# The role of transcription factor MEOX2 in lipofibroblast function during alveolarization

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $39,693

## Abstract

Project Summary
Pulmonary lipofibroblasts (LFs) that reside in the distal lung mesenchyme support alveolar epithelial cell
homeostasis and repair in both adult-onset fibrotic lung diseases (such as idiopathic pulmonary fibrosis, IPF)
and neonatal lung diseases (such as bronchopulmonary dysplasia, BPD). Specifically, LFs: 1) uptake and
transfer fatty acids to alveolar type 2 (AT2) epithelial cells during alveolarization for surfactant production, and
2) provide paracrine ligands such as FGF10 that stimulate alveolar type 1 (AT1) and AT2 proliferation and
differentiation. A better understanding of the transcriptional regulation of the pulmonary lipofibroblast phenotype
will lead to the development of targeted therapies for BPD and IPF. Transcription factor MEOX2 is a signature
gene of the murine developmental lipofibroblast, as identified by publicly available RNA-sequencing datasets. In
other organ systems, MEOX2 controls fatty acid uptake in cardiovascular endothelial cells, is necessary for
brown fat adipogenesis, and is critical for mesenchymal proliferation and differentiation in early limb
development. Although MEOX2 is upregulated in non-small cell lung cancer, the role of MEOX2 in lung
development is completely unknown. We predicted that MEOX2 would have a role in lipofibroblast differentiation,
so we strove to generate preliminary data on MEOX2’s upstream and downstream function. PPAR signaling is
a known activator of lipofibroblast differentiation, so we treated human PDGFRa+ fetal lung fibroblasts (IMR90
cells) with pan-PPAR activator metformin, which induced expression of MEOX2. Additionally, we performed a
transcription factor motif search at the human MEOX2 locus and identified a putative peroxisome proliferator
response element (PPRE). We then overexpressed MEOX2 in IMR90 cells and determined that MEOX2 is
sufficient to induce expression of lipofibroblast signature genes PLIN2 and TCF21. The central hypothesis of this
grant is that MEOX2 is directly regulated by PPARA signaling and is necessary and sufficient for establishment
of the lipofibroblast lineage and function during alveolarization. Aim 1 will investigate if the putative PPRE is
necessary and sufficient for induction of MEOX2 expression through the use of molecular genetic approaches
in immortalized human lung fibroblasts. Aim 2 will investigate if MEOX2 is necessary and sufficient to induce
lipofibroblast gene expression, fatty acid (FA) uptake and transfer, and support of alveolar epithelial
differentiation through 1) in vitro assays combined with transient MEOX2 knockout and overexpression
constructs, and 2) an in vivo conditional fibroblast specific MEOX2 knockout during early alveolarization. Our
long-term goal is to identify MEOX2’s role as a transcription factor in the development of the lung mesenchyme,
with the hope of discovering therapeutic targets for chronic neonatal and adult lung diseases. This training plan
combines, molecular, cellular, and developmental bi...

## Key facts

- **NIH application ID:** 10385997
- **Project number:** 1F31HL162470-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Matthew Riccetti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,693
- **Award type:** 1
- **Project period:** 2022-02-02 → 2024-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385997

## Citation

> US National Institutes of Health, RePORTER application 10385997, The role of transcription factor MEOX2 in lipofibroblast function during alveolarization (1F31HL162470-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10385997. Licensed CC0.

---

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