Biology subjects

Zweck, E.

Publications and source records attributed to Zweck, E..

3 recordsLinked to original sources

bioRxiv2026

Spatial proteomic profiling of cardiac stromal populations and microenvironments in systemic sclerosis-associated primary myocardial involvement

Objectives: To define cardiac stromal heterogeneity and spatial stromal-immune organization in systemic sclerosis-associated virus-negative myocarditis (SSc-VNM), a manifestation of primary SSc heart involvement. Methods: Imaging mass cytometry, a single-cell multiplexed spatial proteomic technology, was applied to endomyocardial biopsies from ten patients with SSc-VNM, seven with VNM associated with other systemic autoimmune rheumatic diseases (a-VNM) and nine with isolated VNM (i-VNM). Single-cell phenotyping, cellular-neighborhood and spatial-interaction analyses, and correlations with histological fibrosis were performed at patient level. Results: Among 82,673 segmented cells, we identified seven fibroblast phenotypes and one CD34+ stromal-cell population. The overall fibroblast/stromal compartment was expanded in SSc-VNM compared with i-VNM (adjusted p = 0.00973). The composition of fibroblasts/stromal cells differed profoundly in SSc-VNM compared with a-VNM and i-VNM, with numerical increases in CD34+ stromal cells and SOX9+ and PI16high/POSTNhigh fibroblasts and de-enrichment of FAPhigh/POSTNhigh fibroblasts and myofibroblasts. Spatial analysis identified ten cellular neighborhoods and revealed distinct SSc-VNM-associated patterns, including altered stromal-immune interaction networks. These included enriched interactions of CD34+ stromal cells and PI16high/POSTNhigh fibroblasts with CD163high/HLA-DR+ macrophages and CD68+ mast cells. PI16high/POSTNhigh and PI16-/POSTNhigh fibroblasts demonstrated the highest collagen type 1 expression among all stromal cell subsets across all VNM entities and PI16high/POSTNhigh fibroblasts were numerically increased in biopsies with [≥]10% fibrotic remodeling and were spatially associated with collagen-rich areas. Conclusions: Our findings refine current concepts of human fibrotic myocardial remodeling and support therapeutic targeting of specific stromal players such as POSTNhigh fibroblast subpopulations. Keywords: Systemic Sclerosis; Myocarditis; Myocardial Fibrosis; Fibroblasts; Imaging Mass Cytometry.

bioinformatics↗

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↗

bioRxiv2024

High-resolution respirometry reveals altered mammalian tissue ketone body oxidation in different cardiometabolic diseases

Background and aimsReduced mitochondrial function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) {beta}-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear. MethodsTargeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human and mouse cohorts with T2D, obesity, and MASLD. ResultsIn humans with T2D, KB-driven mitochondrial OXPHOS capacity was [~]30% lower in the heart (p<0.05) and skeletal muscle (p<0.05) compared to non-diabetic controls. The relative contribution of KB to maximal OXPHOS capacity in T2D was also lower in both the heart ([~]25%, p<0.05) and skeletal muscle ([~]50%, p<0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KB to OXPHOS capacity was [~]15% lower (p<0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p<0.05) in obese humans with MASLD compared to humans without MASLD. ConclusionsMitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD.

cell biology↗