Abstract
BackgroundHypertrophic scar (HTS) is a fibroproliferative skin disorder characterized by excessive cell proliferation, migration, and extracellular matrix (ECM) deposition. The CUB and Sushi multiple domains 1 (CSMD1) has previously been identified as the key regulatory gene of hypertrophic scar by a large sample GWAS study. However, further research has not yet been conducted to verify this finding in other HTS patients and to determine the underlying mechanism.ResultsIn this study, we verified that CSMD1 was downregulated in both HTS tissue and HTS-derived fibroblasts. The knockdown of CSMD1 resulted in enhanced migration and fibronectin1 (FN1) secretion in fibroblasts in vitro. In addition, the upstream and downstream regulatory mechanisms of CSMD1 were also investigated through microRNA (miRNA) databases screening and RNA-sequencing (RNA-seq) respectively. The screening of four common microRNA (miRNA) databases suggested that miR-190a-3p binds to the CSMD1 and may regulate its expression. We confirmed that miR-190a-3p directly targeted the CSMD1–3′-UTR using luciferase reporter assays. Furthermore, the overexpression of miR-190a-3p showed promotion of migratory activity and FN1 secretion in fibroblasts, resembling the effect of CSMD1 knockdown; whereas the knockdown of miR-190a-3p exerted the opposite effect. Finally, transcriptomic analysis showed activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway in the CSMD1 knockdown fibroblasts.ConclusionsThis study has validated the conclusions of the previous GWAS study conducted in Chinese population. In vitro experiments have provided further evidence on the function of CSMD1 in the development of HTS, and have also revealed the underlying upstream and downstream regulating mechanisms. Additionally, the JAK/STAT signaling pathway identified using RNA-seq might provide a potential treatment approach, especially for HTS.
Highlights
Hypertrophic scar (HTS) is a fibroproliferative skin disorder characterized by excessive cell proliferation, migration, and extracellular matrix (ECM) deposition
CUB and Sushi multiple domains 1 (CSMD1) was down-regulated in hypertrophic scar tissue and HTS-derived fibroblasts First, we explored the CSMD1 mRNA level in both human hypertrophic scar (HTS) tissue and the adjacent normal skin (NS) tissue. quantitative real-time PCR (qRT-PCR) result showed significantly down-regulated mRNA level of CSMD1 in the HTS tissue compared to the paired NS tissue (Fig. 1A)
After transfecting the lentiviruses with short hairpin sequences for CSMD1, both the mRNA and protein levels of CSMD1 were significantly reduced as compared to the negative control group (Fig. 2A, B)
Summary
Hypertrophic scar (HTS) is a fibroproliferative skin disorder characterized by excessive cell proliferation, migration, and extracellular matrix (ECM) deposition. The CUB and Sushi multiple domains 1 (CSMD1) has previously been identified as the key regulatory gene of hypertrophic scar by a large sample GWAS study. Hypertrophic scar (HTS) is a frequently encountered fibroproliferative skin disorder characterized by excessive cell proliferation, migration, and extracellular matrix (ECM) deposition, which often severely destroys the patients’ physical appearance and function, decreasing their quality of life and delaying reintegration into society [1]. They successfully collected complete genotypic and clinical data from 538 patients mainly involved the white people who were identified with a common intronic variant in the CUB and Sushi multiple domains 1 (CSMD1) gene related to the severity of postburn HTS [7]. Further research has not yet been conducted to verify this finding in other HTS patients and to determine the underlying mechanism
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