Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Annika Vannan¹, Ruqian Lyu², Arianna L Williams¹, Nicholas M. Negretti³, Evan D. Mee¹, Joseph Hirsh³, Samuel Hirsh³, Niran Hadad¹, David S. Nichols³, Carla L. Calvi ³, Chase J. Taylor³, Vasiliy V. Polosukhin³, Ana P. M. Serezani³, A. Scott McCall³, Jason J. Gokey³, Heejung Shim², Lorraine B. Ware³, Matthew J. Bacchetta³, Ciara M. Shaver³, Timothy S. Blackwell³, Jennifer M. S. Sucre³, Jonathan A. Kropski³, Rajat Walia⁴, Nicholas E. Banovich¹

¹Translational Genomics Research Institute, ²University of Melbourne, ³Vanderbilt University Medical Center, ⁴Norton Thoracic Institute, ^*Corresponding author

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Description Pulmonary fibrosis (PF) is a chronic, progressive condition that represents the end-stage of many interstitial lung diseases (ILDs). Single-cell transcriptomic studies have revealed disease-emergent epithelial, fibroblast, and macrophage cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using image-based spatial transcriptomics to profile gene expression changes in-situ across 28 lung samples from control and PF lungs, we characterized the expression of 343 genes in over 1 million nuclei at subcellular resolution. Using both cell-based and cell-agnostic approaches, we observed a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Overlaying these computationally-defined niches with disease-associated histopathologic features, we identified novel patterns of dysregulation in alveoli informed by spatial context. We computationally segmented individual air spaces and using cell composition, we ordered airspaces from homeostatic to most dysregulated. Using this ordering we identified a series of stepwise molecular changes associated with progressive distal lung remodeling. Together, these results advance our understanding of the molecular programs underlying progressive PF.

Dataset ID LMEX0000004411

Assay Type Xenium

Organism Human

Stages Adult | 65+ years

Technology 10x Genomics Xenium

Reference Vannan et al. (2025)

External databases GEO: GSE250346

Sample	Donor	Age	Health Status	Sample Type	Tobacco	Cell Count	GEO Sample
THD0008	THD0008	53 years	Control	Control	Y	73785	GSM7990532
THD0011	THD0011	47 years	Control	Control	Y	34998	GSM7990533
TILD117	TILD117	54 years	ILD	More Fibrotic	N	52165	GSM7990534
TILD117 (Less Affected)	TILD117	54 years	ILD	Less Fibrotic	N	40810	GSM7990535
TILD175	TILD175	65 years	IPF	ILD - More Affected	Y	38293	GSM7990536
VUHD069	VUHD069	31 years	Control	Control	N	23758	GSM7990537
VUHD095	VUHD095	64 years	Control	Control	N	12578	GSM7990538
VUHD113	VUHD113	40 years	Control	Control	N	14940	GSM7990539
VUHD116	VUHD116	NA	Control	Control		12915	GSM7990540
VUHD116	VUHD116	NA	Control	Control		31189	GSM7990541
VUILD102	VUILD102	58 years	IPF	Less Fibrotic	Y	27973	GSM7990543
VUILD104	VUILD104	69 years	IPF	Less Fibrotic	Y	38984	GSM7990545
VUILD105	VUILD105	66 years	IPF	More Fibrotic	Y	24843	GSM7990546
VUILD106	VUILD106	66 years	IPF	ILD - More Affected	Y	140997	GSM7990548
VUILD107	VUILD107	63 years	IPF	More Fibrotic	Y	72153	GSM7990549
VUILD110	VUILD110	62 years	CTD-ILD	ILD - Less Affected	N	133369	GSM7990550
VUILD115	VUILD115	60 years	cHP	ILD - More Affected	N	108131	GSM7990551
VUILD48	VUILD48	52 years	NSIP	More Fibrotic	Y	32868	GSM7990552
VUILD78	VUILD78	47 years	IPAF	More Fibrotic	N	45690	GSM7990554
VUILD78 (Less Affected)	VUILD78	47 years	IPAF	Less Fibrotic	N	35179	GSM7990555
VUILD91	VUILD91	65 years	IPF	Less Fibrotic	N	16431	GSM7990557
VUILD91 (More Affected)	VUILD91	65 years	IPF	More Affected	N	26396	GSM7990556
VUILD96	VUILD96	61 years	Sarcoidosis	More Fibrotic	N	59609	GSM7990558
VUILD96 (Less Affected)	VUILD96	61 years	Sarcoidosis	Less Fibrotic	N	46277	GSM7990559

LungMAP ID	Alt ID	Species	Sex	Race	Age	Age Group
LMSP0000001432	THD0008	Homo sapiens	Male	European	53 years	Adult
LMSP0000001535	THD0011	Homo sapiens	Male	European	48 years	Adult
LMSP0000001536	TILD117	Homo sapiens	Female	European	54 years	Adult
LMSP0000001548	TILD175	Homo sapiens	Male	American Indian/Alaska Native	65 years	65+ years
LMSP0000001533	VUHD069	Homo sapiens	Female	African American	31 years	Adult
LMSP0000001545	VUHD095	Homo sapiens	Female	European	64 years	Adult
LMSP0000001489	VUHD113	Homo sapiens	Female	European	40 years	Adult
LMSP0000001554	VUHD116	Homo sapiens				Adult
LMSP0000001493	VUILD102	Homo sapiens	Male	European	58 years	Adult
LMSP0000001494	VUILD104	Homo sapiens	Male	European	69 years	65+ years
LMSP0000001550	VUILD105	Homo sapiens	Male	European	66 years	65+ years
LMSP0000001551	VUILD106	Homo sapiens	Male	European	66 years	65+ years
LMSP0000001544	VUILD107	Homo sapiens	Male	European	63 years	Adult
LMSP0000001542	VUILD110	Homo sapiens	Female	European	62 years	Adult
LMSP0000001540	VUILD115	Homo sapiens	Male	European	60 years	Adult
LMSP0000001520	VUILD48	Homo sapiens	Male	European	52 years	Adult
LMSP0000001534	VUILD78	Homo sapiens	Female	European	47 years	Adult
LMSP0000001470	VUILD91	Homo sapiens	Male	European	65 years	65+ years
LMSP0000001448	VUILD96	Homo sapiens	Female	African American	61 years	Adult

7 of this study's 23 samples were also assayed by 1 other LungMAP studies, across 1 modality. Click any node to list those studies. The other 16 appear in no other study and are not drawn.

Shared samples by study