Abstract
Secreted Frizzled Receptor Protein 4 (SFRP4) has been shown to be increased in Scleroderma (SSc). To determine its role in immune-driven fibrosis, we analysed SSc and sclerotic Chronic Graft Versus Host Disease (sclGVHD) biosamples; skin biopsies (n = 24) from chronic GVHD patients (8 with and 5 without sclGVHD), 8 from SSc and 3 healthy controls (HC) were analysed by immunofluorescence (IF) and SSc patient sera (n = 77) assessed by ELISA. Epithelial cell lines used for in vitro Epithelial-Mesenchymal-Transition (EMT) assays and analysed by Western Blot, RT-PCR and immunofluorescence. SclGVHD skin biopsies resembled pathologic features of SSc. IF of fibrotic skin biopsies indicated the major source of SFRP4 expression were dermal fibroblasts, melanocytes and vimentin positive/caveolin-1 negative cells in the basal layer of the epidermis. In vitro studies showed increased vimentin and SFRP4 expression accompanied with decreased caveolin-1 expression during TGFβ-induced EMT. Additionally, SFRP4 serum concentration correlated with severity of lung and skin fibrosis in SSc. In conclusion, SFRP4 expression is increased during skin fibrosis in two different immune-driven conditions, and during an in vitro EMT model. Its serum levels correlate with skin and lung fibrosis in SSc and may function as biomarker of EMT. Further studies are warranted to elucidate the role of SFRP4 in EMT within the pathogenesis of tissue fibrosis.
Highlights
Systemic Sclerosis (SSc) is characterized by excessive deposition of collagen and other connective tissue macromolecules in skin and multiple internal organs, prominent alterations in the microvasculature and immunologic abnormalities [1,2]
Patients with or without fibrotic skin involvement were matched for age, gender, age at Hematopoietic Stem Cell Transplant (HSCT) and time between HSCT and cGVHD onset
Dermal fibrosis score (DFS) values demonstrated that 75% of SSc patients and 87.5% of sclerotic Chronic Graft Versus Host Disease (sclGVHD) patients had a percentage of sclerosis in the full thickness of dermis over 50% (Table 1)
Summary
Systemic Sclerosis (SSc) is characterized by excessive deposition of collagen and other connective tissue macromolecules in skin and multiple internal organs, prominent alterations in the microvasculature and immunologic abnormalities [1,2]. The clinical course of SSc is extremely heterogeneous regarding both the predominance of the fibrotic vs the vasculopathic process and in the nature and severity of organ involvement. Biosamples reflect this heterogeneity and for this reason, identification of disease mechanisms from biosampling is extremely complicated [3]. There is a strong link between activation of signalling pathways, such as the Wnt pathway, and an abnormal repair response as well as representing a hallmark for SSc fibrotic phenotype [6,7]. Single cell RNAseq revealed increased SFRP4 in a distinct subgroup of fibroblasts isolated from SSc-interstitial lung disease (ILD) biosamples, which were hypothesised to be progenitors of myofibroblasts [16]. RNAseq of SSc skin biopsies highlighted SFRP4 increased expression relative to healthy controls, especially in diffuse SSc (dcSSc) [17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
