Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

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Updated February 14, 2025

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.

Ari B MolofskyUniversity of Californiaari.molofsky@ucsf.edu
Tien PengUniversity of Californiatien.peng@ucsf.edu
Chaoqun Wang1
Ben Hyams1
Nancy C Allen1
Kelly Cautivo1
Kiara Monahan1
Minqi Zhou1
Madelene W Dahlgren1
Carlos O Lizama1
Michael Matthay1
Paul Wolters1
Ari B Molofsky (Principal Investigator)1
Tien Peng (Principal Investigator)1
1University of California
Arsenios Chatzigeorgiou

To reference this project, please use the following link:

https://explore.data.humancellatlas.org/projects/f7b46477-0f2a-4bff-a9b7-719e000499a3

Supplementary links are provided by contributors and represent items such as additional data which can’t be hosted here; code that was used to analyze this data; or tools and visualizations associated with this specific dataset.

1.https://cellxgene.cziscience.com/collections/03cdc7f4-bd08-49d0-a395-4487c0e5a168
GEO Series Accessions:
GSE196638, GSE206721

Atlas

LungLung v2.0

Analysis Portals

CZ CELLxGENE
CZ CELLxGENE

Project Label

LungStromaEmphysema

Species

2 species

Sample Type

specimens

Anatomical Entity

lung

Organ Part

Unspecified

Selected Cell Types

hematopoietic cell

Disease Status (Specimen)

2 disease statuses

Disease Status (Donor)

2 disease statuses

Development Stage

2 development stages

Library Construction Method

2 library construction methods

Nucleic Acid Source

single cell

Paired End

true

Analysis Protocol

human_raw_matrix_generation, mouse_raw_matrix_generation

File Format

4 file formats

Cell Count Estimate

Unspecified

Donor Count

12
fastq.gz88 file(s)mtx.gz8 file(s)tsv.gz16 file(s)xlsx1 file(s)
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