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Nat Commun. 2014 Jul 7;5:4330. doi: 10.1038/ncomms5330.

Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.

Author information

1
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
3
Beijing Institute for Brain Disorders, Beijing 100069, China.
4
Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
5
Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.
6
Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, USA.
7
Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
8
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-1511, Luxembourg, Luxembourg.
9
Hematopoiesis and Gene Therapy Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid 28040, Spain.
10
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid 28040, Spain.
11
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid 28040, Spain.
12
Department of Genetics and Microbiology and Center for Biomedical Network Research on Rare Diseases (CIBERER), Universitat Autonoma de Barcelona, Campus de Bellaterra s/n 08193 Bellaterra, Spain.
13
G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16147 Genova Quarto, Italy.
#
Contributed equally

Abstract

Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells.

PMID:
24999918
PMCID:
PMC4291073
DOI:
10.1038/ncomms5330
[Indexed for MEDLINE]
Free PMC Article

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