Abstract
Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention.
Highlights
Systemic sclerosis (SSc) is a multifaceted disease encompassing vascular, autoimmune, and fibrotic components [1]
We found that patients with diffuse cutaneous SSc (dcSSc) have significantly higher alignment of dermal collagen bundles as compared to those with limited cutaneous SSc (lcSSc) and healthy volunteers (HV), compared to healthy controls (Fig 1)
It has been posited that the well-organized ECM ultrastructure within the in vivo microenvironment could be important in maintaining the pathological myofibroblast phenotype in SSc
Summary
Systemic sclerosis (SSc) is a multifaceted disease encompassing vascular, autoimmune, and fibrotic components [1]. Distinct subsets of SSc have been described with varying severity; the two most well defined subsets termed limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) [2, 3]. In dcSSc, skin fibrosis can progress rapidly after onset of disease. The severity of skin disease, as measured by the Modified Rodnan Skin Score (MRSS), a clinical palpation method, has been shown to correlate well with fibrosis of internal organs and worse patient. Collagen dermal bundle alignment in scleraderma manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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