Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis
Abstract Progressive fibrosis of the dermal tissues is a challenging complication of radiotherapy whose underlying mechanism is not fully understood, and there are few available treatments. The canonical Wnt/β-catenin signaling pathway plays an important role in fibrosis as well as in the epithelial...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2020-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-70243-3 |
| _version_ | 1818717011058884608 |
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| author | Dong Won Lee Won Jai Lee Jaeho Cho Chae-Ok Yun Hyun Roh Hsien Pin Chang Tai Suk Roh Ju Hee Lee Dae Hyun Lew |
| author_facet | Dong Won Lee Won Jai Lee Jaeho Cho Chae-Ok Yun Hyun Roh Hsien Pin Chang Tai Suk Roh Ju Hee Lee Dae Hyun Lew |
| author_sort | Dong Won Lee |
| collection | DOAJ |
| description | Abstract Progressive fibrosis of the dermal tissues is a challenging complication of radiotherapy whose underlying mechanism is not fully understood, and there are few available treatments. The canonical Wnt/β-catenin signaling pathway plays an important role in fibrosis as well as in the epithelial-to-mesenchymal transition (EMT). We investigated whether inhibition of Wnt/β-catenin signaling with sLRP6E1E2, a molecule that binds to extracellular Wnt ligands, ameliorated radiation-induced fibrosis both in vitro and in vivo. Radiation with a single dose of 2 Gy not only facilitated fibrosis in cultured human dermal fibroblasts via activation of the Wnt/β-catenin pathway but also initiated EMT in cultured keratinocytes, developing collagen-producing mesenchymal cells. sLRP6E1E2-expressing adenovirus treatment exerted anti-fibrotic activity in irradiated cultured dermal fibroblasts and keratinocytes. In a mouse model, a single fraction of 15 Gy was delivered to the dorsal skins of 36 mice randomized into three groups: those receiving PBS, those receiving control adenovirus, and those receiving decoy Wnt receptor-expressing adenovirus (dE1-k35/sLRP6E1E2). The mice were observed for 16 weeks, and excessive deposition of type I collagen was suppressed by sLRP6E1E2-expressing adenovirus treatment. These results demonstrate that the modulation of the Wnt/β-catenin pathway has the potential to decrease the severity of radiation-induced dermal fibrosis. |
| first_indexed | 2024-12-17T19:28:22Z |
| format | Article |
| id | doaj.art-bf3f13052af349e892ead6c07108c6c5 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T19:28:22Z |
| publishDate | 2020-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-bf3f13052af349e892ead6c07108c6c52022-12-21T21:35:19ZengNature PortfolioScientific Reports2045-23222020-08-0110111010.1038/s41598-020-70243-3Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosisDong Won Lee0Won Jai Lee1Jaeho Cho2Chae-Ok Yun3Hyun Roh4Hsien Pin Chang5Tai Suk Roh6Ju Hee Lee7Dae Hyun Lew8Department of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineDepartment of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineDepartment of Radiation Oncology, Yonsei University College of MedicineDepartment of Bioengineering and Institute of Nano Science and Technology (INST), College of Engineering, Hanyang UniversityDepartment of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineDepartment of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineDepartment of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineDepartment of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of MedicineDepartment of Plastic & Reconstructive Surgery and Institute for Human Tissue Restoration, Yonsei University College of MedicineAbstract Progressive fibrosis of the dermal tissues is a challenging complication of radiotherapy whose underlying mechanism is not fully understood, and there are few available treatments. The canonical Wnt/β-catenin signaling pathway plays an important role in fibrosis as well as in the epithelial-to-mesenchymal transition (EMT). We investigated whether inhibition of Wnt/β-catenin signaling with sLRP6E1E2, a molecule that binds to extracellular Wnt ligands, ameliorated radiation-induced fibrosis both in vitro and in vivo. Radiation with a single dose of 2 Gy not only facilitated fibrosis in cultured human dermal fibroblasts via activation of the Wnt/β-catenin pathway but also initiated EMT in cultured keratinocytes, developing collagen-producing mesenchymal cells. sLRP6E1E2-expressing adenovirus treatment exerted anti-fibrotic activity in irradiated cultured dermal fibroblasts and keratinocytes. In a mouse model, a single fraction of 15 Gy was delivered to the dorsal skins of 36 mice randomized into three groups: those receiving PBS, those receiving control adenovirus, and those receiving decoy Wnt receptor-expressing adenovirus (dE1-k35/sLRP6E1E2). The mice were observed for 16 weeks, and excessive deposition of type I collagen was suppressed by sLRP6E1E2-expressing adenovirus treatment. These results demonstrate that the modulation of the Wnt/β-catenin pathway has the potential to decrease the severity of radiation-induced dermal fibrosis.https://doi.org/10.1038/s41598-020-70243-3 |
| spellingShingle | Dong Won Lee Won Jai Lee Jaeho Cho Chae-Ok Yun Hyun Roh Hsien Pin Chang Tai Suk Roh Ju Hee Lee Dae Hyun Lew Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis Scientific Reports |
| title | Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis |
| title_full | Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis |
| title_fullStr | Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis |
| title_full_unstemmed | Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis |
| title_short | Inhibition of Wnt signaling pathway suppresses radiation-induced dermal fibrosis |
| title_sort | inhibition of wnt signaling pathway suppresses radiation induced dermal fibrosis |
| url | https://doi.org/10.1038/s41598-020-70243-3 |
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