Review Article | Published:

Induced pluripotent stem cells in disease modelling and drug discovery

Nature Reviews Genetics (2019) | Download Citation

Abstract

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human–rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

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References

  1. 1.

    Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

  2. 2.

    Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

  3. 3.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). References 1–3 provide the first descriptions of iPSCs from human cells.

  4. 4.

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This study presents the first description of iPSCs.

  5. 5.

    Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998). This paper describes the isolation of human ESCs.

  6. 6.

    Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O. & Thomson, J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129–1133 (2001).

  7. 7.

    Reubinoff, B. E. et al. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 19, 1134–1140 (2001).

  8. 8.

    He, J. Q., Ma, Y., Lee, Y., Thomson, J. A. & Kamp, T. J. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ. Res. 93, 32–39 (2003).

  9. 9.

    Assady, S. et al. Insulin production by human embryonic stem cells. Diabetes 50, 1691–1697 (2001).

  10. 10.

    Kaufman, D. S., Hanson, E. T., Lewis, R. L., Auerbach, R. & Thomson, J. A. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc. Natl Acad. Sci. USA 98, 10716–10721 (2001).

  11. 11.

    Chadwick, K. et al. Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood 102, 906–915 (2003).

  12. 12.

    Eiges, R. et al. Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell 1, 568–577 (2007).

  13. 13.

    Tulpule, A. et al. Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage. Blood 115, 3453–3462 (2010).

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

    Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).This study represents an early example of reprogramming of diseased somatic cells to generate iPSCs.

  18. 18.

    Maehr, R. et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc. Natl Acad. Sci. USA 106, 15768–15773 (2009).

  19. 19.

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

  20. 20.

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

  21. 21.

    Liu, G. H. et al. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat. Commun. 5, 4330 (2014).

  22. 22.

    Robinton, D. A. & Daley, G. Q. The promise of induced pluripotent stem cells in research and therapy. Nature 481, 295–305 (2012).

  23. 23.

    Shi, Y., Inoue, H., Wu, J. C. & Yamanaka, S. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Discov. 16, 115–130 (2017).

  24. 24.

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

  25. 25.

    Lee, G. et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat. Biotechnol. 30, 1244–1248 (2012).

  26. 26.

    Liu, C., Oikonomopoulos, A., Sayed, N. & Wu, J. C. Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145, dev156166 (2018).

  27. 27.

    McCauley, H. A. & Wells, J. M. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development 144, 958–962 (2017).

  28. 28.

    Dutta, D., Heo, I. & Clevers, H. Disease modeling in stem cell-derived 3D organoid systems. Trends Mol. Med. 23, 393–410 (2017).

  29. 29.

    Quadrato, G., Brown, J. & Arlotta, P. The promises and challenges of human brain organoids as models of neuropsychiatric disease. Nat. Med. 22, 1220–1228 (2016).

  30. 30.

    McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400–404 (2014).

  31. 31.

    Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

  32. 32.

    Mariani, J. et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 109, 12770–12775 (2012).References 31 and 32 describe early neural organoids derived from iPSCs.

  33. 33.

    Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).

  34. 34.

    Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537–550 (2015).

  35. 35.

    Jo, J. et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248–257 (2016).

  36. 36.

    Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).

  37. 37.

    Li, Y. et al. Induction of expansion and folding in human cerebral organoids. Cell Stem Cell 20, 385–396 (2017).

  38. 38.

    Sloan, S. A. et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779–790 (2017).

  39. 39.

    Gabriel, E. et al. CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35, 803–819 (2016).

  40. 40.

    Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).

  41. 41.

    Mellios, N. et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol. Psychiatry 23, 1051–1065 (2018).

  42. 42.

    Bershteyn, M. et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 20, 435–449 (2017).

  43. 43.

    Bian, S. et al. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631–639 (2018).

  44. 44.

    Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

  45. 45.

    Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

  46. 46.

    Workman, M. J. et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat. Med. 23, 49–59 (2017).This study derives a combination of neural and intestinal cells from iPSCs to generate complex intestinal tissue.

  47. 47.

    Rashid, S. T. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127–3136 (2010).

  48. 48.

    Ogawa, M. et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat. Biotechnol. 33, 853–861 (2015).

  49. 49.

    Sampaziotis, F. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat. Biotechnol. 33, 845–852 (2015).

  50. 50.

    Crespo, M. et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat. Med. 23, 878–884 (2017).

  51. 51.

    Freedman, B. S. et al. Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J. Am. Soc. Nephrol. 24, 1571–1586 (2013).

  52. 52.

    Xia, Y. et al. Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells. Nat. Cell Biol. 15, 1507–1515 (2013).

  53. 53.

    Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

  54. 54.

    Freedman, B. S. et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat. Commun. 6, 8715 (2015).

  55. 55.

    Li, Z. et al. 3D culture supports long-term expansion of mouse and human nephrogenic progenitors. Cell Stem Cell 19, 516–529 (2016).

  56. 56.

    Taguchi, A. & Nishinakamura, R. Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21, 730–746 (2017).

  57. 57.

    Musah, S. et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat. Biomed. Eng. 1, 0069 (2017).

  58. 58.

    McCauley, K. B. et al. Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of Wnt signaling. Cell Stem Cell 20, 844–857 (2017).

  59. 59.

    Jacob, A. et al. Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell 21, 472–488 (2017).References 58 and 59 demonstrate the derivation of complex lung organoids and their application in disease modelling.

  60. 60.

    Voges, H. K. et al. Development of a human cardiac organoid injury model reveals innate regenerative potential. Development 144, 1118–1127 (2017).

  61. 61.

    Finkbeiner, S. R. et al. Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo. Stem Cell Rep. 4, 1140–1155 (2015).

  62. 62.

    Pagliuca, F. W. et al. Generation of functional human pancreatic beta cells in vitro. Cell 159, 428–439 (2014).

  63. 63.

    Ronaldson-Bouchard, K. et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556, 239–243 (2018). This study demonstrates the maturation of iPSC-derived cardiomyocytes from a fetal to an adult state.

  64. 64.

    Hoang, P., Wang, J., Conklin, B. R., Healy, K. E. & Ma, Z. Generation of spatial-patterned early-developing cardiac organoids using human pluripotent stem cells. Nat. Protoc. 13, 723–737 (2018).

  65. 65.

    Abilez, O. J. et al. Passive stretch induces structural and functional maturation of engineered heart muscle as predicted by computational modeling. Stem Cells 36, 265–277 (2018).

  66. 66.

    Mills, R. J. et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc. Natl Acad. Sci. USA 114, E8372–E8381 (2017).

  67. 67.

    Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).

  68. 68.

    Brown, J. A. et al. Recreating blood-brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics 9, 054124 (2015).

  69. 69.

    Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018).

  70. 70.

    Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

  71. 71.

    DeBoever, C. et al. Large-scale profiling reveals the influence of genetic variation on gene expression in human induced pluripotent stem cells. Cell Stem Cell 20, 533–546 (2017).

  72. 72.

    Warren, C. R. et al. Induced pluripotent stem cell differentiation enables functional validation of GWAS variants in metabolic disease. Cell Stem Cell 20, 547–557 (2017).

  73. 73.

    Turco, M. Y. et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564, 263–267 (2018).

  74. 74.

    Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013).

  75. 75.

    Chen, P., Stanojcic, M. & Jeschke, M. G. Differences between murine and human sepsis. Surg. Clin. North Am. 94, 1135–1149 (2014).

  76. 76.

    Zhou, T. et al. High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain. Cell Stem Cell 21, 274–283 (2017).

  77. 77.

    Ni, Z. et al. Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. J. Virol. 85, 43–50 (2011).

  78. 78.

    Ni, Z., Knorr, D. A., Bendzick, L., Allred, J. & Kaufman, D. S. Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. Stem Cells 32, 1021–1031 (2014).

  79. 79.

    Ye, L. et al. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Delta32 mutation confers resistance to HIV infection. Proc. Natl Acad. Sci. USA 111, 9591–9596 (2014).

  80. 80.

    Lafaille, F. G. et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491, 769–773 (2012).

  81. 81.

    Lang, J. et al. An hPSC-derived tissue-resident macrophage model reveals differential responses of macrophages to ZIKV and DENV infection. Stem Cell Rep. 11, 348–362 (2018).

  82. 82.

    Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).

  83. 83.

    Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).

  84. 84.

    Gabriel, E. et al. Recent Zika virus isolates induce premature differentiation of neural progenitors in human brain organoids. Cell Stem Cell 20, 397–406 (2017).

  85. 85.

    Nowakowski, T. J. et al. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 18, 591–596 (2016).

  86. 86.

    Wells, M. F. et al. Genetic ablation of AXL does not protect human neural progenitor cells and cerebral organoids from Zika virus infection. Cell Stem Cell 19, 703–708 (2016).References 82–86 apply neural organoids to modelling Zika virus pathogenesis.

  87. 87.

    Finkbeiner, S. R. et al. Stem cell-derived human intestinal organoids as an infection model for rotaviruses. mBio 3, e00159–12 (2012).

  88. 88.

    Chen, Y. W. et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat. Cell Biol. 19, 542–549 (2017).

  89. 89.

    Churin, Y. et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell Biol. 161, 249–255 (2003).

  90. 90.

    Leslie, J. L. et al. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect. Immun. 83, 138–145 (2015).

  91. 91.

    Paredes-Sabja, D., Shen, A. & Sorg, J. A. Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. Trends Microbiol. 22, 406–416 (2014).

  92. 92.

    Forbester, J. L. et al. Interaction of Salmonella enterica serovar Typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect. Immun. 83, 2926–2934 (2015).

  93. 93.

    Nadkarni, R. R. et al. Functional enterospheres derived in vitro from human pluripotent stem cells. Stem Cell Rep. 9, 897–912 (2017).

  94. 94.

    Sturgeon, C. M., Ditadi, A., Awong, G., Kennedy, M. & Keller, G. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat. Biotechnol. 32, 554–561 (2014).

  95. 95.

    Wang, L., Li, L., Menendez, P., Cerdan, C. & Bhatia, M. Human embryonic stem cells maintained in the absence of mouse embryonic fibroblasts or conditioned media are capable of hematopoietic development. Blood 105, 4598–4603 (2005).

  96. 96.

    Tzannou, I. et al. Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncol. 35, 3547–3557 (2017).

  97. 97.

    Bollard, C. M. & Heslop, H. E. T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127, 3331–3340 (2016).

  98. 98.

    Donegan, J. J. & Lodge, D. J. Cell-based therapies for the treatment of schizophrenia. Brain Res. 1655, 262–269 (2017).

  99. 99.

    Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

  100. 100.

    Mandai, M. et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 376, 1038–1046 (2017).

  101. 101.

    Ditadi, A. et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 17, 580–591 (2015).

  102. 102.

    Kennedy, M. et al. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2, 1722–1735 (2012).

  103. 103.

    Wahlster, L. & Daley, G. Q. Progress towards generation of human haematopoietic stem cells. Nat. Cell Biol. 18, 1111–1117 (2016).

  104. 104.

    Lu, Y. F. et al. Engineered murine HSCs reconstitute multi-lineage hematopoiesis and adaptive immunity. Cell Rep. 17, 3178–3192 (2016).

  105. 105.

    Kyba, M., Perlingeiro, R. C. & Daley, G. Q. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002).

  106. 106.

    Doulatov, S. et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell 13, 459–470 (2013).

  107. 107.

    Doulatov, S. et al. Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci. Transl Med. 9, eaah5645 (2017).

  108. 108.

    Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017).This study provides a description of engraftable, functional, multilineage HSPCs derived from iPSCs.

  109. 109.

    Muller, L. U. et al. Overcoming reprogramming resistance of Fanconi anemia cells. Blood 119, 5449–5457 (2012).

  110. 110.

    Uchida, N. et al. Efficient generation of beta-globin-expressing erythroid cells using stromal cell-derived induced pluripotent stem cells from patients with sickle cell disease. Stem Cells 35, 586–596 (2017).

  111. 111.

    Niu, X. et al. Combining single strand oligodeoxynucleotides and CRISPR/Cas9 to correct gene mutations in beta-thalassemia-induced pluripotent stem cells. J. Biol. Chem. 291, 16576–16585 (2016).

  112. 112.

    Davies, G., Duke, D., Grant, A. G., Kelly, S. A. & Hermon-Taylor, J. Growth of human digestive-tumour xenografts in athymic nude rats. Br. J. Cancer 43, 53–58 (1981).

  113. 113.

    Chao, M. P. et al. Human AML-iPSCs reacquire leukemic properties after differentiation and model clonal variation of disease. Cell Stem Cell 20, 329–344 (2017).

  114. 114.

    Kotini, A. G. et al. Stage-specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia. Cell Stem Cell 20, 315–328 (2017).

  115. 115.

    Munoz-Lopez, A. et al. Development refractoriness of MLL-rearranged human B cell acute leukemias to reprogramming into pluripotency. Stem Cell Rep. 7, 602–618 (2016).

  116. 116.

    Tan, Y. T. et al. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. Proc. Natl Acad. Sci. USA 115, 2180–2185 (2018).

  117. 117.

    Taoka, K. et al. Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate. Sci. Rep. 8, 15855 (2018).

  118. 118.

    Stricker, S. H. et al. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev. 27, 654–669 (2013).

  119. 119.

    Lee, D. F. et al. Modeling familial cancer with induced pluripotent stem cells. Cell 161, 240–254 (2015).

  120. 120.

    Aguayo, A. J., Kasarjian, J., Skamene, E., Kongshavn, P. & Bray, G. M. Myelination of mouse axons by Schwann cells transplanted from normal and abnormal human nerves. Nature 268, 753–755 (1977).

  121. 121.

    Barker, R. A., Parmar, M., Studer, L. & Takahashi, J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell 21, 569–573 (2017).

  122. 122.

    Espuny-Camacho, I. et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440–456 (2013).

  123. 123.

    Yuan, T. et al. Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion. Stem Cell Res. Ther. 4, 73 (2013).

  124. 124.

    Jensen, M. B., Yan, H., Krishnaney-Davison, R., Al Sawaf, A. & Zhang, S. C. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J. Stroke Cerebrovasc. Dis. 22, 304–308 (2013).

  125. 125.

    Sundberg, M. et al. Improved cell therapy protocols for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells 31, 1548–1562 (2013).

  126. 126.

    Windrem, M. S. et al. Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 21, 195–208 (2017).

  127. 127.

    Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).

  128. 128.

    Yang, J. et al. Generation of human liver chimeric mice with hepatocytes from familial hypercholesterolemia induced pluripotent stem cells. Stem Cell Rep. 8, 605–618 (2017).

  129. 129.

    Parent, A. V. et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13, 219–229 (2013).

  130. 130.

    Sun, X. et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13, 230–236 (2013).

  131. 131.

    Ma, H., Wert, K. J., Shvartsman, D., Melton, D. A. & Jaenisch, R. Establishment of human pluripotent stem cell-derived pancreatic beta-like cells in the mouse pancreas. Proc. Natl Acad. Sci. USA 115, 3924–3929 (2018).

  132. 132.

    Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

  133. 133.

    Maeda, T. et al. Regeneration of CD8alphabeta T cells from T cell-derived iPSC imparts potent tumor antigen-specific cytotoxicity. Cancer Res. 76, 6839–6850 (2016).

  134. 134.

    Wakao, H. et al. Expansion of functional human mucosal-associated invariant T cells via reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 546–558 (2013).

  135. 135.

    Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181–192 (2018).

  136. 136.

    Vanuytsel, K. et al. Induced pluripotent stem cell-based mapping of beta-globin expression throughout human erythropoietic development. Blood Adv. 2, 1998–2011 (2018).

  137. 137.

    Pashos, E. E. et al. Large, diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci. Cell Stem Cell 20, 558–570 (2017).

  138. 138.

    Kilpinen, H. et al. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature 546, 370–375 (2017).This study highlights the genetic variability between iPSC lines derived from different individuals that can have an impact on differentiation.

  139. 139.

    Yamaguchi, T. et al. Interspecies organogenesis generates autologous functional islets. Nature 542, 191–196 (2017).

  140. 140.

    Yang, Y. et al. Derivation of pluripotent stem cells with in vivo embryonic and extraembryonic potency. Cell 169, 243–257 (2017).

  141. 141.

    Shultz, L. D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

  142. 142.

    Bosma, G. C., Custer, R. P. & Bosma, M. J. A severe combined immunodeficiency mutation in the mouse. Nature 301, 527–530 (1983).

  143. 143.

    Greiner, D. L. et al. Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C. B-17-scid/scid mice. Am. J. Pathol. 146, 888–902 (1995).

  144. 144.

    Palchaudhuri, R. et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat. Biotechnol. 34, 738–745 (2016).

  145. 145.

    McIntosh, B. E. et al. Nonirradiated NOD,B6. SCID Il2rgamma−/− Kit(W41/W41) (NBSGW) mice support multilineage engraftment of human hematopoietic cells. Stem Cell Rep. 4, 171–180 (2015).

  146. 146.

    Kyttala, A. et al. Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Rep. 6, 200–212 (2016).

  147. 147.

    Kajiwara, M. et al. Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 109, 12538–12543 (2012).

  148. 148.

    Hockemeyer, D. & Jaenisch, R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573–586 (2016).

  149. 149.

    Chen, J. R. et al. Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation. Cell Death Differ. 23, 1347–1357 (2016).

  150. 150.

    Mandai, M., Kurimoto, Y. & Takahashi, M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 377, 792–793 (2017).

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Acknowledgements

The authors apologize to researchers whose studies could not be included owing to space constraints.

Reviewer information

Nature Reviews Genetics thanks J. Wu, L. Studer, C. Svendsen and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    • R. Grant Rowe
    •  & George Q. Daley

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Contributions

The authors contributed equally to all aspects of the article.

Competing interests

G.Q.D. holds intellectual property relevant to development of cell and drug therapies based on iPSC technology.

Corresponding author

Correspondence to George Q. Daley.

Glossary

Induced pluripotent stem cells

(iPSCs). Pluripotent cells derived from terminally differentiated somatic cells generated by reprogramming via introduction of a defined set of transcription factors.

Directed differentiation

The use of morphogens and environmental signals to direct the state of pluripotent cells towards a desired lineage.

Cell state conversion

The process by which a cell is converted from one identity to another, frequently via the expression of exogenous transcription factors.

Tissue engineering

The synthetic recapitulation of the cellular composition and matrix structure of a target tissue.

Xenotransplantation

The transplantation of cells from one species into a different species.

Morphogen

A growth factor or chemical signal that regulates cellular differentiation or tissue patterning.

Cas9

A bacterial DNA endonuclease that uses RNAs to localize and cleave targeted sequences within a genome. This enzyme has been exploited as a technology for precise genomic editing to introduce or correct specific genetic mutations in induced pluripotent stem cells.

Organ-on-a-chip

An experimental system in which tissue architecture and cellular composition are assembled on a fabricated synthetic matrix.

Batch effects

Variations between experimental replicates due to differences in cellular source or reagent lot.

Blasts

Undifferentiated, immature haematopoietic cells. They can be either rare, normal haematopoietic progenitors within healthy haematopoietic organs or transformed leukaemic cells arrested at an early state of differentiation.

Immunotherapy

A therapeutic approach using modulation of the immune system.

Chimeric antigen receptor T cells

(CAR T cells). Genetically manipulated T cells bearing a modified T cell receptor against a specific target.

Quantitative trait loci

(QTLs). DNA sequences whose variation contributes to the manifested heterogeneity of a quantitative polygenic trait.

Isogenic

A term to describe two cells, tissues or organisms that have the same genotype.

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DOI

https://doi.org/10.1038/s41576-019-0100-z