Yan Zhang1,2, Yingjin Pan3, Yanhong Liu4, Xiheng Li1,2, Liang Tang1,2, Mengna Duan5, Jiang Li6,7, Guokun Zhang8,9. 1. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China. 2. Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China. 3. Center of Prosthodontics and Oral Implantology, Foshan Stomatology Hospital, School of Stomatology and Medicine, Foshan University, Foshan, 528000, China. 4. Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China. 5. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China. dmnmengna@jlu.edu.cn. 6. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China. ljiang@gzhmu.edu.cn. 7. Affiliated Stomatology Hospital of Guangzhou Medical University, 39 Huangsha Ave., Guangzhou, 510080, Guangdong, China. ljiang@gzhmu.edu.cn. 8. Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 1345 Pudong Rd., Changchun, Jilin, 130600, China. zhang-guokun@hotmail.com. 9. Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), 4899 Juye St., Changchun, Jilin, 130112, China. zhang-guokun@hotmail.com.
Abstract
BACKGROUND: Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated. METHODS: To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated. RESULTS: Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-β (TGF-β) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-β receptor type II (TGFBR2) and TGF-β receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-β1-induced HDF. CONCLUSION: The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-β receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.
BACKGROUND: Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated. METHODS: To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated. RESULTS: Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-β (TGF-β) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-β receptor type II (TGFBR2) and TGF-β receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-β1-induced HDF. CONCLUSION: The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-β receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.