Histone deacefylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress
Histone deacefylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress
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组蛋白去乙酰化酶抑制剂丙戊酸通过抑制重编程诱导的衰老应激促进小鼠成纤维细胞多能性的诱导
DOI：
10.1016/j.yexcr.2015.06.003
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发表时间：
2015
影响因子：
3.7
通讯作者：
Li Wei
中科院分区：
文献类型：
--
作者：
Zhai Yingying;Chen Xi;Yu Dehai;Li Tao;Cui Jiuwei;Wang Guanjun;Hu Ji-Fan;Li Wei
组蛋白去乙酰化酶抑制剂丙戊酸（VPA）已被用于提高体细胞诱导多能干细胞（iPSC）的重编程效率，但这种作用的具体分子机制尚不清楚。在这里，我们证明了携带ipsc诱导因子（Oct4-Sox2-Klf4-cMyc， OSKM）的慢病毒重编程导致小鼠成纤维细胞衰老，为细胞重编程建立了应激屏障。注射VPA可保护细胞免受重编程诱导的衰老应激。通过体外早衰模型，我们发现VPA通过抑制p16/p21通路增加细胞增殖，抑制细胞凋亡。此外，VPA还能抑制衰老应力引起的G2/M相阻滞。这些发现强调了VPA在打破诱导多能性所需的细胞衰老屏障中的作用。
Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using anin vitropre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency.