# FGF18 regulation of postnatal lung development

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $620,385

## Abstract

Title: FGF18 regulation of postnatal lung development
Summary:
 Alveologenesis is the final stage of lung development where the surface area of the lung is increased by
subdividing alveolar saccules through the formation of secondary septae (septal ridges), followed by thinning of
the septal walls to generate an efficient air/blood gas exchange organ. Bronchopulmonary dysplasia (BPD) is a
common complication of preterm birth in which alveologenesis is impaired. BPD often results in chronic
respiratory disease. However, besides Vitamin A and supportive care, no therapies exist to promote lung alveolar
and vascular development to improve the outcomes of infants with BPD.
 Alveologenesis can be divided into two phases in humans and rodents. During the first phase, alveolar
myofibroblasts (AMFs) and other mesenchymal and epithelial cells regulate the formation of secondary septae.
During the second phase, the septal walls undergo a maturation process that involves thinning, through loss of
mesenchymal cells and remodeling of the microvasculature, to a single layer capillary network juxtaposed with
alveolar type 1 (AT1) cells. The mature alveolar wall ensures efficient air/blood gas exchange in the adult lung.
 An in-depth understanding the mechanisms that regulate alveolar septation and septal wall maturation will be
required to develop therapies for premature infants with BPD and for developing potential therapies for adult
lung regeneration. However, there are specific knowledge gaps about the identity of mesenchymal progenitors
that give rise to AMFs, the functions of AMFs and other mesenchymal cell types, and the mechanisms that
terminate and clear AMFs from the lung at the completion of secondary septation.
 Fibroblast Growth Factor 18 (Fgf18) is expressed at high levels in AMFs and AT1 cells during alveologenesis.
We show that conditional inactivation of Fgf18 in the neonatal lung results in impaired alveologenesis. Through
lineage tracing of Fgf18-expressing cells, we find that the AMFs are cleared from the lung after the first phase of
alveologenesis, coinciding with alveolar wall thinning, but that AT1 cells are retained.
 In this proposal, we use a combination of unique genetic tools for lineage tracing and gene inactivation, cell
sorting coupled with RNA deep sequencing, and single cell and single nuclei RNA sequencing, to identify the
relative contribution of mesenchymal and epithelial FGF18 to the first and second phases of alveologenesis, the
cellular response(s) to FGF18 during alveologenesis, the progenitors that give rise to fibroblasts sub-types in
alveolar septae, and the mechanisms that specifically clear AMFs from the lung. The proposed experiments will
also generate an atlas of gene expression for septal mesenchymal cell types present during alveologenesis that
will serve as a resource for the research community.

## Key facts

- **NIH application ID:** 10072838
- **Project number:** 1R01HL154747-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David M Ornitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $620,385
- **Award type:** 1
- **Project period:** 2020-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072838

## Citation

> US National Institutes of Health, RePORTER application 10072838, FGF18 regulation of postnatal lung development (1R01HL154747-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072838. Licensed CC0.

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