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.
|Original language||English (US)|
|State||Published - Jul 7 2014|
Bibliographical noteFunding Information:
We would like to thank K. Mitani, P. Ng and A. Lieber for HDAdV production; I. Sancho-Martinez for helpful discussions; P. Wang, R. Bai, J. Wu and Roser Pujol for technical assistance, L. Mack, E. O’Connor and K. Marquez for help with flow cytometry; and M. Schwarz, P. Schwarz and T. Yuan for administrative help. This work was supported by National Basic Research Program of China (973 Program, 2014CB964600; 2014CB910500), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312), 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 and Spanish Ministry of Economy and Competitiveness (Ref. PLE 2009-0164). Y.T. was partially supported by Uehara Memorial Foundation research fellowship. E.N. was partially supported by F.M. Kirby Foundation postdoctoral fellowship. J.S. was supported by MINECO (SAF2012-31881) and Fundació Marató TV3 (464/C/2012). J.B. was supported by grants from Spanish Ministry of Economy and Competitiveness (International Cooperation on Stem Cell Research Plan E; Ref PLE 2009/0100 and SAF2012-39834) and 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, The National Institutes of Health (5U01HL107442) and The Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)