Santhoshi Navaneetha Krishnan, PhD
Boehringer Ingelheim
In the thick of it: Understanding the effect of the fibrosis-inflammation axes on vasculopathy in systemic sclerosis
Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular dysfunction, immune dysregulation and fibrosis of skin and other organs. One of the earliest clinical manifestations of SSc is Raynaud’s syndrome, a downstream effect of SSc-associated vasculopathy driven by injury to the endothelial cells constituting dermal microvasculature. Factors implicated in endothelial dysfunction include autoantibodies, impaired angiogenesis, fibrosis-driven endothelial-to-mesenchymal transition, and oxidative stress, though definitive mechanisms remain unclear. In this study, we leverage the power of spatial biology to investigate proximity of fibrotic and proinflammatory elements in the microenvironment on vascular health dysfunction in early SSc. Using CosMx Spatial Molecular Imaging (SMI) with a 6,000‑gene panel, we generated a single‑cell resolution spatial transcriptomics dataset from 14 early diffuse SSc (dSSc) skin biopsies and 3 healthy controls. Following data quality control, preprocessing and iterative cell phenotyping, we constructed biologically relevant spatial niches using a novel spatial paradigm, with a focus on vasculature niches. We characterize these niches to elucidate mechanisms enriched during SSc pathogenesis, with an emphasis on the evolution of profibrotic and proinflammatory gene signature patterns on disease progression. Our goal is to leverage study insights to generate testable hypotheses for potential in vitro validation.
Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular dysfunction, immune dysregulation and fibrosis of skin and other organs. One of the earliest clinical manifestations of SSc is Raynaud’s syndrome, a downstream effect of SSc-associated vasculopathy driven by injury to the endothelial cells constituting dermal microvasculature. Factors implicated in endothelial dysfunction include autoantibodies, impaired angiogenesis, fibrosis-driven endothelial-to-mesenchymal transition, and oxidative stress, though definitive mechanisms remain unclear. In this study, we leverage the power of spatial biology to investigate proximity of fibrotic and proinflammatory elements in the microenvironment on vascular health dysfunction in early SSc. Using CosMx Spatial Molecular Imaging (SMI) with a 6,000‑gene panel, we generated a single‑cell resolution spatial transcriptomics dataset from 14 early diffuse SSc (dSSc) skin biopsies and 3 healthy controls. Following data quality control, preprocessing and iterative cell phenotyping, we constructed biologically relevant spatial niches using a novel spatial paradigm, with a focus on vasculature niches. We characterize these niches to elucidate mechanisms enriched during SSc pathogenesis, with an emphasis on the evolution of profibrotic and proinflammatory gene signature patterns on disease progression. Our goal is to leverage study insights to generate testable hypotheses for potential in vitro validation.
