MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation
| Autor: | Kei Takahashi, Yumiko Chiba, Shinjiro Kodama, Shojiro Sawada, Sohei Tsukita, Yoichiro Asai, Keizo Kaneko, Junta Imai, Hironobu Takahashi, Shinichiro Hosaka, Takashi Sugisawa, Yuta Shirai, Junhong Gao, Tetsuya Yamada, Kenji Uno, Hideki Katagiri, Yuichiro Munakata |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment lcsh:Medicine Exosomes DAPI 4′ 6-Diamidino-2-phenylindole Mice 0302 clinical medicine Insulin-Secreting Cells Bone Marrow Transplantation GFP green fluorescent protein lcsh:R5-920 Diabetes Nuclear Proteins Cip/Kip family General Medicine GNZ a nuclear-localized GFP/LacZ fusion protein Cip/Kip CDK interacting protein/kinase inhibitory protein medicine.anatomical_structure β-cell regeneration 030220 oncology & carcinogenesis RNA Interference lcsh:Medicine (General) Co-Repressor Proteins Research Paper medicine.drug PBS phosphate-buffered saline Bone Marrow Cells CHOP C/EBP homologous protein Biology STZ streptozotocin General Biochemistry Genetics and Molecular Biology Diabetes Mellitus Experimental Islets of Langerhans 03 medical and health sciences Diabetes mellitus TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling microRNA medicine Animals Regeneration miRNAs microRNAs Cell Proliferation TM tamoxifen Cell growth Insulin lcsh:R Calcium-Binding Proteins Streptozotocin medicine.disease BMT bone marrow transplantation Pri-miR primary microRNA Microvesicles Transplantation Disease Models Animal MicroRNAs Diabetes Mellitus Type 1 030104 developmental biology Gene Expression Regulation Hyperglycemia Immunology BM bone marrow Cancer research Bone marrow Carrier Proteins |
| Zdroj: | EBioMedicine EBioMedicine, Vol 15, Iss C, Pp 163-172 (2017) |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2016.12.002 |
| Popis: | Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes. Graphical Abstract miR-106b-5p and miR-222-3p contribute to post-injury β-cell proliferation through down-regulation of Cip/Kip family members (p21Cip1and p27Kip1).Image 1 Highlights • BMT regenerates β-cells in mice with STZ-induced diabetes and increases miR-106b and miR-222 in serum exosomes and islets. • Inhibition with anti-miRs against these miRs suppresses BMT-induced β-cell regeneration. • Injection of miR-106b and miR-222 mimics promotes β-cell proliferation and improves hyperglycemia in STZ-treated mice. Regeneration of pancreatic β-cells is a promising therapeutic strategy not only for type 1 diabetes but also for certain forms of type 2 diabetes. However, natural regeneration of β-cells hardly ever occurs. Interestingly, bone marrow transplantation (BMT) has been shown to promote β-cell regeneration through an undetermined mechanism(s). In this study, we found that two microRNAs (miR-106b/-222) contribute to BMT-induced β-cell proliferation. Inhibition of miR-106b/-222 using specific anti-miRNAs significantly suppressed BMT-induced β-cell proliferation. Furthermore, intravenously administered miR-106b/222 promoted β-cell proliferation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to novel therapeutic strategies for diabetes. |
| Databáze: | OpenAIRE |
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