Stem Cell Reports
Volume 9, Issue 2, 8 August 2017, Pages 409-418
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Report
p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita

https://doi.org/10.1016/j.stemcr.2017.06.015Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

embryonic stem cells
hematopoiesis
bone marrow failure
telomerase
dyskeratosis congenita
disease modeling
telomeres
telomere damage

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