Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis

Clinically uninvolved systemic sclerosis skin shows a pre-fibrotic collapse of dense stromal niches, with LGR5+SCARA5+PI16+ progenitor fibroblasts reduced and spatially isolated.

• Why it matters: Disease mechanisms in early, clinically uninvolved skin are unclear, limiting how to target the transition toward fibrosis despite genetic risk and heterogeneous presentation.
• What they did: High-resolution spatial transcriptomics compared paired clinically uninvolved and clinically affected donor skin from systemic sclerosis with healthy controls, followed by cell neighborhood analyses of fibroblast niches and vascular smooth muscle states.
• The result: Uninvolved tissue is clinically and histopathologically comparable to healthy skin yet shows transcriptional reprogramming and niche collapse, while vascular smooth muscle shifts toward a synthetic activated state, supporting an intermediate disease stage.

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