effects of normal and
diseased COPD ECM on relevant actions of BCs obtained from both normal and COPD lungs. Endpoint
assessments will be BC self-renewal and differentiation into mature airway epithelial cells. Importantly, we
have built an outstanding collaborative team including Dr. Amy Ryan (University of Iowa) with which to achieve
these goals. These studies will provide novel and important new information concerning ECM regulation of BC
homeostasis that will enhance knowledge of lung injury and repair and provide potential new therapeutic
avenues for use of BCs in cell-based and other therapies.

## Key facts

- **NIH application ID:** 10951279
- **Project number:** 1R21HL175617-01
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Xi Ren
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $203,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951279

## Citation

> US National Institutes of Health, RePORTER application 10951279, Extracellular Matrix Regulation of Airway Epithelial Homeostasis (1R21HL175617-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10951279. Licensed CC0.

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