A p53-Dependent Checkpoint Induced upon DNA Damage Alters Cell Fate during hiPSC Differentiation.
A p53-Dependent Checkpoint Induced upon DNA Damage Alters Cell Fate during hiPSC Differentiation.
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DNA损伤诱导的p53依赖性检查点改变hiPSC分化期间的细胞命运。
DOI：
10.1016/j.stemcr.2020.08.003
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发表时间：
2020-10-13
影响因子：
5.9
通讯作者：
Sale JE
中科院分区：
文献类型：
--
作者：
Eldridge CB;Allen FJ;Crisp A;Grandy RA;Vallier L;Sale JE
人诱导多能干细胞（hiPSC）在体外分化为三种胚层谱系中的每一种的能力使其成为早期人类发育的重要模型和组织工程的工具。然而，干扰分化的复杂转录编排的因素仍然不完全清楚。在这里，我们发现了一个关键的时间窗口，在此期间，DNA损伤显着降低了hiPSC分化为定形内胚层的效率和保真度。DNA损伤阻止了p53水平的正常降低，因为细胞通过上皮-间充质转化，将转录程序转向中胚层，而不诱导凋亡反应。相反，TP 53缺陷细胞在DNA损伤后以高效率分化为内胚层，这表明p53在早期内胚层分化中实施“分化检查点”，其响应于DNA损伤而改变细胞命运。DNA损伤损害了人干细胞分化的效率和保真度，p53在定型内胚层过程中瞬时减少。防止p53减少使细胞远离内胚层而不发生凋亡，p53缺陷细胞在DNA损伤面前有效地分化为内胚层。证明了一个时间窗口，在此期间，人iPSC向定形内胚层的分化对低水平的DNA损伤敏感，导致分化程序转向更中胚层的命运。这种作用几乎完全依赖于p53，在受损的p53缺陷细胞中，内胚层分化的效率和保真度都得到恢复。
The ability of human induced pluripotent stem cells (hiPSCs) to differentiate in vitro to each of the three germ layer lineages has made them an important model of early human development and a tool for tissue engineering. However, the factors that disturb the intricate transcriptional choreography of differentiation remain incompletely understood. Here, we uncover a critical time window during which DNA damage significantly reduces the efficiency and fidelity with which hiPSCs differentiate to definitive endoderm. DNA damage prevents the normal reduction of p53 levels as cells pass through the epithelial-to-mesenchymal transition, diverting the transcriptional program toward mesoderm without induction of an apoptotic response. In contrast, TP53-deficient cells differentiate to endoderm with high efficiency after DNA damage, suggesting that p53 enforces a “differentiation checkpoint” in early endoderm differentiation that alters cell fate in response to DNA damage. DNA damage impairs the efficiency and fidelity of human stem cell differentiation p53 is reduced transiently during the commitment to definitive endoderm Preventing p53 reduction diverts cells away from endoderm without apoptosis p53-deficient cells differentiate to endoderm efficiently in the face of DNA damage Eldridge et al. demonstrate a temporal window during which the differentiation of human iPSCs to definitive endoderm is sensitive to low levels of DNA damage, causing diversion of the differentiation program toward a more mesodermal fate. This effect is almost entirely dependent on p53, with both the efficiency and the fidelity of endoderm differentiation being restored in damaged p53-deficient cells.
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有条件和可逆基因敲除一步的一代。
影响因子：
48
作者：
Andersson-Rolf A;Mustata RC;Merenda A;Kim J;Perera S;Grego T;Andrews K;Tremble K;Silva JC;Fink J;Skarnes WC;Koo BK
通讯作者：
Koo BK
DOI：
10.1073/pnas.0909734107
发表时间：
2010-01-05
影响因子：
11.1
作者：
Lee, Kyoung-Hwa;Li, Mangmang;Huang, Jing
通讯作者：
Huang, Jing
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
DOI：
10.1016/0027-5107(90)90173-2
发表时间：
1990-07-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
BERANEK, DT
通讯作者：
BERANEK, DT
DOI：
10.1242/dev.014357
发表时间：
2008-02
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Arnold SJ;Hofmann UK;Bikoff EK;Robertson EJ
通讯作者：
Robertson EJ