Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis
Abstract Hypertrophic scar (HS) is a common fibroproliferative disorders with no fully effective treatments. The conversion of fibroblasts to myofibroblasts is known to play a critical role in HS formation, making it essential to identify molecules that promote myofibroblast dedifferentiation and to...
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BMC
2025-01-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03157-9 |
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| author | Shixin Zhao Haoran Kong Dahu Qi Yushuang Qiao Yu Li Zhiming Cao Hanwen Wang Xuefeng He Hengdeng Liu Hao Yang Suyue Gao Tao Liu Julin Xie |
| author_facet | Shixin Zhao Haoran Kong Dahu Qi Yushuang Qiao Yu Li Zhiming Cao Hanwen Wang Xuefeng He Hengdeng Liu Hao Yang Suyue Gao Tao Liu Julin Xie |
| author_sort | Shixin Zhao |
| collection | DOAJ |
| description | Abstract Hypertrophic scar (HS) is a common fibroproliferative disorders with no fully effective treatments. The conversion of fibroblasts to myofibroblasts is known to play a critical role in HS formation, making it essential to identify molecules that promote myofibroblast dedifferentiation and to elucidate their underlying mechanisms. In this study, we used comparative transcriptomics and single-cell sequencing to identify key molecules and pathways that mediate fibrosis and myofibroblast transdifferentiation. Epidermal stem cell-derived extracellular vesicles (EpiSC-EVs) were isolated via ultracentrifugation and filtration, followed by miRNA sequencing to identify miRNAs targeting key molecules. After in vitro and in vivo treatment with EpiSC-EVs, we assessed antifibrotic effects through scratch assays, collagen contraction assays, Western blotting, and immunofluorescence. Transcriptomic sequencing and rescue experiments were used to investigate the molecular mechanism by which miR-203a-3p in EpiSC-EVs induces myofibroblast dedifferentiation. Our results indicate that PIK3CA is overexpressed in HS tissues and positively correlates with fibrosis. EpiSC-EVs were absorbed by scar-derived fibroblasts, promoting dedifferentiation from myofibroblasts to quiescent fibroblasts. Mechanistically, miR-203a-3p in EpiSC-EVs plays an essential role in inhibiting PIK3CA expression and PI3K/AKT/mTOR pathway hyperactivation, thereby reducing scar formation. In vivo studies confirmed that EpiSC-EVs attenuate excessive scarring through the miR-203a-3p/PIK3CA axis, suggesting EpiSC-EVs as a promising therapeutic approach for HS. Graphical abstract |
| format | Article |
| id | doaj-art-3899edcf21b449c18781c68c40253751 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-3899edcf21b449c18781c68c402537512025-02-02T12:40:58ZengBMCJournal of Nanobiotechnology1477-31552025-01-0123112010.1186/s12951-025-03157-9Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axisShixin Zhao0Haoran Kong1Dahu Qi2Yushuang Qiao3Yu Li4Zhiming Cao5Hanwen Wang6Xuefeng He7Hengdeng Liu8Hao Yang9Suyue Gao10Tao Liu11Julin Xie12Department of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Traumatic Orthopedics, Henan Provincial People’s Hospital & The People’s Hospital of Zhengzhou UniversityDepartment of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen UniversityAbstract Hypertrophic scar (HS) is a common fibroproliferative disorders with no fully effective treatments. The conversion of fibroblasts to myofibroblasts is known to play a critical role in HS formation, making it essential to identify molecules that promote myofibroblast dedifferentiation and to elucidate their underlying mechanisms. In this study, we used comparative transcriptomics and single-cell sequencing to identify key molecules and pathways that mediate fibrosis and myofibroblast transdifferentiation. Epidermal stem cell-derived extracellular vesicles (EpiSC-EVs) were isolated via ultracentrifugation and filtration, followed by miRNA sequencing to identify miRNAs targeting key molecules. After in vitro and in vivo treatment with EpiSC-EVs, we assessed antifibrotic effects through scratch assays, collagen contraction assays, Western blotting, and immunofluorescence. Transcriptomic sequencing and rescue experiments were used to investigate the molecular mechanism by which miR-203a-3p in EpiSC-EVs induces myofibroblast dedifferentiation. Our results indicate that PIK3CA is overexpressed in HS tissues and positively correlates with fibrosis. EpiSC-EVs were absorbed by scar-derived fibroblasts, promoting dedifferentiation from myofibroblasts to quiescent fibroblasts. Mechanistically, miR-203a-3p in EpiSC-EVs plays an essential role in inhibiting PIK3CA expression and PI3K/AKT/mTOR pathway hyperactivation, thereby reducing scar formation. In vivo studies confirmed that EpiSC-EVs attenuate excessive scarring through the miR-203a-3p/PIK3CA axis, suggesting EpiSC-EVs as a promising therapeutic approach for HS. Graphical abstracthttps://doi.org/10.1186/s12951-025-03157-9Epidermal stem cellExtracellular vesiclesHypertrophic scarDedifferentiationMyofibroblasts |
| spellingShingle | Shixin Zhao Haoran Kong Dahu Qi Yushuang Qiao Yu Li Zhiming Cao Hanwen Wang Xuefeng He Hengdeng Liu Hao Yang Suyue Gao Tao Liu Julin Xie Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis Journal of Nanobiotechnology Epidermal stem cell Extracellular vesicles Hypertrophic scar Dedifferentiation Myofibroblasts |
| title | Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis |
| title_full | Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis |
| title_fullStr | Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis |
| title_full_unstemmed | Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis |
| title_short | Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis |
| title_sort | epidermal stem cell derived exosomes induced dedifferentiation of myofibroblasts inhibits scarring via the mir 203a 3p pik3ca axis |
| topic | Epidermal stem cell Extracellular vesicles Hypertrophic scar Dedifferentiation Myofibroblasts |
| url | https://doi.org/10.1186/s12951-025-03157-9 |
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