Spatial transcriptomics reveals layered immune-metabolic architecture of giant cell myocarditis
Musigk, N.; Sudy, A.; Suwalski, P.; Jechow, K.; Liebig, J.; Bischoff, P.; Just, I. A.; Falk, V.; Schoenrath, F.; Eils, R.; Landmesser, U.; Knosalla, C.; Conrad, C.; Heidecker, B.
Show abstract
Giant cell myocarditis (GCM) represents the most fulminant form of inflammatory cardiomyopathy, yet its spatial pathophysiology remains poorly defined. We applied full-transcriptome spatial capture in-situ RNA sequencing to a human GCM explant, generating a comprehensive high-resolution molecular atlas across twelve cardiac localizations. Spatial clustering and cell-type deconvolution delineated a complex cellular landscape dominated by cardiomyocytes, fibroblasts, and immune cells, with pronounced transcriptional heterogeneity along the epicardial-endocardial axis. Myeloid cells localized to inflammatory hotspots and exhibited SPP1- and IL1B-driven activation, whereas lymphoid cells displayed a continuum from IgM- to IgG4-secreting plasma-cell differentiation. Layer-resolved pathway analysis revealed epicardial enrichment of IL-6/JAK/STAT3 and TNF-/NF-{kappa}B signaling, myocardial upregulation of oxidative phosphorylation and myogenesis, and endocardial activation of stress and apoptosis programs. These data uncover a layered immune-metabolic architecture linking epicardial inflammation to myocardial remodeling and endocardial stress, providing a spatial framework for understanding immune-mediated myocardial injury in GCM.
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