MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation.
MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation.
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DOI：
10.1016/j.ebiom.2016.12.002
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Katagiri H
中科院分区：
文献类型：
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作者：
Tsukita S;Yamada T;Takahashi K;Munakata Y;Hosaka S;Takahashi H;Gao J;Shirai Y;Kodama S;Asai Y;Sugisawa T;Chiba Y;Kaneko K;Uno K;Sawada S;Imai J;Katagiri H
一旦胰腺β细胞数量不足，糖尿病的主要症状就会显现出来。虽然β细胞在损伤后的自然再生非常有限，但骨髓（BM）移植（BMT）通过涉及细胞间（BM细胞-β细胞）串扰的未确定机制促进其再生。我们发现两种microRNA（miRNAs）有助于BMT诱导的β细胞再生。在BMT后血清外泌体中筛选小鼠miRNA显示42种miRNA增加。这些miRNA中的两种（miR-106 b-5 p和miR-222- 3 p）显示由BM细胞分泌，并且在BMT后在胰岛细胞中增加。用相应的抗miRNA处理抑制了BMT诱导的β细胞再生。此外，静脉内给予相应的miRNA模拟物通过Cip/Kip家族下调促进损伤后β细胞增殖，从而改善患有胰岛素缺乏型糖尿病的小鼠的高血糖症。因此，这些鉴定的miRNAs可能导致糖尿病治疗策略的发展。miR-106 b-5 p和miR-222- 3 p通过下调Cip/Kip家族成员（p21 Cip 1和p27 Kip 1）促进损伤后β细胞增殖。BMT在STZ诱导的糖尿病小鼠中再生β细胞，并增加血清外泌体和胰岛中的miR-106 b和miR-222。用针对这些miR的抗miR抑制抑制了BMT诱导的β细胞再生。注射miR-106 b和miR-222模拟物促进β细胞增殖并改善STZ处理的小鼠中的高血糖症。胰腺β细胞的再生不仅是1型糖尿病的一种有前途的治疗策略，而且也是某些形式的2型糖尿病的一种有前途的治疗策略。然而，β细胞的自然再生几乎从未发生。有趣的是，骨髓移植（BMT）已显示通过一种未确定的机制促进β细胞再生。在这项研究中，我们发现两种microRNA（miR-106 b/-222）有助于BMT诱导的β细胞增殖。使用特异性抗miRNA抑制miR-106 b/-222显著抑制了BMT诱导的β细胞增殖。此外，静脉内施用的miR-106 b/222促进β细胞增殖，从而改善患有胰岛素缺乏型糖尿病的小鼠的高血糖症。因此，这些鉴定的miRNAs可能导致糖尿病的新治疗策略。
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). 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.