HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells.
HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells.
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DOI：
10.1002/stem.1142
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发表时间：
2012-08
期刊：
影响因子：
5.2
通讯作者：
Yeger, Herman
中科院分区：
文献类型：
--
作者：
Das, Bikul;Bayat-Mokhtari, Reza;Tsui, Micky;Lotfi, Shamim;Tsuchida, Rika;Felsher, Dean W.;Yeger, Herman
关键词：
据报道，人胚胎干细胞 (hESC) 在组织损伤区域发挥细胞保护活性。然而，损伤区域普遍存在的缺氧/氧化应激可能激活p53，导致hESC死亡和分化。在此，我们报道，当暴露于缺氧/氧化应激时，一小部分 hESC，即 SSEA3+/ABCG2+ 部分会经历短暂的重编程状态，形成低 p53 和高缺氧诱导因子 (HIF)-2α 转录活性状态。这种状态可以持续 2 周，并且与 Oct-4 和 Nanog 转录活性的增强有关，同时具有高致畸潜力。从缺氧后的 SSEA3+/ABCG2+ hESC 获得的条件培养基在体外和体内均显示出细胞保护作用。我们将这种表型称为“增强干性”状态。然后我们证明了这种增强干性的短暂表型的潜在分子机制涉及高 Bcl-2、成纤维细胞生长因子 (FGF)-2 和 MDM2 表达以及 p53/MDM2 振荡系统的改变状态。 HIF-2α 和 p53 的特异性沉默可抵抗 SSEA3+/ABCG2+ 重编程为增强的干性表型。因此，我们的研究发现了 hESC 中独特的瞬时重编程活性，即增强的干性重编程，通过瞬时抑制 p53 活性实现高度细胞保护和未分化状态。我们认为这种短暂的重编程是干细胞利他主义的一种形式，在组织再生过程中有益于周围组织。
Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the “enhanced stemness” state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration.
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影响因子：
37.8
作者：
Cao, F;Lin, S;Wu, JC
通讯作者：
Wu, JC
影响因子：
5.2
作者：
Das, Bikul;Tsuchida, Rika;Yeger, Herman
通讯作者：
Yeger, Herman
DOI：
10.1073/pnas.1019047108
发表时间：
2011-02-22
影响因子：
11.1
作者：
Ardehali, Reza;Inlay, Matthew A.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
12.4
作者：
Drowley, Lauren;Okada, Masaho;Huard, Johnny
通讯作者：
Huard, Johnny
影响因子：
4.8
作者：
Das, Bikul;Antoon, Roula;Baruchel, Sylvain
通讯作者：
Baruchel, Sylvain