MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation

• Published in: EBioMedicine 2017-02, Vol.15 (C), p.163-172
• Main Authors: Tsukita, Sohei, Yamada, Tetsuya, Takahashi, Kei, Munakata, Yuichiro, Hosaka, Shinichiro, Takahashi, Hironobu, Gao, Junhong, Shirai, Yuta, Kodama, Shinjiro, Asai, Yoichiro, Sugisawa, Takashi, Chiba, Yumiko, Kaneko, Keizo, Uno, Kenji, Sawada, Shojiro, Imai, Junta, Katagiri, Hideki
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; Calcium-Binding Proteins - genetics; Carrier Proteins - genetics; Cell Proliferation; Cip/Kip family; Diabetes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Disease Models, Animal; Exosomes; Gene Expression Regulation; Hyperglycemia - genetics; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; Mice; MicroRNAs; MicroRNAs - genetics; Regeneration; Research Paper; RNA Interference; β-cell regeneration
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.12.002

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. miR-106b-5p and miR-222-3p contribute to post-injury β-cell proliferation through down-regulation of Cip/Kip family members (p21Cip1and p27Kip1). [Display omitted] •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.