Identification of small-molecule inducers of pancreatic β-cell expansion
Identification of small-molecule inducers of pancreatic β-cell expansion
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DOI：
10.1073/pnas.0811848106
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发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
Schultz, Peter G.
中科院分区：
文献类型：
--
作者：
Wang, Weidong;Walker, John R.;Schultz, Peter G.
为了鉴定可以诱导β细胞复制的小分子，通过使用自动化高通量筛选平台，针对生长停滞的可逆永生化小鼠β细胞的增殖筛选大型化学文库。鉴定了许多结构多样的活性化合物，包括可能通过蛋白激酶C起作用的佛波酯，以及一组通过激活Wnt信号通路刺激β细胞增殖的噻吩-嘧啶。一组二氢吡啶（DHP）衍生物也显示通过激活L型钙通道（LTCC）在体外可逆地诱导β细胞复制。我们的数据表明，LTCC激动剂2a影响参与细胞周期进程和细胞增殖的基因的表达。此外，用LTCC激动剂2a和Glp-1受体激动剂Exendin-4处理β细胞显示出对β细胞复制的累加效应。诱导β-细胞增殖的小分子的鉴定表明，可以可逆地扩增其他静止细胞以克服与退行性和/或自身免疫性疾病相关的缺陷。
To identify small molecules that can induce beta-cell replication, a large chemical library was screened for proliferation of growth-arrested, reversibly immortalized mouse beta cells by using an automated high-throughput screening platform. A number of structurally diverse, active compounds were identified, including phorbol esters, which likely act through protein kinase C, and a group of thiophene-pyrimidines that stimulate beta-cell proliferation by activating the Wnt signaling pathway. A group of dihydropyridine (DHP) derivatives was also shown to reversibly induce beta-cell replication in vitro by activating L-type calcium channels (LTCCs). Our data suggest that the LTCC agonist 2a affects the expression of genes involved in cell cycle progression and cellular proliferation. Furthermore, treatment of beta cells with both LTCC agonist 2a and the Glp-1 receptor agonist Exendin-4 showed an additive effect on beta-cell replication. The identification of small molecules that induce beta-cell proliferation suggests that it may be possible to reversibly expand other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.