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

Author

Listed:
  • Guang-Hui Liu

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    Gene Expression Laboratory, Salk Institute for Biological Studies
    Beijing Institute for Brain Disorders)

  • Keiichiro Suzuki

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Mo Li

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Jing Qu

    (Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences)

  • Nuria Montserrat

    (Center for Regenerative Medicine in Barcelona)

  • Carolina Tarantino

    (Center for Regenerative Medicine in Barcelona)

  • Ying Gu

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Fei Yi

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Xiuling Xu

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Weiqi Zhang

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Sergio Ruiz

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Nongluk Plongthongkum

    (University of California at San Diego)

  • Kun Zhang

    (University of California at San Diego)

  • Shigeo Masuda

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Emmanuel Nivet

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Yuji Tsunekawa

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Rupa Devi Soligalla

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • April Goebl

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Emi Aizawa

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Na Young Kim

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Jessica Kim

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Ilir Dubova

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Ying Li

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Ruotong Ren

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Chris Benner

    (Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies)

  • Antonio del Sol

    (Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg)

  • Juan Bueren

    (Medioambientales y Tecnológicas (CIEMAT)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER)
    Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM))

  • Juan Pablo Trujillo

    (Universitat Autonoma de Barcelona, Campus de Bellaterra s/n 08193 Bellaterra)

  • Jordi Surralles

    (Universitat Autonoma de Barcelona, Campus de Bellaterra s/n 08193 Bellaterra)

  • Enrico Cappelli

    (Clinical and Experimental Hematology Unit, G. Gaslini Children’s Hospital)

  • Carlo Dufour

    (Clinical and Experimental Hematology Unit, G. Gaslini Children’s Hospital)

  • Concepcion Rodriguez Esteban

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Juan Carlos Izpisua Belmonte

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

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.

Suggested Citation

  • Guang-Hui Liu & Keiichiro Suzuki & Mo Li & Jing Qu & Nuria Montserrat & Carolina Tarantino & Ying Gu & Fei Yi & Xiuling Xu & Weiqi Zhang & Sergio Ruiz & Nongluk Plongthongkum & Kun Zhang & Shigeo Masu, 2014. "Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs," Nature Communications, Nature, vol. 5(1), pages 1-17, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5330
    DOI: 10.1038/ncomms5330
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    Cited by:

    1. Baolei Yuan & Xuan Zhou & Keiichiro Suzuki & Gerardo Ramos-Mandujano & Mengge Wang & Muhammad Tehseen & Lorena V. Cortés-Medina & James J. Moresco & Sarah Dunn & Reyna Hernandez-Benitez & Tomoaki Hish, 2022. "Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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