Spatial transcriptomics reveals altered communities and drivers of aberrant epithelia and pro-fibrotic fibroblasts in interstitial lung diseases

Ramnik J. Xavier¹, Alok Jaiswal¹, Benjamin D. Medoff², Jacques Deguine¹

¹The Broad Institute, ²Harvard Medical School, ^*Corresponding author

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Description Single-nucleus RNA sequencing of the distal human lung across interstitial lung disease. Forty libraries from 18 donors, 133,327 nuclei, annotated against CellRef2.0 v7 into 80 cell states. The disease groups are IPF, COPD, NSIP, RA-ILD, PH, HP, IPAF, PAH and healthy control. Interstitial lung diseases (ILD) are characterized by fibrotic scarring of the lung parenchyma with remarkably unfavorable prognosis. Using single-nucleus RNA sequencing and spatial transcriptomics, we generated a comprehensive cellular network of the distal lung and its alterations in fibrosis. Integration with histopathology revealed that the transformation of normal parenchyma into fibrotic tissue is accompanied by ectopic bronchiolization and decellularization. Areas of active fibrosis were characterized by co-localization of pro-fibrotic CTHRC1-hi fibroblasts and aberrant transitional epithelial cells. We modeled this maladaptive differentiation of alveolar epithelial cells using organoids, demonstrating that all three pro-inflammatory ligands present in this pathogenic niche, TGF-beta, IL-1beta, and TNF-alpha, are jointly required for their induction. Additionally, we identified a requirement for the transcription factor NFATC4 during myofibroblast differentiation driven by soluble factors or mechanosensing. Collectively, this work identifies essential molecular drivers of aberrant cell states in fibrotic lung disease.

Dataset ID LMEX0000090005

Assay Type Single-nucleus RNA-seq

Organism Human

Stages Adult | 65+ years

Cell Count 133327

Technology 10x Genomics Chromium Single Cell Gene Expression

Reference Jaiswal et al. (2026)

External databases dbGaP: phs004408.v1.p1

File	Description	Size
MGH_ILD_library_metadata.tsv	Harmonized library metadata for the 40 libraries, every column, one row per library. The Samples tab shows only the fourteen columns the site defines for a human sample, so this file carries the rest: disease detail, pulmonary function, smoking status, anatomic region, assay and provenance.	39.2 KB
MGH_ILD_release_counts.h5ad	Release object for this study, HDF5 AnnData, gzip compressed. 133,327 nuclei x 34,659 genes over 80 CellRef2.0 v7 cell states and 40 libraries. X holds RAW INTEGER COUNTS, not a normalized matrix. obs carries the cell state, its short name, the library, the donor covariates and the UMAP. The site viewers read a log2 counts per ten thousand matrix rebuilt from these counts.	755.2 MB

LungMAP ID	Alt ID	Species	Sex	Race	Age	Age Group	Health Status
LMSPMGH0000001	M10_1090438_R1	Homo sapiens	Female	European	52 years	Adult	COPD
LMSPMGH0000002	M10_1090438_R2	Homo sapiens	Female	European	52 years	Adult	COPD
LMSPMGH0000003	M10_1090487_R1	Homo sapiens	Female	European	52 years	Adult	COPD
LMSPMGH0000004	M10_1090487_R2	Homo sapiens	Female	European	52 years	Adult	COPD
LMSPMGH0000005	M11_1092560	Homo sapiens	Male	European	49 years	Adult	COPD
LMSPMGH0000006	M11_1092561	Homo sapiens	Male	European	49 years	Adult	COPD
LMSPMGH0000007	M12_1111095	Homo sapiens	Female	European	61 years	Adult	PH
LMSPMGH0000008	M12_1111099	Homo sapiens	Female	European	61 years	Adult	PH
LMSPMGH0000009	M13_1104938	Homo sapiens	Male	European	59 years	Adult	IPF
LMSPMGH0000010	M13_1104950	Homo sapiens	Male	European	59 years	Adult	IPF
LMSPMGH0000011	M15_F_CST	Homo sapiens	Male	European	69 years	65+ years	IPF
LMSPMGH0000012	M15_F_TST	Homo sapiens	Male	European	69 years	65+ years	IPF
LMSPMGH0000013	M15_N_CST	Homo sapiens	Male	European	69 years	65+ years	IPF
LMSPMGH0000014	M15_N_TST	Homo sapiens	Male	European	69 years	65+ years	IPF
LMSPMGH0000015	M19_1111034	Homo sapiens	Male	European	65 years	65+ years	IPF
LMSPMGH0000016	M1_1123764	Homo sapiens	Female	European	79 years	65+ years	healthy
LMSPMGH0000017	M20_F_TST	Homo sapiens	Male		70 years	65+ years	IPF
LMSPMGH0000018	M20_N_CST	Homo sapiens	Male		70 years	65+ years	IPF
LMSPMGH0000019	M20_N_TST	Homo sapiens	Male		70 years	65+ years	IPF
LMSPMGH0000020	M23_1114257	Homo sapiens	Male	European	58 years	Adult	HP
LMSPMGH0000021	M23_1114261	Homo sapiens	Male	European	58 years	Adult	HP
LMSPMGH0000022	M25_1104918	Homo sapiens	Female		42 years	Adult	NSIP
LMSPMGH0000023	M25_1104919	Homo sapiens	Female		42 years	Adult	NSIP
LMSPMGH0000024	M26_1113132	Homo sapiens	Female	European	67 years	65+ years	NSIP
LMSPMGH0000025	M26_1113141	Homo sapiens	Female	European	67 years	65+ years	NSIP
LMSPMGH0000026	M27_1111019	Homo sapiens	Male	European	63 years	Adult	RA-ILD
LMSPMGH0000027	M27_1111025	Homo sapiens	Male	European	63 years	Adult	RA-ILD
LMSPMGH0000028	M28_1105845	Homo sapiens	Female	European	53 years	Adult	RA-ILD
LMSPMGH0000029	M28_1105849_R1	Homo sapiens	Female	European	53 years	Adult	RA-ILD
LMSPMGH0000030	M28_1105849_R2	Homo sapiens	Female	European	53 years	Adult	RA-ILD
LMSPMGH0000031	M28_1105849_R3	Homo sapiens	Female	European	53 years	Adult	RA-ILD
LMSPMGH0000032	M29_F_TST	Homo sapiens	Male	European	54 years	Adult	IPAF
LMSPMGH0000033	M29_N_TST	Homo sapiens	Male	European	54 years	Adult	IPAF
LMSPMGH0000034	M5_1124615	Homo sapiens	Female	European	73 years	65+ years	healthy
LMSPMGH0000035	M7_SN	Homo sapiens	Female	European	68 years	65+ years	healthy
LMSPMGH0000036	M8_SN	Homo sapiens	Female	European	78 years	65+ years	healthy
LMSPMGH0000037	M9_1105572_R1	Homo sapiens	Female	European	56 years	Adult	PAH
LMSPMGH0000038	M9_1105572_R2	Homo sapiens	Female	European	56 years	Adult	PAH
LMSPMGH0000039	M9_1105576_R1	Homo sapiens	Female	European	56 years	Adult	PAH
LMSPMGH0000040	M9_1105576_R2	Homo sapiens	Female	European	56 years	Adult	PAH