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Modeling Fanconi anemia pathogenesis and therapeutics using integration-free patient iPSCs
Liu, Guang-Hui (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Suzuki (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Li, Mo (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Qu, Jing (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Montserrat, Núria (Centre de Medicina Regenerativa de Barcelona)
Tarantino, Carolina (Centre de Medicina Regenerativa de Barcelona)
Gu, Ying (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Yi, Fei (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Xu, Xiuling (Zhongguo ke xue yuan. National Laboratory of Biomacromolecules)
Zhang, Weiqi (Zhongguo ke xue yuan. National Laboratory of Biomacromolecules)
Ruiz, Sergio (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Plongthongkum, Nongluk (University of California. Department of Bioengineering)
Zhang, Kun (University of California. Department of Bioengineering)
Masuda, Shigeo (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Nivet, Emmanuel (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Tsunokawa, Yuji (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Soligalla, Rupa Devi (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Goebl, April (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Aizawa, Emi (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Kim, Na Young (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Kim, Jessica (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Dubova, Ilir (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Li, Ying (Zhongguo ke xue yuan. National Laboratory of Biomacromolecules)
Ren, Ruotong (Zhongguo ke xue yuan. National Laboratory of Biomacromolecules)
Benner, Chris (Integrative Genomics and Bioinformatics Core. Salk Institute for Biological Studies)
Sol, Antonio del (Luxembourg Centre for Systems Biomedicine)
Bueren, Juan (Fundación Jiménez Díaz. Instituto de Investigación Sanitaria)
Trujillo Quintero, Juan Pablo (Universitat Autonoma de Barcelona. Departament de Genètica i de Microbiologia)
Surrallés i Calonge, Jordi (Universitat Autonoma de Barcelona. Departament de Genètica i de Microbiologia)
Cappelli, Enrico (Istituto "Giannina Gaslini" di Genova)
Dufour, Carlo (Istituto "Giannina Gaslini" di Genova)
Rodriguez Esteban, Concepción (Laboratory of Gene Expression, Salk Institute for Biological Studies)
Izpisua Belmonte, Juan Carlos (Laboratory of Gene Expression, Salk Institute for Biological Studies)

Date: 2014
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.
Abstract: Altres ajuts: Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312), National Basic Research Program of China (973 Program,2014CB964600;2014CB910500), NSFC (81271266, 31222039, 81330008, 31201111, 81371342, 81300261, 81300677), Key Research Program of the Chinese Academy of Sciences (KJZD-EW-TZ-L05), Beijing Natural Science Foundation (7141005; 5142016), the Thousand Young Talents program of China, National Laboratory of Biomacromolecules (012kf02, 2013kf05;2013kf11;2014kf02), and State Key Laboratory of Drug Research (SIMM1302KF-17). M. L. and K. S. are supported by CIRM fellowship. N. M was partially supported by La Fundació Privada La Marató de TV3, 121430/31/32. Y. T. was partially supported by an Uehara Memorial Foundation research fellowship. E. N. was partially supported by an F. M. Kirby Foundation postdoctoral fellowship. J. S. was supported by Fundació Marató TV3 (464/C/2012). J. A. B. was supported by grants from La Fundació Privada La Marató de TV3, 121430/31/32. J. C. I. B. was supported by grants from the G. Harold and Leila Y. Mathers Charitable Foundation, The California Institute of Regenerative Medicine, Ellison Medical Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002.
Note: Número d'acord de subvenció MINECO/PLE 2009-0164
Note: Número d'acord de subvenció MINECO/SAF2012-31881
Note: Número d'acord de subvenció MINECO/PLE 2009/0100
Note: Número d'acord de subvenció MINECO/SAF2012-39834
Rights: Tots els drets reservats.
Language: Anglès.
Document: article ; recerca ; acceptedVersion
Subject: Fanconi anemia
Published in: Nature Communications, Vol. 5, article 4330 (July 2014) , ISSN 2041-1723

DOI: 10.1038/ncomms5330
PMID: 24999918


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 Record created 2015-06-03, last modified 2019-02-03



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