Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRT pathway in the regulation of maintenance and differentiation of human-induced pluripotent stem (iPS) cells is not fully elucidated. We evaluated the effects of specific inhibitors of NAMPT or SIRT2 on the pluripotency, proliferation, survival, and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells. We demonstrated that NAMPT is indispensable for the maintenance, survival, and hematopoietic differentiation of iPS cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affect hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system. Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.

中文翻译：

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NAMPT / SIRT2介导的对p53-p21信号通路的抑制对于人类iPS细胞的维持和造血分化必不可少

烟酰胺磷酸核糖基转移酶（NAMPT）通过依赖烟酰胺腺嘌呤二核苷酸（NAD +）的沉默调节蛋白（SIRT）的蛋白质脱乙酰活性来调节细胞功能。SIRT调节组蛋白和非组蛋白的功能。NAMPT / SIRT途径在人类诱导的多能干（iPS）细胞的维持和分化调控中的作用尚未完全阐明。我们评估了NAMPT或SIRT2特异性抑制剂对人iPS细胞多能性，增殖，存活和造血分化的影响。我们还研究了iPS细胞中NAMPT / SIRT下游的分子机制。我们证明，NAMPT对于iPS细胞的维持，存活和造血分化是必不可少的。我们发现抑制iPS细胞中的NAMPT或SIRT2可通过促进其赖氨酸乙酰化来诱导p53蛋白。这导致p53靶标p21激活，随后细​​胞周期停滞并诱导iPS细胞凋亡。NAMPT和SIRT2抑制也会影响基于类胚体（EB）的细胞培养系统中iPS细胞的造血分化。我们的数据证明了NAMPT / SIRT2 / p53 / p21信号转导轴在iPS细胞的维持和造血分化中的重要作用。