Induced Pluripotent Stem Cells from Ataxia-Telangiectasia Recapitulate the Cellular Phenotype

Nayler, Sam, Gatei, Magtouf, Kozlov, Sergei, Gatti, Richard, Mar, Jessica C., Wells, Christine A., Lavin, Martin and Wolvetang, Ernst (2012) Induced Pluripotent Stem Cells from Ataxia-Telangiectasia Recapitulate the Cellular Phenotype. Stem Cells Translational Medicine, 1 7: 523-535. doi:10.5966/sctm.2012-0024

Author Nayler, Sam
Gatei, Magtouf
Kozlov, Sergei
Gatti, Richard
Mar, Jessica C.
Wells, Christine A.
Lavin, Martin
Wolvetang, Ernst
Title Induced Pluripotent Stem Cells from Ataxia-Telangiectasia Recapitulate the Cellular Phenotype
Journal name Stem Cells Translational Medicine   Check publisher's open access policy
ISSN 2157-6564
Publication date 2012-07
Sub-type Article (original research)
DOI 10.5966/sctm.2012-0024
Open Access Status DOI
Volume 1
Issue 7
Start page 523
End page 535
Total pages 13
Place of publication Durham, NC, United States
Publisher AlphaMed Press
Collection year 2013
Language eng
Abstract Pluripotent stem cells can differentiate into every cell type of the human body. Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) therefore provides an opportunity to gain insight into the molecular and cellular basis of disease. Because the cellular DNA damage response poses a barrier to reprogramming, generation of iPSCs from patients with chromosomal instability syndromes has thus far proven to be difficult. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T), a disorder characterized by chromosomal instability, progressive neurodegeneration, high risk of cancer, and immunodeficiency, can be reprogrammed to bona fide iPSCs, albeit at a reduced efficiency. A-T iPSCs display defective radiation-induced signaling, radiosensitivity, and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSCs identifies abnormalities in DNA damage signaling pathways, as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSCs can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T-associated neurodegeneration. Collectively, our data show that iPSCs can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention.
Keyword Experimental models
Gene expression
Double-Strand Breaks
Dna-Damage Response
Oxidative Stress
Mitochondrial Dysfunction
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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