p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita
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 clinicall...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671117302783 |
| _version_ | 1818152379111964672 |
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| author | Wilson Chun Fok Evandro Luis de Oliveira Niero Carissa Dege Kirsten Ann Brenner Christopher Michael Sturgeon Luis Francisco Zirnberger Batista |
| author_facet | Wilson Chun Fok Evandro Luis de Oliveira Niero Carissa Dege Kirsten Ann Brenner Christopher Michael Sturgeon Luis Francisco Zirnberger Batista |
| author_sort | Wilson Chun Fok |
| collection | DOAJ |
| description | 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. : 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. Keywords: embryonic stem cells, hematopoiesis, bone marrow failure, telomerase, dyskeratosis congenita, disease modeling, telomeres, telomere damage |
| first_indexed | 2024-12-11T13:53:47Z |
| format | Article |
| id | doaj.art-1b11f02c1fe64883b770de947cbea729 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-11T13:53:47Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-1b11f02c1fe64883b770de947cbea7292022-12-22T01:04:08ZengElsevierStem Cell Reports2213-67112017-08-0192409418p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis CongenitaWilson Chun Fok0Evandro Luis de Oliveira Niero1Carissa Dege2Kirsten Ann Brenner3Christopher Michael Sturgeon4Luis Francisco Zirnberger Batista5Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADepartment of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADepartment of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADepartment of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USADepartment 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; Corresponding authorDepartment 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; Corresponding authorSummary: 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. : 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. Keywords: embryonic stem cells, hematopoiesis, bone marrow failure, telomerase, dyskeratosis congenita, disease modeling, telomeres, telomere damagehttp://www.sciencedirect.com/science/article/pii/S2213671117302783 |
| spellingShingle | Wilson Chun Fok Evandro Luis de Oliveira Niero Carissa Dege Kirsten Ann Brenner Christopher Michael Sturgeon Luis Francisco Zirnberger Batista p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita Stem Cell Reports |
| title | p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita |
| title_full | p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita |
| title_fullStr | p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita |
| title_full_unstemmed | p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita |
| title_short | p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita |
| title_sort | p53 mediates failure of human definitive hematopoiesis in dyskeratosis congenita |
| url | http://www.sciencedirect.com/science/article/pii/S2213671117302783 |
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