Response to Stimulations Inducing Circadian Rhythm in Human Induced Pluripotent Stem Cells
Response to Stimulations Inducing Circadian Rhythm in Human Induced Pluripotent Stem Cells
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DOI：
10.3390/cells9030620
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发表时间：
2020-03-01
期刊：
影响因子：
6
通讯作者：
Tomizawa, Kazuhito
中科院分区：
文献类型：
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作者：
Kaneko, Hitomi;Kaitsuka, Taku;Tomizawa, Kazuhito
随着人类诱导多能干细胞(HiPSCs)的发展，再生医学和疾病模型正在迅速发展。许多外源性补充剂经常用于将HiPSCs定向分化为特定的谱系，如化学物质和激素。其中一些已知可以同步生物钟，如forsklin(Frk)和地塞米松(Dex)；然而，对于HiPSCs来说，对这些刺激的反应还没有完全阐明。在这项研究中，我们检测了时钟基因对同步刺激的反应，并将其与完全分化的细胞、U2OS和成纤维细胞进行了比较。在带有Frk和Dex的HiPSCs中，时钟基因的表达没有表现出昼夜节律，这可能是由于BMAL1水平显著降低所致。另一方面，通过在模拟体温的环境中培养HiPSCs，观察到D-box结合蛋白(DBP)表达的昼夜节律。然而，参与温度节律诱导同步化的温度诱导因子的抑制不能抑制这种节律的表达，而抑制HIF-1α则显著抑制这种节律的表达。综上所述，我们认为时钟基因对HiPSCs中的同步剂没有反应；相反，温度节律诱导了独特的昼夜节律。
Regenerative medicine and disease modeling are expanding rapidly, through the development of human-induced pluripotent stem cells (hiPSCs). Many exogeneous supplements are often used for the directed differentiation of hiPSCs to specific lineages, such as chemicals and hormones. Some of these are known to synchronize the circadian clock, like forskolin (Frk) and dexamethasone (Dex); however, the response to these stimulations has not been fully elucidated for hiPSCs. In this study, we examined the response of clock genes to synchronizing stimulation, and compared it with fully differentiated cells, U2OS, and fibroblasts. The expression of clock genes did not show circadian rhythms in hiPSCs with Frk and Dex, which could be due to the significantly low levels of BMAL1. On the other hand, a circadian-like rhythm of D-box binding protein (DBP) expression was observed in hiPSCs by culturing them in an environment with a simulated body temperature. However, the inhibition of temperature-inducible factors, which are involved in temperature rhythm-induced synchronization, could not repress the expression of such rhythms, while the inhibition of HIF-1 alpha significantly repressed them. In summary, we suggest that clock genes do not respond to the synchronizing agents in hiPSCs; instead, a unique circadian-like rhythm is induced by the temperature rhythm.