Experimental Models of Systemic Sclerosis: Investigating Pathophysiological Mechanisms in Skin, Lung, and Kidney Involvement

Fibrosis and Immune Dysregulation

Abstract

Systemic sclerosis (SSc) is a complex, multisystem autoimmune connective tissue disease characterized by microvascular injury, immune dysregulation, and progressive fibrosis involving multiple organs. The absence of a single in vivo model that fully reproduces the multifaceted pathogenesis of human SSc remains a major challenge in translational research. In this structured narrative synthesis, we reviewed experimental SSc models based on their ability to recapitulate immune activation, vasculopathy, fibrosis, and organ-specific disease phenotypes. Models were grouped by induction strategy, including induced, genetic, spontaneous, and chimeric models, and were complemented by emerging human in vitro platforms. Each model was evaluated primarily in terms of translational fidelity across key pathogenic domains rather than protocol convenience. Induced models, including bleomycin-, hypochlorous acid-, and angiotensin II-based models, are useful for investigating early inflammatory responses, oxidative stress, and fibrotic activation. Genetic models, such as Tight-Skin 1, Fra-2 transgenic, and Klf5/Fli1 double heterozygous mice, provide important mechanistic insights into fibrillin-1 alterations, AP-1–related transcriptional regulation, epigenetic dysregulation, fibrogenesis, and vasculopathy. Spontaneous and chimeric models, including the UCD-200 avian model and graft-versus-host disease models, more closely reflect spontaneous autoimmunity and deep organ involvement. Emerging concepts such as endothelial-to-mesenchymal transition, macrophage polarization, type I interferon signaling, and microbiome-related mechanisms are increasingly recognized as central components of SSc pathogenesis. Overall, no single model adequately reproduces the full spectrum of human SSc. Therefore, model selection should be guided by the dominant pathogenic domain under investigation rather than by convenience or historical use. The combinatorial use of complementary animal models with emerging technologies, including single-cell RNA sequencing, 3D organoid systems, and spatial transcriptomics, offers a pragmatic strategy to narrow the translational gap and support the development of domain-targeted therapeutics.