Liu Guang-Hui, Suzuki Keiichiro, Li Mo, Qu Jing, Montserrat Nuria, Tarantino Carolina, Gu Ying, Yi Fei, Xu Xiuling, Zhang Weiqi, Ruiz Sergio, Plongthongkum Nongluk, Zhang Kun, Masuda Shigeo, Nivet Emmanuel, Tsunekawa Yuji, Soligalla Rupa Devi, Goebl April, Aizawa Emi, Kim Na Young, Kim Jessica, Dubova Ilir, Li Ying, Ren Ruotong, Benner Chris, Del Sol Antonio, Bueren Juan, Trujillo Juan Pablo, Surralles Jordi, Cappelli Enrico, Dufour Carlo, Esteban Concepcion Rodriguez, Belmonte Juan Carlos Izpisua
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nat Commun. 2014 Jul 7;5:4330. doi: 10.1038/ncomms5330.
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.
范可尼贫血（FA）是一种隐性疾病，其特征为基因组不稳定、先天性异常、癌症易感性和骨髓（BM）衰竭。然而，由于当前疾病模型的局限性，FA的发病机制尚未完全明确。在此，我们从一名FA患者中获得了无基因互补的整合自由诱导多能干细胞（iPSC），并报告了FA-iPSC中的原位基因校正以及等基因FANCA缺陷人类胚胎干细胞（ESC）系的生成。FA细胞表型在iPSC/ESC及其成体干细胞/祖细胞衍生物中得以重现。通过使用等基因无致病突变对照以及细胞和基因组工具，我们的模型有助于发现新的疾病特征。我们通过鉴定几种可改善FA-iPSC造血分化的化合物，验证了我们的模型作为药物筛选平台的有效性。这些化合物还能够挽救FA患者BM细胞的造血表型。
