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Human blood vessel organoids recapitulate key mechanisms of transition from vasculopathy to fibrosis in systemic sclerosis

Xiao Y, Hong X, Zhi L, Li YN, Regensburger M, Marxreiter F, Görg B, Koziel S, Györfi AH, Filla T, Bruch PM, Tripal P, Adjaye J, Dietrich S, Winkler J, Matei AE, Distler JH (2026)

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Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1016/j.ard.2026.02.021

Abstract

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. We aimed to develop a complex multicellular human model of SSc vasculopathy and use it to investigate the mechanisms underlying this process.MethodsBlood vessel organoids (BVOs) were derived from induced pluripotent stem cells of patients with SSc and healthy controls. Organoids were exposed to serum from patients with SSc with clinically manifest microvasculopathy or healthy donors. Structural and molecular changes were evaluated using confocal imaging, transcriptomic (RNA sequencing), epigenetic (assay for transposase-accessible chromatin sequencing), and spatial proteomic (codetection by indexing) profiling. Serum immunoglobulin G (IgG) was selectively depleted or enriched to investigate antibody contributions. Therapeutic interventions included bosentan and the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT).ResultsSSc-derived BVOs exposed to SSc serum exhibited profound angiogenic defects, characterised by reduced vessel integrity, loss of endothelial-pericyte interactions, and induction of endothelial-to-mesenchymal transition (EndMT). Epigenetic and transcriptional profiling revealed upregulation of fibrosis-related genes and loss of endothelial markers. Spatial proteomic data confirmed EndMT at the protein level and demonstrated shifts in endothelial and pericyte subpopulation as well as alterations in their interactions reminiscent of those seen in tissues of patient with SSc. IgG depletion from SSc serum restored vascular structure, and transfer of SSc IgG to healthy serum phenocopied the pathological phenotype, implicating autoantibodies in endothelial injury. Both bosentan and DAPT partially reversed vascular abnormalities and downregulated EndMT markers.ConclusionsThis study establishes BVOs as a complex human model of SSc vasculopathy and demonstrates in a multiomic approach that they recapitulate disease-specific vascular dysfunction and its transition to fibrosis. We show that genetic susceptibility and pathogenic autoantibodies synergise in driving microvascular injury in SSc. Furthermore, we provide evidence that SSc BVOs are a promising platform for evaluating therapies that prevent the transition from vasculopathy to fibrosis, and present Notch/γ-secretase inhibition as a potential novel target in SSc vasculopathy.

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APA:

Xiao, Y., Hong, X., Zhi, L., Li, Y.N., Regensburger, M., Marxreiter, F.,... Distler, J.H. (2026). Human blood vessel organoids recapitulate key mechanisms of transition from vasculopathy to fibrosis in systemic sclerosis. Annals of the Rheumatic Diseases. https://doi.org/10.1016/j.ard.2026.02.021

MLA:

Xiao, Yanhua, et al. "Human blood vessel organoids recapitulate key mechanisms of transition from vasculopathy to fibrosis in systemic sclerosis." Annals of the Rheumatic Diseases (2026).

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