# Metabolic Reprogramming of the Alveolar Stem Cell Niche in Pulmonary Fibrosis

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $609,272

## Abstract

PROJECT SUMMARY
 Cell metabolism regulates epigenetic reprograming to determine cellular identity and fate.
Intermediary metabolites serve as essential cofactors for epigenetic modifying enzymes. Epithelial-
mesenchymal crosstalk is critical for the maintenance of adult tissues/organs and in regenerative
responses to tissue injury. In the lung, alveolar maintenance and regeneration are orchestrated by the
interaction of alveolar type 2 (AT2) cells, a facultative stem/progenitor cell population, with the
adjacent mesenchyme that contributes to “niche” support of the regenerating epithelium. These
homeostatic type 2 niche-supporting stromal cells (T2NSCs) may transition to pathological
mesenchymal states/fates during lung injury-repair.
 We have identified a metabolic enzyme, nicotinamide N-methyltransferase (NNMT), that regulates
the plasticity of tissue-resident fibroblasts (FBs) and the transition of lipofibroblasts (lipo-FBs) into
myofibroblasts (myo-FBs). NNMT catalyzes the N-methylation of nicotinamide and other pyridine
compounds; by utilizing the universal methyl donor, SAM in this reaction, NNMT functions as a
“methyl sink” in many tissues, while also depleting cellular NAD+ levels. Our data indicate that NNMT
is upregulated in lung mesenchymal cells of idiopathic pulmonary fibrosis (IPF), and is induced by the
pro-fibrotic cytokine, transforming growth factor-β1, in human lung fibroblasts. NNMT functions as a
critical switch from lipo-FB to myo-FB differentiation that acquire apoptosis resistance, thus impairing
fibrosis resolution.
 In this project we will test the hypothesis that metabolic-epigenetic reprogramming of activated
stromal T2NSCs by targeting NNMT potentiates lung regenerative capacity and facilitates fibrosis
resolution by augmenting cellular levels of NAD+ and/or SAM. Our specific aims are to: (1) identify
T2NSCs subpopulations and characterize their regulation by NNMT; (2) determine mechanisms by
which NNMT regulates lipo-FB to myo-FB transition; and (3) determine whether targeting NNMT
accelerates fibrosis resolution in an animal model of lung injury-induced fibrosis. A combination of
bulk and single-cell RNA-seq, ATAC-seq, metabolomics, bioenergetics, and epigenetic profiling in 3D
alveolospheres, IPF lung FBs, and an in-vivo lung injury model will be employed. The studies
proposed in this grant application will advance the field by identifying a critical regulatory switch in
lipo-FB to myo-FB differentiation, linking metabolism to epigenetics by an enzyme that controls both
cellular bioenergetics and protein methylation, defining a therapeutic strategy that achieves fibrosis
resolution/reversal in established lung fibrosis, and elucidating a functional role of alveolar stem cell
niche-supporting fibroblasts in stem cell rejuvenation and tissue regeneration.

## Key facts

- **NIH application ID:** 10858462
- **Project number:** 1R01HL173154-01
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Victor J. Thannickal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $609,272
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10858462

## Citation

> US National Institutes of Health, RePORTER application 10858462, Metabolic Reprogramming of the Alveolar Stem Cell Niche in Pulmonary Fibrosis (1R01HL173154-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10858462. Licensed CC0.

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