Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells.
Cell Cycle Proteins
/ genetics
Cell Differentiation
Cells, Cultured
Cellular Reprogramming
Dyskeratosis Congenita
/ genetics
Fibroblasts
/ cytology
Hematopoiesis
Humans
Induced Pluripotent Stem Cells
/ cytology
Karyotype
Mutation
Nuclear Proteins
/ genetics
Telomerase
/ genetics
Telomere
/ metabolism
Telomere Shortening
DKC1
Hematopoietic differentiation
Induced pluripotent stem cells (iPSCs)
Telomerase
Telomeres
X-linked dyskeratosis congenita
Journal
Stem cell research
ISSN: 1876-7753
Titre abrégé: Stem Cell Res
Pays: England
ID NLM: 101316957
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
10
01
2019
revised:
08
08
2019
accepted:
19
08
2019
pubmed:
4
9
2019
medline:
1
5
2020
entrez:
4
9
2019
Statut:
ppublish
Résumé
Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.
Identifiants
pubmed: 31479877
pii: S1873-5061(19)30170-9
doi: 10.1016/j.scr.2019.101540
pmc: PMC8376098
mid: NIHMS1733129
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
DKC1 protein, human
0
Nuclear Proteins
0
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101540Subventions
Organisme : Intramural NIH HHS
ID : ZIA HL006062
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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