Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis
- 1Benaroya Research Institute
Abstract
Systemic sclerosis, or scleroderma, is a chronic autoimmune disease characterized by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Heterogeneous clinical presentation and polygenic risk complicate our understanding of disease mechanisms and the path to effective therapy. Single-cell analyses have revealed substantial transcriptional diversity in skin, but disease-associated reprogramming remains poorly defined. To address this, we performed high-resolution spatial transcriptomic profiling of paired clinically uninvolved and clinically affected scleroderma donor skin alongside healthy controls. We identified a continuum of cellular, molecular, and spatial changes to the stroma that were already evident in clinically uninvolved tissue yet still distinct from the broader and more advanced changes in paired fibrotic samples. Uninvolved skin was comparable to healthy tissue by clinical and histopathological assessment, but distinguishable by the numerical reduction, transcriptional reprogramming, and spatial isolation of LGR5+SCARA5+PI16+ progenitor fibroblasts. In parallel, the dermal vascular smooth muscle compartment shifted from a contractile to a synthetic, activated state, suggesting reprogramming that begins before overt fibrosis. Cell neighborhood analysis revealed that progenitor fibroblasts occupy dense stromal niches in healthy skin that collapse in clinically uninvolved tissue, replaced by isolated, disease-associated cellular networks. These data indicate that clinically uninvolved skin occupies an intermediate stage along the pathologic continuum of scleroderma, establishing a framework for strategies to preserve homeostatic fibroblast niches before tissue remodeling and fibrotic commitment.
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BibTeX
@misc{hu2026homeostatic,
title = {{Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis}},
author = {A. Hu and L. W. Tung and T. Pulliam and C. L. Simpson and S. Lord and J. S. Carlin and H. A. DeBerg and D. J. Campbell and P. J. Morawski},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764714},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764714v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis
AU - A. Hu
AU - L. W. Tung
AU - T. Pulliam
AU - C. L. Simpson
AU - S. Lord
AU - J. S. Carlin
AU - H. A. DeBerg
AU - D. J. Campbell
AU - P. J. Morawski
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764714
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764714v1
AB - Systemic sclerosis, or scleroderma, is a chronic autoimmune disease characterized by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Heterogeneous clinical presentation and polygenic risk complicate our understanding of disease mechanisms and the path to effective therapy. Single-cell analyses have revealed substantial transcriptional diversity in skin, but disease-associated reprogramming remains poorly defined. To address this, we performed high-resolution spatial transcriptomic profiling of paired clinically uninvolved and clinically affected scleroderma donor skin alongside healthy controls. We identified a continuum of cellular, molecular, and spatial changes to the stroma that were already evident in clinically uninvolved tissue yet still distinct from the broader and more advanced changes in paired fibrotic samples. Uninvolved skin was comparable to healthy tissue by clinical and histopathological assessment, but distinguishable by the numerical reduction, transcriptional reprogramming, and spatial isolation of LGR5+SCARA5+PI16+ progenitor fibroblasts. In parallel, the dermal vascular smooth muscle compartment shifted from a contractile to a synthetic, activated state, suggesting reprogramming that begins before overt fibrosis. Cell neighborhood analysis revealed that progenitor fibroblasts occupy dense stromal niches in healthy skin that collapse in clinically uninvolved tissue, replaced by isolated, disease-associated cellular networks. These data indicate that clinically uninvolved skin occupies an intermediate stage along the pathologic continuum of scleroderma, establishing a framework for strategies to preserve homeostatic fibroblast niches before tissue remodeling and fibrotic commitment.
ER -