Modulation of an aberrant basal cell program in human alveolar epithelial spheroids and lung slices subtitle: modulating aberrant basal cells in human cells and tissues

Yong Li; Jack H Wellmerling; Lorena Rosas; Patrick A Link; Daniela Chow; Joshua Alvarez; Kyoung M Choi; Ana M Diaz Espinosa; Rachel M Gilbert; Nicholas P Goplen; Donghao Li; Andrew J Haak; Y S Prakash; Mauricio Rojas; Daniel J Tschumperlin

doi:10.1186/s12931-025-03441-0

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Modulation of an aberrant basal cell program in human alveolar epithelial spheroids and lung slices subtitle: modulating aberrant basal cells in human cells and tissues

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Modulation of an aberrant basal cell program in human alveolar epithelial spheroids and lung slices subtitle: modulating aberrant basal cells in human cells and tissues

Yong Li, Jack H Wellmerling, Lorena Rosas, Patrick A Link, Daniela Chow, Joshua Alvarez, Kyoung M Choi, Ana M Diaz Espinosa, Rachel M Gilbert, Nicholas P Goplen, …

Respiratory research, Vol.27(1), 89

2026

DOI: 10.1186/s12931-025-03441-0

PMCID: PMC12918232

PMID: 41388287

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Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease marked by the accumulation of aberrant basal cells that are thought to promote disease progression. The cellular origin and disease-relevant cues that lead to aberrant basal cells remain poorly understood. We sought to identify the signals regulating formation and maintenance of aberrant basal cells from human alveolar type II (ATII) cells using 3D spheroids, and test whether inhibition of select pathways could reduce aberrant basal signatures in human precision-cut lung slices (PCLS) from diseased lungs. We characterized aberrant basal cell signatures in human ATII spheroids in response to TGFβ1 and hypoxia mimic dimethyloxalylglycine (DMOG) treatment alone or in combination. We tested whether a Notch inhibitor (LY-411575) could inhibit/reverse these signatures in human ATII spheroids and IPF PCLS. Readouts included immunofluorescence analysis, western blotting, and quantitative PCR of aberrant basal signature genes. We found that human ATII spheroids acquire aberrant basal cell signatures upon TGFβ1 and DMOG treatment, with the combination most effectively programming cells to an aberrant basal state. LY-411575 was able to significantly inhibit or reverse a subset of the aberrant basal cell signatures in 3D spheroids and IPF PCLS. TGFβ1 and hypoxia are disease relevant signals capable of driving ATII cells to acquire aberrant basal cell signatures found in IPF. Notch inhibition may provide a tractable approach to normalize these programs in the fibrotic human lung.

Details

Title: Subtitle: Modulation of an aberrant basal cell program in human alveolar epithelial spheroids and lung slices subtitle: modulating aberrant basal cells in human cells and tissues
Creators: Yong Li - University of Virginia
Jack H Wellmerling - Mayo Clinic in Florida
Lorena Rosas - The Ohio State University
Patrick A Link - University of Iowa
Daniela Chow - Mayo Clinic
Joshua Alvarez - The Ohio State University
Kyoung M Choi - Mayo Clinic in Florida
Ana M Diaz Espinosa - Mayo Clinic
Rachel M Gilbert - Mayo Clinic in Florida
Nicholas P Goplen - Mayo Clinic in Florida
Donghao Li - Mayo Clinic in Florida
Andrew J Haak - Mayo Clinic
Y S Prakash - Mayo Clinic in Florida
Mauricio Rojas - The Ohio State University
Daniel J Tschumperlin - Mayo Clinic in Florida
Resource Type: Journal article
Publication Details: Respiratory research, Vol.27(1), 89
DOI: 10.1186/s12931-025-03441-0
PMID: 41388287
PMCID: PMC12918232
NLM abbreviation: Respir Res
ISSN: 1465-993X
eISSN: 1465-993X
Publisher: Springer Nature
Grant note: HL092961 / NIH R01 HL152967 / NIH U01
Language: English
Electronic publication date: 12/12/2025
Date published: 2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
Record Identifier: 9985090605502771

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