Biology subjects

Distler, J. H. W.

Publications and source records attributed to Distler, J. H. W..

8 recordsLinked to original sources

bioRxiv2026

Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium

Myocardial fibrosis is a common end point of acute and chronic cardiovascular injury, yet the spatially organized fibroblast (Fb) and immune-cell states that sustain fibrotic remodeling across etiologies remain incompletely defined. We applied cyclic in situ hybridization (cISH)-based spatial transcriptomics to myocardial biopsies from patients with acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), postviral myocardial fibrosis (PVMF), and systemic sclerosis associated primary heart involvement (SSc-pHI). CODEX-based protein imaging provided orthogonal support for cell subpopulations and cellular neighborhoods. Spatially informed clustering identified six Fb subpopulations: COL1A1hi/POSTNhi, NOTCH3+, TIMP1hi, GSNhi/DCNhi, AP1hi Fbs, and myofibroblasts. COL1A1hi/POSTNhi and NOTCH3+ Fbs were enriched in AMI, whereas GSNhi/DCNhi Fbs and myofibroblasts predominated in chronic fibrotic remodeling. These subpopulations displayed distinct extracellular matrix, inflammatory, and vasoregulatory programs. Infarction-associated reparative niches were enriched in COL1A1hi/POSTNhi or NOTCH3+ Fbs and SPP1+ or APOE+ macrophages (M{Phi}), whereas chronic fibroinflammatory niches were enriched in GSNhi/DCNhi or AP1hi Fbs or myofibroblasts with C1Q+ M{Phi} and plasma cells. The GSNhi/DCNhi Fb niche marked areas of subendocardial fibrosis, whereas the AP1hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1hi/POSTNhi Fb state characteristic of infarct scar formation was present at higher frequency than in other chronic entities and was individually associated with cardiac dysfunction, whereas the chronic GSNhi/DCNhi Fb niche was associated with the extent of interstitial fibrosis and anti-topoisomerase I autoantibodies. These data show that human myocardial fibrosis is organized into spatially distinct Fb subpopulations that assemble into context-specific fibroinflammatory niches across chronic fibrotic remodeling and repair after AMI.

cell biology↗

bioRxiv2025

Distinct myeloid precursors and their interaction with mesenchymal cells orchestrate the spreading of psoriatic disease from the skin to the joints

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/665302v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@38c440org.highwire.dtl.DTLVardef@dc574dorg.highwire.dtl.DTLVardef@1e79f72org.highwire.dtl.DTLVardef@19508cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Single cell mapping of the metabolic landscape of skin fibrosis in systemic sclerosis

AbstractTissue resident cells undergo metabolic reprogramming during fibrotic tissue remodeling to meet their changing metabolic demands required for extracellular matrix production and phenotypic transitions in fibrosis. However, the metabolic reprogramming in fibrotic tissues has not yet been explored at single cell level with spatial resolution. Moreover, the spatial organization of metabolic niches in fibrotic tissues remains understudied. To address these gaps, we used imaging mass cytometry (IMC) and characterized the metabolic regulome, indicative of the activity in several key metabolic pathways in systemic sclerosis (SSc) as a prototypic systemic fibrotic disease. We identified a distinct metabolically active profile with high activity of glycolysis, TCA/OXPHOS, hypoxia and ROS signaling in fibroblasts, endothelial cells and macrophages in SSc patients with progressive skin fibrosis. These metabolic profiles are associated with expression of markers of profibrotic activation. Metabolically active fibroblasts might shape their microenvironment to induce a similar metabolic phenotype in neighboring endothelial cells and macrophages, facilitating profibrotic interactions. Consistently, specific interactions between metabolically defined, activated cell subsets are associated with the extent or progression of skin fibrosis. Thus, interfering with these metabolic niches might provide therapeutic opportunities in fibrotic diseases.

cell biology↗

bioRxiv2025

Human blood vessel organoids recapitulate key mechanisms of transition from vasculopathy to fibrosis in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. Here we characterized blood vessel organoids (BVOs) as a novel model system of vasculopathy in SSc. We demonstrate that exposure of SSc-BVOs to SSc serum triggers changes on epigenetic, mRNA and protein levels and recapitulates key pathogenic features of SSc vasculopathy, with shifts from angiogenic endothelial cell subsets to those undergoing endothelial-to-mesenchymal transition, loss of endothelial cells-pericytes interactions and profound angiogenic defects. The genetic predisposition of SSc donors and serum IgGs are required for the deleterious effects of SSc serum. We further validate SSc-BVOs as a human model system to evaluate candidate therapies targeting SSc microvasculopathy and use this system to provide evidence that {gamma}-secretase inhibition is a potential therapeutic approach.

biophysics↗

bioRxiv2025

Mapping spatially-resolved transcriptomes in systemic sclerosis

Systemic sclerosis (SSc) is a prototypical fibrotic disease with high mortality and limited treatment options. Despite advances in single-cell RNA sequencing (scRNA-seq), the comprehensive understanding of cellular heterogeneity and cell-cell interaction within the fibrogenesis microenvironment remains limited. We generated spatially resolved transcriptome maps from healthy and SSc skin and built a scRNA-seq atlas to map the single-cell data to spatial space. This enabled us to identify a fibrotic niche, enriched with fibroblasts and macrophages, which is significantly expanded in SSc and correlated with clinical outcome. We revealed disease-specific cell states of fibroblasts and macrophages, and evaluated their spatial dependency on other cell types. We identified selective expression of ACKR3 in fibroblast progenitors that diminishes with SSc progression, which may serve to regulate CXCL12/CXCR4-mediated macrophage recruitment and fibrotic remodeling. Together, we provided an in-depth description at cellular and spatial levels of fine-tuned regulatory events occurring in SSc, offering spatiotemporal insights. One Sentence SummaryIntegrated spatial omics provide insight into the cellular and transcriptional landscape in spatially distinct microenvironments, which may drive fibrosis progression in SSc.

immunology↗

bioRxiv2024

Spatially informed phenotyping by cyclic-in-situ-hybridization identifies novel fibroblast populations and their pathogenic niches in systemic sclerosis

Spatially non-resolved transcriptomic data identified functionally distinct populations of fibroblasts in health and disease. However, in-depth transcriptional profiling in situ at single-cell resolution has not been possible so far. Here, we studied fibroblast populations in the skin of SSc patients and healthy individuals using cyclic in situ hybridization (cISH) as a novel approach for spatially-resolved transcriptional phenotyping with subcellular resolution. cISH deconvoluted the heterogeneity of 20,979 cells including 3,764 fibroblasts (FB). BANKSY-based spatially-informed clustering identified nine FB subpopulations, with SFRP2+ RetD FB and CCL19+ nonPV FB as novel subpopulations that reside in specific cellular niches and display unique gene expression profiles. SFRP2+ RetD FB and CCL19+ nonPV FB as well as COL8A1+ FB, display altered frequencies in SSc skin and play specific, disease-promoting roles for extracellular matrix release and leukocyte recruitment as revealed by their transcriptional profile, their cellular interactions and ligand-receptor analyses. The frequencies of COL8A1+ FB and their interactions with monocytic cells and B cells are associated with progression of skin fibrosis in SSc. In summary, our spatially-resolved transcriptomic approach identified novel fibroblast subpopulations deregulated in SSc skin with specific pathogenic roles, some of which may potentially serve as biomarkers for progression of skin fibrosis.

immunology↗

bioRxiv2023

Molecular Imaging with Fibroblast Activation Protein Tracers depicts Inflammatory Joint Damage and its Transition to Resolution of Inflammation

Joint fibroblasts play an important role in the transition from joint inflammation to irreversible joint damage. There is no established clinical method to measure fibroblast activation during inflammation and their phenotypic dynamics upon therapy to date. Here we show that upon treatment with IL-17A/TNF-blocking antibodies fibroblasts change their phenotype from a destructive IL-6+/MMP3+THY1+ to a CD200+DKK3+ subtype, actively inducing resolution of inflammation. This phenotypic switch can be visualized due to so far unexplored different capacities of fibroblast subtypes with regard to receptor internalization of small molecular tracers with high affinity to FAP. Although FAP expression levels are comparable between fibroblast subtypes in the joint, FAP internalisation rate correlates with the destructive potential of fibroblasts and resolving fibroblasts have a lower FAP internalisation rate, providing a valuable imaging tool to visualize the transition from joint damage to resolution of inflammation.

immunology↗

bioRxiv2020

Targeting BDCA2 suppresses Plasmacytoid dendritic cell dependent interferon response and tissue fibrosis

Plasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of Scleroderma (SSc) through their ability to infiltrate the skin and secrete interferons (IFN) and proinflammatory chemokines. Blood Dendritic Cells Antigen 2 (BDCA2) is an inhibitory type II C-type lectin expressed by human pDC. Here we determined the effects of BDCA2 internalisation on pDC mediated skin inflammation and fibrosis in human preclinical models of skin inflammation and fibrosis in vitro and in vivo. BDCA2 targeting reversed TLR-signalling induced transcriptome and differentiation of pDC and suppressed their ability to induce IFN response in organotypic 3D human skin cultures in vitro. In vivo, xenotransplantation of human pDC into immunocompromised mice (XenoSCID) significantly increased IFN induced responses to topical TLR7/9 agonist and separately enhanced the fibrotic response to bleomycin. Targeting of BDCA2 strongly suppressed both of these pathological responses ameliorating skin inflammation and fibrosis. Together, these preclinical data strongly support the notion that human pDC play a key role in immune driven skin fibrosis, which can be effectively blocked by targeting BDCA2.

immunology↗