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Fibrotic remodeling in the NOD/ShiLtJ mouse model of Sjögren's disease: insights from single-cell transcriptomics and
Jennifer M Morrissey1,2, Deirdre A Nelson2, Li Chen3
1Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, United States.
Introduction:
Sjögren's Disease (SjD) is an autoimmune disorder characterized by salivary gland hypofunction and lymphocytic infiltration, yet the contribution of fibrosis to glandular dysfunction remains unclear.
Methods:
We evaluated the NOD/ShiLtJ mouse as a model for salivary gland fibrosis and used it to examine the impact of antifibrotic therapy on extracellular matrix (ECM) remodeling. To assess therapeutic potential, we treated NOD/ShiLtJ female mice with nintedanib, an FDA-approved antifibrotic agent used to treat chronic fibrosing interstitial lung disease. Fibrosis was assessed using single-cell RNA sequencing combined with Picrosirius red staining and AI-assisted digital pathology quantification of collagen I patterning with FibroNest.
Results:
Single-cell RNA sequencing revealed that fibroblast populations in the submandibular and sublingual salivary glands of the female NOD/ShiLtJ mouse exhibited increased levels of ECM genes, including Col1a1, Col1a2, and Col3a1, relative to control mice. Consistent with these transcriptional changes, Picrosirius Red staining, combined with AI-assisted fibrosis quantification of collagen I patterns, demonstrated significant fibrotic remodeling in the periacinar ECM in submandibular glands of female NOD/ShiLtJ mice relative to controls. Notably, fibrosis severity strongly correlated with the diabetic phenotype characteristic of this strain, and both periductal and periacinar fibrosis progressed with age. An 8-week nintedanib treatment resulted in modest but measurable reductions across multiple fibrotic indices.
Discussion:
Collectively, these findings establish the NOD/ShiLtJ strain as a model of SjD-associated salivary gland fibrosis and provide proof-of-concept evidence supporting antifibrotic strategies as a potential therapeutic avenue for salivary gland dysfunction in SjD.
