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

Stuetz, A. N.; De Luca, G.; Matei, A.-E.; Li, Y.-N.; Filla, T.; Batani, V.; Tuemerdem, B. S.; Rigau, A. R.; Bruno, C.; Merkt, W.; Zweck, E.; Buettner-Herold, M.; Rizzo, S.; Peretto, G.; De Gaspari, M.; Eckstein, M.; Schett, G.; Basso, C.; Matucci-Cerinic, M.; Distler, J.; Gyoerfi, A.-H.

doi:10.64898/2026.10.17.758293

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bioRxiv · 10.64898/2026.10.17.758293

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

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Abstract

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.

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Stuetz, A. N., De Luca, G., Matei, A.-E., Li, Y.-N., Filla, T., Batani, V., Tuemerdem, B. S., Rigau, A. R., Bruno, C., Merkt, W., Zweck, E., Buettner-Herold, M., Rizzo, S., Peretto, G., De Gaspari, M., Eckstein, M., Schett, G., Basso, C., Matucci-Cerinic, M., Distler, J., Gyoerfi, A.-H.. 2026-10-19. Spatial proteomic profiling of cardiac stromal populations and microenvironments in systemic sclerosis-associated primary myocardial involvement. https://doi.org/10.64898/2026.10.17.758293

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