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Stem Cell Reports. 2017 Aug 8;9(2):409-418. doi: 10.1016/j.stemcr.2017.06.015. Epub 2017 Jul 27.

p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita.

Author information

1
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
2
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: csturgeon@wustl.edu.
3
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: lbatista@wustl.edu.

Abstract

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:

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

PMID:
28757166
PMCID:
PMC5550027
DOI:
10.1016/j.stemcr.2017.06.015
[Indexed for MEDLINE]
Free PMC Article

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