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

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 Masuda; Emmanuel Nivet; Yuji Tsunekawa; Rupa Devi Soligalla; April Goebl; Emi Aizawa; Na Young Kim; Jessica Kim; Ilir Dubova; Ying Li; Ruotong Ren; Chris Benner; Antonio Del Sol; Juan Bueren; Juan Pablo Trujillo; Jordi Surralles; Enrico Cappelli; Carlo Dufour; Concepcion Rodriguez Esteban; Juan Carlos Izpisua Belmonte

doi:10.1038/ncomms5330

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

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 Masuda, Emmanuel Nivet, Yuji Tsunekawa, Rupa Devi Soligalla, April Goebl, Emi Aizawa, Na Young KimJessica Kim, Ilir Dubova, Ying Li, Ruotong Ren, Chris Benner, Antonio Del Sol, Juan Bueren, Juan Pablo Trujillo, Jordi Surralles, Enrico Cappelli, Carlo Dufour, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

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.

Original language	English (US)
Article number	4330
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5330
State	Published - Jul 7 2014
Externally published	Yes

Bibliographical note

Funding 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

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms5330

Cite this

Liu, G. H., Suzuki, K., Li, M., Qu, J., Montserrat, N., Tarantino, C., Gu, Y., Yi, F., Xu, X., Zhang, W., Ruiz, S., Plongthongkum, N., Zhang, K., Masuda, S., Nivet, E., Tsunekawa, Y., Soligalla, R. D., Goebl, A., Aizawa, E., ... Belmonte, J. C. I. (2014). Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nature Communications, 5, Article 4330. https://doi.org/10.1038/ncomms5330

@article{7ccf327dd05b4a689fb88ef158038852,

title = "Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs",

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.",

author = "Liu, {Guang Hui} and Keiichiro Suzuki and Mo Li and Jing Qu and Nuria Montserrat and Carolina Tarantino and Ying Gu and Fei Yi and Xiuling Xu and Weiqi Zhang and Sergio Ruiz and Nongluk Plongthongkum and Kun Zhang and Shigeo Masuda and Emmanuel Nivet and Yuji Tsunekawa and Soligalla, {Rupa Devi} and April Goebl and Emi Aizawa and Kim, {Na Young} and Jessica Kim and Ilir Dubova and Ying Li and Ruotong Ren and Chris Benner and {Del Sol}, Antonio and Juan Bueren and Trujillo, {Juan Pablo} and Jordi Surralles and Enrico Cappelli and Carlo Dufour and Esteban, {Concepcion Rodriguez} and Belmonte, {Juan Carlos Izpisua}",

note = "Funding 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{\textquoteright}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 Fundaci{\'o} Privada La Marat{\'o} 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 Fundaci{\'o} Marat{\'o} 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 Fundaci{\'o} Privada La Marat{\'o} 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.",

year = "2014",

month = jul,

day = "7",

doi = "10.1038/ncomms5330",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Liu, GH, Suzuki, K, Li, M, Qu, J, Montserrat, N, Tarantino, C, Gu, Y, Yi, F, Xu, X, Zhang, W, Ruiz, S, Plongthongkum, N, Zhang, K, Masuda, S, Nivet, E, Tsunekawa, Y, Soligalla, RD, Goebl, A, Aizawa, E, Kim, NY, Kim, J, Dubova, I, Li, Y, Ren, R, Benner, C, Del Sol, A, Bueren, J, Trujillo, JP, Surralles, J, Cappelli, E, Dufour, C, Esteban, CR & Belmonte, JCI 2014, 'Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs', Nature Communications, vol. 5, 4330. https://doi.org/10.1038/ncomms5330

TY - JOUR

T1 - Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs

AU - Liu, Guang Hui

AU - Suzuki, Keiichiro

AU - Li, Mo

AU - Qu, Jing

AU - Montserrat, Nuria

AU - Tarantino, Carolina

AU - Gu, Ying

AU - Yi, Fei

AU - Xu, Xiuling

AU - Zhang, Weiqi

AU - Ruiz, Sergio

AU - Plongthongkum, Nongluk

AU - Zhang, Kun

AU - Masuda, Shigeo

AU - Nivet, Emmanuel

AU - Tsunekawa, Yuji

AU - Soligalla, Rupa Devi

AU - Goebl, April

AU - Aizawa, Emi

AU - Kim, Na Young

AU - Kim, Jessica

AU - Dubova, Ilir

AU - Li, Ying

AU - Ren, Ruotong

AU - Benner, Chris

AU - Del Sol, Antonio

AU - Bueren, Juan

AU - Trujillo, Juan Pablo

AU - Surralles, Jordi

AU - Cappelli, Enrico

AU - Dufour, Carlo

AU - Esteban, Concepcion Rodriguez

AU - Belmonte, Juan Carlos Izpisua

N1 - Funding 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.

PY - 2014/7/7

Y1 - 2014/7/7

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms5330

DO - 10.1038/ncomms5330

M3 - Article

C2 - 24999918

AN - SCOPUS:84903979340

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4330

ER -

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

Abstract

Bibliographical note

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UN SDGs

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