Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation

Supplementary Website

Study overview

Reconstruction of skin granuloma architecture based on multi-omics data and experimental validation.

Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organ. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposes transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue-remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.


Identification of granuloma-associated cell types

Characterization of disease-driving cell subsets

Inference of cellular interaction networks and validation of therapeutic targets


Data download

Description Links
Raw sequencing data:
 The raw sequencing data are available from the European Genome-phenome Archive repository under accession number EGAS00001006970.
To request access to the raw sequencing data, please e-mail the filled and signed Data Access Agreement to Georg Stary (georg.stary@meduniwien.ac.at).
Raw imaging data:
 The microscopy imaging data are available from zenodo: 10.5281/zenodo.7584110.
Processed data:
 The processed sequencing data (count matrices) are available from the NCBI Gene Expression Omnibus repository repository under accession number GSE192461.
Analysis code:
 The analysis source code is available as a ZIP archive or via zenodo: 10.5281/zenodo.7523056.
Supplementary data:
 The projection of literature-derived gene signatures on the spatial data are available as a ZIP archive.

Citation

If you use these data in your research, please cite:

Thomas Krausgruber*, Anna Redl*, Daniele Barreca*, Konstantin Doberer, Daria Romanovskaia, Lina Dobnikar, Maria Guarini, Luisa Unterluggauer, Lisa Kleissl, Denise Atzmüller, Carolina Mayerhofer, Aglaja Kopf, Simona Saluzzo, Clarice X. Lim, Praveen Rexie, Thomas Weichhart, Christoph Bock#, Georg Stary#
Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation.
Immunity 2023. DOI: 10.1016/j.immuni.2023.01.014.

* These authors contributed equally to this work
# Correspondence: georg.stary@meduniwien.ac.at (G.S.), cbock@cemm.oeaw.ac.at (C.B.)