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Spatial Transcriptomics identifies Prosaposin (PSAP) as a Novel Therapeutic Vulnerability in Pulmonary Sarcoidosis [Mouse_Spatial]

ABSTRACT: Sarcoidosis is a chronic inflammatory disorder characterized by the presence of tiny collections of immune cells known as granulomas. An incomplete understanding of etiology and immune-pathologic pathways have limited the development of quality biomarkers and novel targeted therapies. We found a Fsp1-Cre mediated TSC1/2 deletion mice unexpectedly led to development of a disease state, which was identified and characterized by spatial transcriptomics and single-cell RNA sequencing, similar to sarcoidosis. Notably, we identified CCL24 as a novel key chemotactic regulator in this model of sarcoidosis and found decreased CCL24 in the sarcoid group, thus translating our model and hypothesis to the human form of the disease. Intriguingly, we found that CCL24 and azithromycin significantly blocked the progression of granuloma formation in this model. Our findings not only improve an integrated understanding of the progression of sarcoidosis but also provide the basis for developing novel potential clinical interventions in sarcoidosis therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE263088 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Cardiac involvement is an important determinant of mortality amongst sarcoidosis patients. While granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases. We leveraged spatial transcriptomics (GeoMx DSP) and single nucleus RNA sequencing (snRNAseq) to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX DSP technology, we compared the transcriptomal profile of CD68+ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed snRNAseq of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multi-channel immunofluorescence staining, we validated immune cell populations identified by snRNAseq, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases. Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. snRNAseq revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB as a novel marker of multinucleated giant cells and predicted that the MITF family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including HLA-DR+ macrophages, SYTL3+ macrophages and CD163+ resident macrophages. HLA-DR+ macrophages were found immediately adjacent to GPMMB+ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3+ macrophages were located scattered throughout the granuloma and CD163+ macrophages, CD1c+ dendritic cells, non-classical monocytes, and T-cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR pathway activation is associated with proliferation and is selectively found in HLA-DR+ and SYLT3+ macrophages. In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.

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Spatial Transcriptomics identifies Prosaposin (PSAP) as a Novel Therapeutic Vulnerability in Pulmonary Sarcoidosis [Mouse_Spatial]

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