IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice
IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice
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DOI：
10.1007/s00125-008-1087-8
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发表时间：
2008-10-01
期刊：
影响因子：
8.2
通讯作者：
Bosch, F.
中科院分区：
文献类型：
--
作者：
Agudo, J.;Ayuso, E.;Bosch, F.
目的/假设从糖尿病中恢复需要β细胞群的恢复。在1型糖尿病期间，转基因小鼠β细胞中igf 1的表达使内分泌胰腺再生。然而，IGF-I介导的恢复β细胞质量的机制尚未完全了解。在这里，我们研究的贡献预先存在的β细胞增殖和转分化的祖细胞从骨髓中IGF-I诱导的胰岛regeneration.Methods链脲佐菌素（STZ）处理的Igf 1表达转基因小鼠移植绿色荧光蛋白（GFP）表达骨髓细胞。骨髓细胞转分化和β细胞复制分别通过GFP/胰岛素和单克隆抗体Ki 67/胰岛素免疫染色胰腺切片鉴定的抗原来测量。关键的细胞周期蛋白测定Western blot，定量RT-PCR和免疫组化。结果尽管升高IGF-I的生产，招募和骨髓细胞分化为β细胞没有增加无论是在健康或STZ处理的转基因小鼠。相比之下，STZ治疗后，IGF-I过度产生减少β细胞凋亡，并通过调节关键细胞周期蛋白增加β细胞复制。细胞周期蛋白依赖性激酶抑制剂1B（p27）的核水平降低和细胞周期蛋白依赖性激酶（CDK）-4的核定位增加与β细胞增殖增加一致。然而，胰岛细胞周期蛋白D1的表达增加后，STZ治疗。与此相反，更高水平的细胞周期蛋白依赖性激酶抑制剂1A（p21）在胰岛中检测到非STZ处理的转基因migrations.Conclusions/interpretation这些研究结果表明，IGF-I调节细胞周期蛋白和增加复制的预先存在的β细胞损伤后。因此，我们的研究表明，局部生产IGF-I可能是一种安全的方法来再生内分泌胰腺，以逆转糖尿病。
Aims/hypothesis Recovery from diabetes requires restoration of beta cell mass. Igf1 expression in beta cells of transgenic mice regenerates the endocrine pancreas during type 1 diabetes. However, the IGF-I-mediated mechanism(s) restoring beta cell mass are not fully understood. Here, we examined the contribution of pre-existing beta cell proliferation and transdifferentiation of progenitor cells from bone marrow in IGF-I-induced islet regeneration.Methods Streptozotocin (STZ)-treated Igf1-expressing transgenic mice transplanted with green fluorescent protein (GFP)-expressing bone marrow cells were used. Bone marrow cell transdifferentiation and beta cell replication were measured by GFP/insulin and by the antigen identified by monoclonal antibody Ki67/insulin immunostaining of pancreatic sections respectively. Key cell cycle proteins were measured by western blot, quantitative RT-PCR and immunohistochemistry.Results Despite elevated IGF-I production, recruitment and differentiation of bone marrow cells to beta cells was not increased either in healthy or STZ-treated transgenic mice. In contrast, after STZ treatment, IGF-I overproduction decreased beta cell apoptosis and increased beta cell replication by modulating key cell cycle proteins. Decreased nuclear levels of cyclin-dependent kinase inhibitor 1B (p27) and increased nuclear localisation of cyclin-dependent kinase (CDK)-4 were consistent with increased beta cell proliferation. However, islet expression of cyclin D1 increased only after STZ treatment. In contrast, higher levels of cyclin-dependent kinase inhibitor 1A (p21) were detected in islets from non-STZ-treated transgenic mice.Conclusions/interpretation These findings indicate that IGF-I modulates cell cycle proteins and increases replication of pre-existing beta cells after damage. Therefore, our study suggests that local production of IGF-I may be a safe approach to regenerate endocrine pancreas to reverse diabetes.