Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells
Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells
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DOI：
10.1016/j.cmet.2018.12.005
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发表时间：
2019-03-05
期刊：
影响因子：
29
通讯作者：
Stewart, Andrew F.
中科院分区：
文献类型：
--
作者：
Wang, Peng;Karakose, Esra;Stewart, Andrew F.
双特异性酪氨酸调节激酶1A（DYRK 1A）的小分子抑制剂诱导人β细胞增殖，产生1.5%-3%的标记指数。在这里，我们证明了DYRK 1A和转化生长因子β超家族（TGF β SF）/SMAD信号传导的组合药理学抑制在人β细胞增殖中产生显著的进一步协同增加（平均标记指数，5%-8%，并且高达15%-18%），并且在小鼠和人β细胞数量中增加。这种协同作用反映了DYRK 1A抑制对细胞周期蛋白和cdk的激活，同时伴随着关键细胞周期抑制剂（CDKN 1C和CDKN 1A）的减少。后者是由于干扰了基础的雷公藤和SMAD介导的CDKN 1C和CDKN 1A的反式激活。值得注意的是，组合的DYRK 1A和TGF β抑制允许保留β细胞分化功能。这些有益效果从正常的人β细胞和干细胞衍生的人β细胞延伸到2型糖尿病患者的那些细胞，并且在体外和体内都发生。
Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGF beta SF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax-and SMAD-mediated transactivation of CDKN1C and CDKN1A. Notably, combined DYRK1A and TGF beta inhibition allows preservation of beta cell differentiated function. These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.