Biology subjects

Fuge, J.

Publications and source records attributed to Fuge, J..

3 recordsLinked to original sources

bioRxiv2025

A multicenter spatial transcriptomics atlas of human tuberculosis and non-tuberculous mycobacterial disease

Granulomas are the hallmark of mycobacterial (MB) infections, forming structured immune environments that contain bacteria but also drive disease persistence. However, their spatial and functional organization remains unclear. Using spatial RNA sequencing on 38 patient samples, we identified five distinct granuloma niches: a necrotic core, an immune-activated inner niche, an inflammatory and an extracellular matrix (ECM)-remodeling middle niche, an outer structural niche, and a tertiary lymphoid structure niche supporting antigen presentation. Immune activity peaks in the inner niche, transitioning to fibrosis at the periphery. Lymph node granulomas display reduced fibroblast involvement but stronger JAK-STAT activation. Mycobacterium tuberculosis (MTB) granulomas exhibit heightened JAK-STAT and IFN-{gamma} signaling, while non-tuberculous mycobacteria (NTM) granulomas show increased hypoxia signatures. Compared to sarcoidosis, MB granulomas feature a structured adaptive immune response, marked by the clustering of plasma cells. Our findings, accessible via https://lab-li.ciim-hannover.de/mb-granuloma/, define key disease signatures, guiding biomarker discovery and therapeutic targeting in granuloma-related diseases.

bioinformatics↗

bioRxiv2025

The pleuroparenchymal fibroelastosis atlas reveals aberrant cell states and their zonation as an alternate roadmap to lung fibrosis

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease with higher prevalence in females, histologically characterized by intra-alveolar fibrosis with septal elastosis (AFE). Effective treatments are lacking, highlighting the need to dissect its pathogenesis at single-cell resolution. MethodsWe performed single-nucleus RNA sequencing (snRNAseq) on explanted lungs from a German (n=23) and a French cohort (n=17) of PPFE patients, and controls (n=16). Identified cell populations were localized by immunofluorescence and multiplex RNA in-situ hybridization. Hierarchical phase-contrast computed tomography (HiP-CT) and micro-CT provided 3D spatial context. Reanalyzed snRNAseq data from a Belgian IPF cohort (n=9) served as disease comparator. FindingsWe present the first snRNAseq atlas of PPFEs cellular and structural landscape based on a European multinational cohort. 24 PPFE patients were female (60.0%), while 34 were non-smokers (85.0%). 519,920 nuclear transcriptomes from PPFE and IPF patients, and controls were profiled. We identified PPFE-specific accumulations of MFAP5+PI16+SFRP2+ adventitial and LEPR+ITGA8+SFRP2+DIO2+ elastofibrotic fibroblasts as main drivers of elastotic remodeling in PPFE. Multiple PPFE fibroblast subsets acquire an inflammatory activation state as highlighted by the expression of CXCL12 and CXCL14. This is accompanied by a marked increase in lymphocytes and the formation of tertiary lymphoid structures (TLS) in a disease that was previously considered to be purely elastofibrotic. We identified CTHRC1+ fibrotic fibroblasts and Aberrant Basaloid cells in PPFE as well, forming the "Usual Fibrotic Niche". 3D reconstruction of the pronounced COL15A1+ vascular conglomerate at the border of the elastofibrotic and subpleural fibrosis indicates communication with interlobar veins. Last, we observed a zonation of the PPFE lesion, constructed by the above-mentioned PPFE-associated cell types. InterpretationOur unprecedented cellular and molecular survey uncovers previously unobserved PPFE-specific inflammatory and elastogenic fibroblast populations, as well as the presence of CTHRC1+ fibroblasts and Aberrant Basaloid cells common to other fibrotic ILDs. These findings provide the foundation for including PPFE patients in current antifibrotic trials, as well as development of PPFE-specific therapies. FundingSupported mainly by the Else Kroner-Fresenius Foundation, the German Center for Lung Research and the Fondation du Souffle.

cell biology↗

bioRxiv2025

Spatial transcriptomics uncovers hybrid, pro-inflammatory and pro-fibrotic cellular niches in pulmonary granuloma of patients with chronic sarcoidosis

BackgroundSarcoidosis is a disease of unknown etiology characterized by the formation of immune cell accumulation (granuloma) in the lung and other tissues. Chronic sarcoidosis may lead to pulmonary fibrosis. AimTo unravel cellular niches within pulmonary granuloma of chronic sarcoidosis patients using spatial transcriptomics. MethodsSpatial transcriptomics using the Visium platform (10x Genomics) was performed on nine granuloma-containing lung explants from sarcoidosis patients. Validation of gene expression was performed through immunohistofluorescence protein staining and RNA in situ hybridization. ResultsSpatial gene expression covered 30,587 gene expression spots and 173 granulomas. A CD68+ macrophage niche was localized in the center of the granuloma, with a CD3+ T and CD20+ B cell niche in close proximity, surrounded by a COL3A1+ fibroblast niche. In the central granuloma macrophage niche, expression of the pro-fibrotic macrophage genes SPP1, CHIT1 and CHI3L1 was observed, genes whose expression has recently been described for macrophages in idiopathic pulmonary fibrosis. Additionally, pro-inflammatory macrophage genes were expressed in the central granuloma niche: macrophages appear armed for lysosomal degradation and ready for phagocytosis. Inner granuloma niches showed high responsiveness to interferon gamma (IFN-{gamma}), expressing a multitude of IFN-{gamma}-induced genes. High collagen and CTHRC1 expression were observed in granuloma fibroblasts niches, characteristics of pro-fibrotic lung remodeling. Ligand-receptor analysis identified pro-inflammatory and pro-fibrotic interactions between granuloma niches. ConclusionTaken together, macrophages in the center of the sarcoidosis granuloma form an armed-and-ready, hybrid pro-inflammatory and pro-fibrotic niche, supporting granuloma persistence through continuous IFN-{gamma}-stimulation and fibrotic remodeling conducted by fibrotic fibroblasts surrounding the granuloma.

molecular biology↗