Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1
Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1
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DOI：
10.1038/cr.2011.107
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发表时间：
2011-09-01
期刊：
影响因子：
44.1
通讯作者：
You, Seungkwon
中科院分区：
文献类型：
--
作者：
Moon, Jai-Hee;Heo, June Seok;You, Seungkwon
转录因子Oct4、Sox2和Klf4与c-Myc结合可将体细胞重新编程为诱导多能干细胞(IPS)。最近，Sox2+Oct4被证明可以重新编程成纤维细胞，而单独使用Oct4能够将小鼠和人类神经干细胞(NSCs)重新编程为iPS细胞。在此，我们报道了Bmi1能诱导小鼠成纤维细胞转分化为NSC样细胞，并与Oct4联合使用，可以在成纤维细胞重编程为iPS细胞的过程中取代Sox2、Klf4和c-Myc。此外，Sonic Hedgehog信号的激活(由Shh、紫色胺或氧固醇)可以补偿Bmi1的影响，并与Oct4结合，将小鼠胚胎和成年成纤维细胞重新编程为iPS细胞。单因素和双因素iPS细胞在全球基因表达谱、表观遗传状态、体外和体内分化为所有三种生殖层以及体内畸胎瘤形成和生殖系传播方面与小鼠胚胎干细胞相似。这些数据支持，将带有Bmi1的成纤维细胞转化为表达Sox2、Klf4和N-Myc的中间细胞类型的Sonic Hedgehog通路，允许通过添加Oct4产生iPS。
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One-and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4.