Biology subjects

Bermea, K. C.

Publications and source records attributed to Bermea, K. C..

3 recordsLinked to original sources

bioRxiv2025

Tissue transcriptomics of endomyocardial biopsies reveals widespread molecular perturbations independent of leukocyte-rich foci in human myocarditis

BackgroundMyocarditis is an inflammatory disease of the myocardium, classically defined and graded by histologic criteria that emphasize immune infiltrates and focal cardiomyocyte injury. The broader transcriptional landscape and intercellular signaling networks underlying human myocarditis, particularly among non-immune cells, remain poorly understood. MethodsWe performed integrated spatial transcriptomic profiling of 38 endomyocardial biopsy (EMBx) specimens using two complementary platforms: 10X Visium FFPE and GeoMx Digital Spatial Profiling (DSP). The cohort included cases of histologically confirmed myocarditis, borderline myocarditis, and controls. For 10X Visium, data was refined by excluding leukocyte-enriched spots and enriching for cardiomyocyte-specific regions based on canonical marker expression. For GeoMx, immunohistochemistry-guided segmentation enabled targeted transcriptomic analysis of disparate cardiac cellular compartments. Differential gene expression was analyzed independently for each platform and subsequently integrated. These results were further leveraged to infer molecular interaction networks and ligand-receptor relationships in myocarditis relative to controls. ResultsBoth platforms revealed widespread gene expression changes consistent with immune activation in myocarditis and borderline myocarditis, particularly within cardiomyocyte-enriched regions. These included upregulation of HLA-A, HLA-DQA1, B2M, and CD74 in myocarditis, consistent with activation of major histocompatibility complex (MHC) class I and II related pathways. Molecular interaction analysis identified STAT1 and ISG15 as likely central immune signaling nodes. Ligand-receptor inference highlighted HLA-A, HLA-E, and HLA-DQA1 as key receptor hubs interacting with immune ligands such as IFNG, CD8A, and several members of the (NK) killer-cell immunoglobulin-like receptor (KIR) family. ConclusionsOur findings demonstrate that human myocarditis is characterized by widespread transcriptional dysregulation beyond immune cell foci, including upregulation of genes typically associated with professional antigen-presenting cells in cardiomyocytes. These insights extend our current understanding of myocarditis pathophysiology and suggest new opportunities for its diagnosis and therapeutic targeting.

immunology↗

bioRxiv2023

B cells occupy a unique, dynamic, biological niche within the human myocardium

IntroductionGrowing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy. MethodsWe integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. ResultsWe identified 1,100 B cells, including naive B cells and plasma cells. B cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interaction; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation. DiscussionThe human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy myocardium, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.

immunology↗

bioRxiv2023

Cardiomyocyte-specific adenylyl cyclase type-8 overexpression induces cell-autonomous activation of RelA and non-cell-autonomous myocardial and systemic inflammation

BackgroundMice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TGAC8) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. ResultsHere we demonstrate that activation of ACVIII in cardiomyocytes results in cell-autonomous RelA-mediated NF-{kappa}B signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. These changes precede the appearance of cardiac fibrosis. We provide evidence indicating that ACVIII-driven RelA activation in cardiomyocytes is mediated by calcium-Protein Kinase A (PKA) signaling. ConclusionsUsing a model of chronic cardiomyocyte stress and accelerated aging we highlight a novel, PKA/RelA-dependent connection between cardiomyocyte stress, myocardial para-inflammation and systemic inflammation. These findings point to RelA-mediated signaling in cardiomyocytes and inter-organ communication between the heart and lymphoid organs as novel potential therapeutic targets to reduce age-associated myocardial deterioration.

cell biology↗