Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation
Abstract Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are...
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BMC
2021-08-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-021-02371-0 |
| _version_ | 1819138213320589312 |
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| author | Qin He Jia Song Chen Cui Jinbang Wang Huiqing Hu Xinghong Guo Mengmeng Yang Lingshu Wang Fei Yan Kai Liang Zhaojian Liu Fuqiang Liu Zheng Sun Ming Dong Xinguo Hou Li Chen |
| author_facet | Qin He Jia Song Chen Cui Jinbang Wang Huiqing Hu Xinghong Guo Mengmeng Yang Lingshu Wang Fei Yan Kai Liang Zhaojian Liu Fuqiang Liu Zheng Sun Ming Dong Xinguo Hou Li Chen |
| author_sort | Qin He |
| collection | DOAJ |
| description | Abstract Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM. |
| first_indexed | 2024-12-22T11:03:12Z |
| format | Article |
| id | doaj.art-a4cd5a9a772d4b4b8351c3662173d9cb |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-22T11:03:12Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-a4cd5a9a772d4b4b8351c3662173d9cb2022-12-21T18:28:25ZengBMCStem Cell Research & Therapy1757-65122021-08-0112111610.1186/s13287-021-02371-0Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiationQin He0Jia Song1Chen Cui2Jinbang Wang3Huiqing Hu4Xinghong Guo5Mengmeng Yang6Lingshu Wang7Fei Yan8Kai Liang9Zhaojian Liu10Fuqiang Liu11Zheng Sun12Ming Dong13Xinguo Hou14Li Chen15Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Cell Biology, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityAbstract Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM.https://doi.org/10.1186/s13287-021-02371-0ExosomeMesenchymal stem cellType 2 diabetes mellitusβ-cell dedifferentiationmiR-146a |
| spellingShingle | Qin He Jia Song Chen Cui Jinbang Wang Huiqing Hu Xinghong Guo Mengmeng Yang Lingshu Wang Fei Yan Kai Liang Zhaojian Liu Fuqiang Liu Zheng Sun Ming Dong Xinguo Hou Li Chen Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation Stem Cell Research & Therapy Exosome Mesenchymal stem cell Type 2 diabetes mellitus β-cell dedifferentiation miR-146a |
| title | Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation |
| title_full | Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation |
| title_fullStr | Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation |
| title_full_unstemmed | Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation |
| title_short | Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation |
| title_sort | mesenchymal stem cell derived exosomal mir 146a reverses diabetic β cell dedifferentiation |
| topic | Exosome Mesenchymal stem cell Type 2 diabetes mellitus β-cell dedifferentiation miR-146a |
| url | https://doi.org/10.1186/s13287-021-02371-0 |
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