p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita.
p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita.
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DOI：
10.1016/j.stemcr.2017.06.015
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发表时间：
2017-08-08
影响因子：
5.9
通讯作者：
Batista LFZ
中科院分区：
文献类型：
--
作者：
Fok WC;Niero ELO;Dege C;Brenner KA;Sturgeon CM;Batista LFZ
先天性角化不良（DC）是一种与端粒功能障碍相关的骨髓衰竭综合征。DC中造血功能衰竭的进展和分子决定因素仍然知之甚少。在这里，我们使用人类胚胎干细胞的定向分化窝藏临床相关的端粒酶突变，以了解原始和最终的造血程序的DC相关突变的后果。有趣的是，端粒缩短不会广泛损害造血，因为原始造血在DC细胞中不受损害。相比之下，虽然表型永久造血内皮细胞是指定的，内皮细胞到造血细胞的转换是受损的细胞缩短端粒。这种失败是由DNA损伤累积引起的，并由p53稳定化介导。这些观察结果表明，端粒缩短在造血系统中的有害影响是特定的造血谱系。这项工作说明了端粒功能障碍如何损害造血发育，并为治疗DC患者的治疗发现创造了一个强大的平台。CRISPR/Cas9用于在hESC中产生不同的DC相关突变端粒缩短特异性地损害确定性造血特化遗传不稳定性和p53活化调节DC中的造血特化体外造血衰竭类似于DC中再生障碍性贫血的表型通过直接评估源自端粒酶突变hESC的原始或确定性造血，Batista和他的同事们发现，端粒缩短会特异性地损害最终的造血潜能，而原始的造血反而会增强。该系统提供了前所未有的能力来研究造血功能衰竭，并表明DC患者的骨髓衰竭是可逆的。
Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients. CRISPR/Cas9 was used to generate different DC-associated mutations in hESCs Telomere shortening specifically impairs definitive hematopoietic specification Genetic instability and p53 activation regulate hematopoietic specification in DC In vitro hematopoietic failure resembles phenotypes of aplastic anemia in DC By directly assessing primitive or definitive hematopoiesis derived from telomerase-mutant hESCs, Batista and colleagues show that telomere shortening specifically impairs definitive hematopoietic potential, while primitive hematopoiesis is instead enhanced. This system offers the unprecedented capability to study hematopoietic failure and suggests that bone marrow failure in DC patients is reversible.
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影响因子：
64.8
作者：
Batista, Luis F. Z.;Pech, MatthewF.;Zhong, Franklin L.;Nguyen, Ha Nam;Xie, Kathleen T.;Zaug, Arthur J.;Crary, Sharon M.;Choi, Jinkuk;Sebastiano, Vittorio;Cherry, Athena;Giri, Neelam;Wernig, Marius;Alter, Blanche P.;Cech, Thomas R.;Savage, Sharon A.;Pera, Renee A. Reijo;Artandi, Steven E.
通讯作者：
Artandi, Steven E.
影响因子：
46.9
作者：
Hockemeyer, Dirk;Soldner, Frank;Beard, Caroline;Gao, Qing;Mitalipova, Maisam;DeKelver, Russell C.;Katibah, George E.;Amora, Ranier;Boydston, Elizabeth A.;Zeitler, Bryan;Meng, Xiangdong;Miller, Jeffrey C.;Zhang, Lei;Rebar, Edward J.;Gregory, Philip D.;Urnov, Fyodor D.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
21.3
作者：
Ditadi A;Sturgeon CM;Tober J;Awong G;Kennedy M;Yzaguirre AD;Azzola L;Ng ES;Stanley EG;French DL;Cheng X;Gadue P;Speck NA;Elefanty AG;Keller G
通讯作者：
Keller G
影响因子：
3.7
作者：
Gu，Bai-Wei;Apicella，Marisa;Mason，Philip J.
通讯作者：
Mason，Philip J.