Review Article | Published:

Diseases in a dish: modeling human genetic disorders using induced pluripotent cells

Nature Medicine volume 17, pages 15701576 (2011) | Download Citation

Abstract

The derivation of induced pluripotent cells (iPSCs) from individuals suffering from genetic syndromes offers new opportunities for basic research into these diseases and the development of therapeutic compounds. iPSCs can self renew and can be differentiated to many cell types, offering a potentially unlimited source of material for study. In this review we discuss the conceptual and practical issues to consider when attempting to model genetic diseases using iPSCs.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat. Genet. 39, 730–732 (2007).

  2. 2.

    Animal models of human disease for gene therapy. J. Clin. Invest. 97, 1138–1141 (1996).

  3. 3.

    et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. Br. Med. J. 334, 197 (2007).

  4. 4.

    A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp. Neurol. 205, 20–25 (2007).

  5. 5.

    New potential for human embryonic stem cells. Science 282, 1061–1062 (1998).

  6. 6.

    et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

  7. 7.

    et al. Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum. Reprod. 21, 503–511 (2006).

  8. 8.

    et al. Creation of a registry for human embryonic stem cells carrying an inherited defect: joint collaboration between ESHRE and hESCreg. Hum. Reprod. 24, 1556–1560 (2009).

  9. 9.

    , & Modeling for Lesch-Nyhan disease by gene targeting in human embryonic stem cells. Stem Cells 22, 635–641 (2004).

  10. 10.

    & Genetic modification of human embryonic stem cells for derivation of target cells. Cell Stem Cell 2, 422–433 (2008).

  11. 11.

    & Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

  12. 12.

    et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).

  13. 13.

    et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009).

  14. 14.

    et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402–406 (2009).

  15. 15.

    et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).

  16. 16.

    et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).

  17. 17.

    et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).

  18. 18.

    et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472, 221–225 (2011).

  19. 19.

    et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53–59 (2009).

  20. 20.

    , & Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat. Rev. Genet. 12, 231–242 (2011).

  21. 21.

    et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26, 1276–1284 (2008).

  22. 22.

    et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009).

  23. 23.

    et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol. 28, 848–855 (2010).

  24. 24.

    et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat. Cell Biol. 13, 541–549 (2011).

  25. 25.

    , , & Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9, 17–23 (2011).

  26. 26.

    et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

  27. 27.

    et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).

  28. 28.

    & Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3, 595–605 (2008).

  29. 29.

    , , & Directed differentiation of pluripotent stem cells: from developmental biology to therapeutic applications. Cold Spring Harb. Symp. Quant. Biol. 73, 101–110 (2008).

  30. 30.

    & Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

  31. 31.

    et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).

  32. 32.

    et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–234 (2011).

  33. 33.

    et al. A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011).

  34. 34.

    et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694 (2011).

  35. 35.

    & Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 5, 584–595 (2009).

  36. 36.

    , , & Investigating monogenic and complex diseases with pluripotent stem cells. Nat. Rev. Genet. 12, 266–275 (2011).

  37. 37.

    et al. LRRK2 mutant iPSC–derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011).

  38. 38.

    et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).

Download references

Acknowledgements

The authors thank R. Vassena and M. Barragan Monasterio for their critical reading of the manuscript. Work in the laboratory of J.C.I.B. was funded by Ramon y Cajal, The Helmsley Charitable Trust, Sanofi-Aventis, The G. Harold and Leila Y. Mathers Charitable Foundation and Fundacion Cellex.

Author information

Affiliations

  1. Centre of Regenerative Medicine in Barcelona, Barcelona, Spain.

    • Gustavo Tiscornia
    • , Erica Lorenzo Vivas
    •  & Juan Carlos Izpisúa Belmonte
  2. Salk Institute for Biological Studies, La Jolla, California, USA.

    • Juan Carlos Izpisúa Belmonte

Authors

  1. Search for Gustavo Tiscornia in:

  2. Search for Erica Lorenzo Vivas in:

  3. Search for Juan Carlos Izpisúa Belmonte in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Juan Carlos Izpisúa Belmonte.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nm.2504

Further reading