Review Article

Stem cells and genome editing: approaches to tissue regeneration and regenerative medicine

  • Journal of Human Geneticsvolume 63pages165178 (2018)
  • doi:10.1038/s10038-017-0348-0
  • Download Citation
Received:
Revised:
Accepted:
Published:

Subjects

Abstract

Understanding the basis of regeneration of each tissue and organ, and incorporating this knowledge into clinical treatments for degenerative tissues and organs in patients, are major goals for researchers in regenerative biology. Here we provide an overview of current work, from high-regeneration animal models, to stem cell-based culture models, transplantation technologies, large-animal chimeric models, and programmable nuclease-based genome-editing technologies. Three-dimensional culture generating organoids, which represents intact tissue/organ identity including cell fate and morphology are getting more general approaches in the fields by taking advantage of embryonic stem cells, induced pluripotent stem cells and adult stem cells. The organoid culture system potentially has profound impact on the field of regenerative medicine. We also emphasize that the large animal model, in particular pig model would be a hope to manufacture humanized organs in in vivo empty (vacant) niche, which now potentially allows not only appropriate cell fate identity but nearly the same property as human organs in size. Therefore, integrative and collaborative researches across different fields might be critical to the aims needed in clinical trial.

  • Subscribe to Journal of Human Genetics for full access:

    $421

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1

    Eiraku M, Sasai Y. Self-formation of layered neural structures in three-dimensional culture of ES cells. Curr Opin Neurobiol. 2012;22:768–77. https://doi.org/10.1016/j.conb.2012.02.005

  2. 2

    Sasai Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. Cell Stem Cell. 2013;12:520–30. https://doi.org/10.1016/j.stem.2013.04.009

  3. 3

    Sato T, Clevers H. SnapShot: growing organoids from stem cells. Cell. 2015;161:1700–1700.e1. https://doi.org/10.1016/j.cell.2015.06.028

  4. 4

    Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol. 2014;32:773–85. https://doi.org/10.1038/nbt.2958

  5. 5

    Song JJ, Ott HC. Organ engineering based on decellularized matrix scaffolds. Trends Mol Med. 2011;17:424–32. https://doi.org/10.1016/j.molmed.2011.03.005

  6. 6

    Soto-Gutierrez A, Wertheim JA, Ott HC, Gilbert TW. Perspectives on whole-organ assembly: moving toward transplantation on demand. J Clin Invest. 2012;122:3817–23. https://doi.org/10.1172/Jci61974

  7. 7

    Badylak SF, Taylor D, Uygun K. Whole-Organ Tissue Engineering: Decellularization and Recellularization of Three-Dimensional Matrix Scaffolds. Annu Rev Biomed Eng. 2011;13:27–53. https://doi.org/10.1146/annurev-bioeng-071910-124743

  8. 8

    Ekser B, Ezzelarab M, Hara H, van der Windt DJ, Wijkstrom M, Bottino R, et al. Clinical xenotransplantation: the next medical revolution? Lancet. 2012;379:672–83. https://doi.org/10.1016/S0140-6736(11)61091-X

  9. 9

    Sgroi A, Buhler LH, Morel P, Sykes M, Noel L. International human xenotransplantation inventory. Transplantation. 2010;90:597–603. https://doi.org/10.1097/TP.0b013e3181eb2e8c

  10. 10

    Cooper, D. K. A brief history of cross-species organ transplantation. Proc (Bayl Univ Med Cent). 2012;25:49-57.

  11. 11

    Peng Y, Clark KJ, Campbell JM, Panetta MR, Guo Y, Ekker SC. Making designer mutants in model organisms. Development. 2014;141:4042–54. https://doi.org/10.1242/dev.102186

  12. 12

    Cornu TI, Mussolino C, Cathomen T. Refining strategies to translate genome editing to the clinic. Nat Med. 2017;23:415–23. https://doi.org/10.1038/nm.4313

  13. 13

    Blasco RB, Karaca E, Ambrogio C, Cheong TC, Karayol E, Minero VG, et al. Simple and rapid in vivo generation of chromosomal rearrangements using CRISPR/Cas9 technology. Cell Reports. 2014;9:1219–27. https://doi.org/10.1016/j.celrep.2014.10.051

  14. 14

    Li Y, Park AI, Mou H, Colpan C, Bizhanova A, Akama-Garren E, et al. A versatile reporter system for CRISPR-mediated chromosomal rearrangements. Genome Biol. 2015;16:111. https://doi.org/10.1186/s13059-015-0680-7

  15. 15

    Jiang J, Zhang L, Zhou X, Chen X, Huang G, Li F, et al. Induction of site-specific chromosomal translocations in embryonic stem cells by CRISPR/Cas9. Sci Rep. 2016;6:21918. https://doi.org/10.1038/srep21918

  16. 16

    Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, et al. Editing DNA methylation in the mammalian genome. Cell. 2016;167:233–47.e217. https://doi.org/10.1016/j.cell.2016.08.056

  17. 17

    Epigenetics: CRISPR edits gene methylation. Nature 2016;537:588, https://doi.org/10.1038/537588c.

  18. 18

    Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33:510–7. https://doi.org/10.1038/nbt.3199

  19. 19

    Thakore PI, Black JB, Hilton IB, Gersbach CA. Editing the epigenome: technologies for programmable transcription and epigenetic modulation. Nat Methods. 2016;13:127–37. https://doi.org/10.1038/nmeth.3733

  20. 20

    Xu T, Li Y, Van Nostrand JD, He Z, Zhou J. Cas9-based tools for targeted genome editing and transcriptional control. Appl Environ Microbiol. 2014;80:1544–52. https://doi.org/10.1128/AEM.03786-13

  21. 21

    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21. https://doi.org/10.1126/science.1225829

  22. 22

    Ledford H. CRISPR, the disruptor. Nature. 2015;522:20–4. https://doi.org/10.1038/522020a

  23. 23

    Travis J. Making the cut. Science. 2015;350:1456–7. https://doi.org/10.1126/science.350.6267.1456

  24. 24

    Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide-sequence of the iap gene, responsible for alkaline-phosphatase isozyme conversion in Escherichia coli, and identification of the gene-product. J Bacteriol. 1987;169:5429–33.

  25. 25

    Sorek R, Kunin V, Hugenholtz P. CRISPR - a widespread system that provides acquired resistance against phages in bacteria and archaea. Nat Rev Microbiol. 2008;6:181–6. https://doi.org/10.1038/nrmicro1793

  26. 26

    Garneau JE, Dupuis ME, Villion M, Romero DA, Barrangou R, Boyaval P, et al. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature. 2010;468:67–+. https://doi.org/10.1038/nature09523

  27. 27

    Sander JD, Joung JK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol. 2014;32:347–55. https://doi.org/10.1038/nbt.2842

  28. 28

    Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346:1258096 https://doi.org/10.1126/science.1258096

  29. 29

    DiCarlo JE, Norville JE, Mali P, Rios X, Aach J, Church GM. Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Res. 2013;41:4336–43. https://doi.org/10.1093/nar/gkt135

  30. 30

    Bortesi L, Fischer R. The CRISPR/Cas9 system for plant genome editing and beyond. Biotechnol Adv. 2015;33:41–52. https://doi.org/10.1016/j.biotechadv.2014.12.006

  31. 31

    Dickinson DJ, Ward JD, Reiner DJ, Goldstein B. Engineering the Caenorhabditis elegans genome using Cas9-triggered homologous recombination. Nat Methods. 2013;10:1028–+. https://doi.org/10.1038/Nmeth.2641

  32. 32

    Bassett AR, Tibbit C, Ponting CP, Liu JL. Highly efficient targeted mutagenesis of Drosophila with the CRISPR/Cas9 system. Cell Rep. 2013;4:220–8. https://doi.org/10.1016/j.celrep.2013.06.020

  33. 33

    Awata H, Watanabe T, Hamanaka Y, Mito T, Noji S, Mizunami M. Knockout crickets for the study of learning and memory: dopamine receptor Dop1 mediates aversive but not appetitive reinforcement in crickets. Sci Rep. 2015;5:15885. https://doi.org/10.1038/srep15885

  34. 34

    Chang N, Sun C, Gao L, Zhu D, Xu X, Zhu X, et al. Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res. 2013;23:465–72. https://doi.org/10.1038/cr.2013.45

  35. 35

    Guo X, Zhang T, Hu Z, Zhang Y, Shi Z, Wang Q, et al. Efficient RNA/Cas9-mediated genome editing in Xenopus tropicalis. Development. 2014;141:707–14. https://doi.org/10.1242/dev.099853

  36. 36

    Wang HY, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153:910–8. https://doi.org/10.1016/j.cell.2013.04.025

  37. 37

    Yang H, Wang HY, Shivalila CS, Cheng AW, Shi LY, Jaenisch R. One-Step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell. 2013;154:1370–9. https://doi.org/10.1016/j.cell.2013.08.022

  38. 38

    Yang H, Wang HY, Jaenisch R. Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nat Protoc. 2014;9:1956–68. https://doi.org/10.1038/nprot.2014.134

  39. 39

    Cong L, Ran FA, Cox D, Lin SL, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23. https://doi.org/10.1126/science.1231143

  40. 40

    Mali P, Yang LH, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339:823–6. https://doi.org/10.1126/science.1232033

  41. 41

    Karl MO, Reh TA. Regenerative medicine for retinal diseases: activating endogenous repair mechanisms. Trends Mol Med. 2010;16:193–202. https://doi.org/10.1016/j.molmed.2010.02.003

  42. 42

    Ramachandran R, Zhao XF, Goldman D. Insm1a-mediated gene repression is essential for the formation and differentiation of Müller glia-derived progenitors in the injured retina. Nat Cell Biol. 2012;14:1013–+. https://doi.org/10.1038/ncb2586

  43. 43

    Wan J, Ramachandran R, Goldman D. HB-EGF is necessary and sufficient for Müller Glia dedifferentiation and retina regeneration. Dev Cell. 2012;22:334–47. https://doi.org/10.1016/j.devcel.2011.11.020

  44. 44

    Nagashima M, Barthel LK, Raymond PA. A self-renewing division of zebrafish Müller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons. Development. 2013;140:4510–21. https://doi.org/10.1242/dev.090738

  45. 45

    Jopling C, Sleep E, Raya M, Marti M, Raya A, Belmonte JCI. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464:606–9. https://doi.org/10.1038/nature08899

  46. 46

    Kikuchi K. Dedifferentiation, transdifferentiation, and proliferation: mechanisms underlying cardiac muscle regeneration in zebrafish. Curr Pathobiol Rep. 2015;3:81–8. https://doi.org/10.1007/s40139-015-0063-5

  47. 47

    Kikuchi K, Poss KD. Cardiac regenerative capacity and mechanisms. Annu Rev Cell Dev Biol. 2012;28:719–41. https://doi.org/10.1146/annurev-cellbio-101011-155739

  48. 48

    Gemberling M, Bailey TJ, Hyde DR, Poss KD. The zebrafish as a model for complex tissue regeneration. Trends Genet. 2013;29:611–20. https://doi.org/10.1016/j.tig.2013.07.003

  49. 49

    Hata S, Namae M, Nishina H. Liver development and regeneration: From laboratory study to clinical therapy. Dev Growth Differ. 2007;49:163–70. https://doi.org/10.1111/j.1440-169x.2007.00910.x

  50. 50

    Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331:1078–80. https://doi.org/10.1126/science.1200708

  51. 51

    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276:60–6.

  52. 52

    Kang J, Hu J, Karra R, Dickson AL, Tornini VA, Nachtrab G, et al. Modulation of tissue repair by regeneration enhancer elements. Nature. 2016;532:201–6. https://doi.org/10.1038/nature17644

  53. 53

    Seeger T, Porteus M, Wu JC. Genome editing in cardiovascular biology. Circ Res. 2017;120:778–80. https://doi.org/10.1161/CIRCRESAHA.116.310197

  54. 54

    Ail D, Perron M. Retinal degeneration and regeneration-lessons from fishes and amphibians. Curr Pathobiol Rep. 2017;5:67–78. https://doi.org/10.1007/s40139-017-0127-9

  55. 55

    Locker M, Borday C, Perron M. Stemness or not stemness? Current status and perspectives of adult retinal stem cells. Curr Stem Cell Res Ther. 2009;4:118–30.

  56. 56

    Lamba D, Karl M, Reh T. Neural regeneration and cell replacement: a view from the eye. Cell Stem Cell. 2008;2:538–49. https://doi.org/10.1016/j.stem.2008.05.002

  57. 57

    Stone LS, Steinitz H. Regeneration of neural retina and lens from retina pigment cell grafts in adult newts. J Exp Zool. 1957;135:301–17.

  58. 58

    Moshiri A, Close J, Reh TA. Retinal stem cells and regeneration. Int J Dev Biol. 2004;48:1003–14. https://doi.org/10.1387/ijdb.041870am

  59. 59

    Yasumuro H, Sakurai K, Toyama F, Maruo F, Chiba C. Implications of a multi-step trigger of retinal regeneration in the adult Newt. Biomedicines. 2017;5. https://doi.org/10.3390/biomedicines5020025.

  60. 60

    Merrell AJ, Stanger BZ. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol. 2016;17:413–25. https://doi.org/10.1038/nrm.2016.24

  61. 61

    Fischer AJ, Bosse JL, El-Hodiri HM. The ciliary marginal zone (CMZ) in development and regeneration of the vertebrate eye. Exp Eye Res. 2013;116:199–204. https://doi.org/10.1016/j.exer.2013.08.018

  62. 62

    Centanin L, Hoeckendorf B, Wittbrodt J. Fate restriction and multipotency in retinal stem cells. Cell Stem Cell. 2011;9:553–62. https://doi.org/10.1016/j.stem.2011.11.004

  63. 63

    Tropepe V, Coles BL, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, et al. Retinal stem cells in the adult mammalian eye. Science. 2000;287:2032–6.

  64. 64

    Coles BL, Angenieux B, Inoue T, Del Rio-Tsonis K, Spence JR, McInnes RR, et al. Facile isolation and the characterization of human retinal stem cells. Proc Natl Acad Sci USA. 2004;101:15772–7. https://doi.org/10.1073/pnas.0401596101

  65. 65

    Kuwahara A, Ozone C, Nakano T, Saito K, Eiraku M, Sasai Y. Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. Nat Commun. 2015;6:6286 https://doi.org/10.1038/ncomms7286

  66. 66

    Mitashov VI. Retinal regeneration in amphibians. Int J Dev Biol. 1997;41:893–905.

  67. 67

    Goldman D. Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci. 2014;15:431–42. https://doi.org/10.1038/nrn3723

  68. 68

    Young RW. Cell differentiation in the retina of the mouse. Anat Rec. 1985;212:199–205. https://doi.org/10.1002/ar.1092120215

  69. 69

    Ooto S, Akagi T, Kageyama R, Akita J, Mandai M, Honda Y, et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci USA. 2004;101:13654–9. https://doi.org/10.1073/pnas.0402129101

  70. 70

    Chohan A, Singh U, Kumar A, Kaur J. Müller stem cell dependent retinal regeneration. Clin Chim Acta. 2017;464:160–4. https://doi.org/10.1016/j.cca.2016.11.030

  71. 71

    Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signaling promotes regeneration in the retina of adult mammals. J Neurosci. 2007;27:4210–9. https://doi.org/10.1523/JNEUROSCI.4193-06.2007

  72. 72

    Suga A, Sadamoto K, Fujii M, Mandai M, Takahashi M. Proliferation potential of Müller glia after retinal damage varies between mouse strains. PLoS ONE. 2014;9:e94556. https://doi.org/10.1371/journal.pone.0094556

  73. 73

    Hamon A, Roger JE, Yang XJ, Perron M. Müller glial cell-dependent regeneration of the neural retina: an overview across vertebrate model systems. Dev Dyn. 2016;245:727–38. https://doi.org/10.1002/dvdy.24375

  74. 74

    Lust K, Sinn R, Perez Saturnino A, Centanin L, Wittbrodt J. De novo neurogenesis by targeted expression of atoh7 to Müller glia cells. Development. 2016;143:1874–83. https://doi.org/10.1242/dev.135905

  75. 75

    Nelson BR, Ueki Y, Reardon S, Karl MO, Georgi S, Hartman BH et al. Genome-wide analysis of Müller glial differentiation reveals a requirement for notch signaling in postmitotic cells to maintain the glial Fate. PLoS ONE. 2011;6. https://doi.org/10.1371/journal.pone.0022817

  76. 76

    Zelinka CP, Volkov L, Goodman ZA, Todd L, Palazzo I, Bishop WA, et al. mTor signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development. 2016;143:1859–73. https://doi.org/10.1242/dev.133215

  77. 77

    Powell C, Grant AR, Cornblath E, Goldman D. Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration. Proc Natl Acad Sci USA. 2013;110:19814–9. https://doi.org/10.1073/pnas.1312009110

  78. 78

    Jorstad NL, Wilken MS, Grimes WN, Wohl SG, VandenBosch LS, Yoshimatsu T, et al. Stimulation of functional neuronal regeneration from Müller glia in adult mice. Nature. 2017;548:103–7. https://doi.org/10.1038/nature23283

  79. 79

    Roesch K, Jadhav AP, Trimarchi JM, Stadler MB, Roska B, Sun BB, et al. The transcriptome of retinal Müller glial cells. J Comp Neurol. 2008;509:225–38. https://doi.org/10.1002/cne.21730

  80. 80

    Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim EJ, et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 2016;540:144–9. https://doi.org/10.1038/nature20565

  81. 81

    Krikorian AD, Berquam DL. Plant cell and tissue cultures - role of Haberlandt. Bot Rev. 1969;35:59–+. https://doi.org/10.1007/Bf02859888

  82. 82

    Thorpe TA. History of plant tissue culture. Mol Biotechnol. 2007;37:169–80.

  83. 83

    Sugiyama M. Historical review of research on plant cell dedifferentiation. J Plant Res. 2015;128:349–59. https://doi.org/10.1007/s10265-015-0706-y

  84. 84

    Wilson HV. A new method by which sponges may be artificially reared. Science. 1907;25:912–5. https://doi.org/10.1126/science.25.649.912

  85. 85

    Weiss P, Taylor AC. Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation. Proc Natl Acad Sci USA. 1960;46:1177–85.

  86. 86

    Pierce GB Jr, Dixon FJ Jr, Verney EL. Teratocarcinogenic and tissue-forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest. 1960;9:583–602.

  87. 87

    Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975;6:331–43.

  88. 88

    Rheinwald JG, Green H. Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma. Cell. 1975;6:317–30.

  89. 89

    Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345. https://doi.org/10.1126/science.1247125

  90. 90

    Clevers H. Modeling development and disease with organoids. Cell. 2016;165:1586–97. https://doi.org/10.1016/j.cell.2016.05.082

  91. 91

    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. https://doi.org/10.1016/j.cell.2006.07.024

  92. 92

    Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2017;16:115–30. https://doi.org/10.1038/nrd.2016.245

  93. 93

    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72. https://doi.org/10.1016/j.cell.2007.11.019

  94. 94

    Zhou H, Martinez H, Sun B, Li A, Zimmer M, Katsanis N, et al. Rapid and efficient generation of transgene-free iPSC from a small volume of cryopreserved blood. Stem Cell Rev. 2015;11:652–65. https://doi.org/10.1007/s12015-015-9586-8

  95. 95

    Agu CA, Soares FAC, Alderton A, Patel M, Ansari R, Patel S, et al. Successful generation of human induced pluripotent stem cell lines from blood samples held at room temperature for up to 48 hr. Stem Cell Rep. 2015;5:660–71. https://doi.org/10.1016/j.stemcr.2015.08.012

  96. 96

    Hu Q, Friedrich AM, Johnson LV, Clegg DO. Memory in induced pluripotent stem cells: reprogrammed human retinal-pigmented epithelial cells show tendency for spontaneous redifferentiation. Stem Cells. 2010;28:1981–91. https://doi.org/10.1002/stem.531

  97. 97

    Hiler D, Chen X, Hazen J, Kupriyanov S, Carroll PA, Qu C, et al. Quantification of Retinogenesis in 3D cultures reveals epigenetic memory and higher efficiency in iPSCs derived from rod photoreceptors. Cell Stem Cell. 2015;17:101–15. https://doi.org/10.1016/j.stem.2015.05.015

  98. 98

    Hiler DJ, Barabas ME, Griffiths LM, Dyer MA. Reprogramming of mouse retinal neurons and standardized quantification of their differentiation in 3D retinal cultures. Nat Protoc. 2016;11:1955–76. https://doi.org/10.1038/nprot.2016.109

  99. 99

    Yamanaka S. A fresh look at iPS cells. Cell. 2009;137:13–7. https://doi.org/10.1016/j.cell.2009.03.034

  100. 100

    Mandai M, Fujii M, Hashiguchi T, Sunagawa GA, Ito S, Sun JN, et al. iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice (vol 8, pg 69, 2017). Stem Cell Rep. 2017;8:1112–3. https://doi.org/10.1016/j.stemcr.2017.03.024

  101. 101

    Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385:509–16. https://doi.org/10.1016/S0140-6736(14)61376-3

  102. 102

    Schwartz SD, Tan G, Hosseini H, Nagiel A. Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: an assessment at 4 years. Invest Ophth Vis Sci. 2016;57. https://doi.org/10.1167/iovs.15-18681.

  103. 103

    Chiba C. The retinal pigment epithelium: an important player of retinal disorders and regeneration. Exp Eye Res. 2014;123:107–14. https://doi.org/10.1016/j.exer.2013.07.009

  104. 104

    Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017;376:1038–46. https://doi.org/10.1056/NEJMoa1608368

  105. 105

    Galdos FX, Guo YX, Paige SL, VanDusen NJ, Wu SM, Pu WT. Cardiac regeneration lessons from development. Circ Res. 2017;120:941–59. https://doi.org/10.1161/Circresaha.116.309040

  106. 106

    Doppler SA, Deutsch MA, Serpooshan V, Li G, Dzilic E, Lange R, et al. Mammalian heart regeneration the race to the finish line. Circ Res. 2017;120:630–2. https://doi.org/10.1161/Circresaha.116.310051

  107. 107

    Matsuo T, Masumoto H, Tajima S, Ikuno T, Katayama S, Minakata K, et al. Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells. Sci Rep. 2015;5:16842. https://doi.org/10.1038/srep16842

  108. 108

    Nakane T, Masumoto H, Tinney JP, Yuan F, Kowalski WJ, Ye F, et al. Impact of cell composition and geometry on human induced pluripotent stem cells-derived engineered cardiac tissue. Sci Rep. 2017;7:45641. https://doi.org/10.1038/srep45641

  109. 109

    Yamashita JK. ES and iPS cell research for cardiovascular regeneration. Exp Cell Res. 2010;316:2555–9. https://doi.org/10.1016/j.yexcr.2010.04.004

  110. 110

    Masumoto H, Yamashita JK. Human iPS cell-derived cardiac tissue sheets: a platform for cardiac regeneration. Curr Treat Options Cardiovasc Med. 2016;18:65 https://doi.org/10.1007/s11936-016-0489-z

  111. 111

    Shkumatov A, Baek K, Kong H. Matrix rigidity-modulated cardiovascular organoid formation from embryoid bodies. PLoS ONE. 2014;9:e94764. https://doi.org/10.1371/journal.pone.0094764

  112. 112

    McCracken KW, Cata EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE, et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature. 2014;516:400–4. https://doi.org/10.1038/nature13863

  113. 113

    Qian XY, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165:1238–54. https://doi.org/10.1016/j.cell.2016.04.032

  114. 114

    Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–+. https://doi.org/10.1038/nature12517

  115. 115

    Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521:43–7. https://doi.org/10.1038/nature14415

  116. 116

    Soldatow VY, Lecluyse EL, Griffith LG, Rusyn I. In vitro models for liver toxicity testing. Toxicol Res. 2013;2:23–39. https://doi.org/10.1039/C2TX20051A

  117. 117

    Nantasanti S, de Bruin A, Rothuizen J, Penning LC, Schotanus BA. Concise review: organoids are a powerful tool for the study of liver disease and personalized treatment design in humans and animals. Stem Cells Transl Med. 2016;5:325–30. https://doi.org/10.5966/sctm.2015-0152

  118. 118

    Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol. 2016;17:170–82. https://doi.org/10.1038/nrm.2015.27

  119. 119

    Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10:771–85. https://doi.org/10.1016/j.stem.2012.05.009

  120. 120

    Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015;526:564–8. https://doi.org/10.1038/nature15695

  121. 121

    McCauley HA, Wells JM. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development. 2017;144:958–62. https://doi.org/10.1242/dev.140731

  122. 122

    Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D, Fish JL, et al. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci. 2010;13:690–9. https://doi.org/10.1038/nn.2553

  123. 123

    Hansen DV, Lui JH, Parker PR, Kriegstein AR. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature. 2010;464:554–61. https://doi.org/10.1038/nature08845

  124. 124

    Smart IH, Dehay C, Giroud P, Berland M, Kennedy H. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb Cortex. 2002;12:37–53.

  125. 125

    Shitamukai A, Konno D, Matsuzaki F. Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J Neurosci. 2011;31:3683–95. https://doi.org/10.1523/JNEUROSCI.4773-10.2011

  126. 126

    Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell. 2008;3:519–32. https://doi.org/10.1016/j.stem.2008.09.002

  127. 127

    Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci USA. 2013;110:20284–9. https://doi.org/10.1073/pnas.1315710110

  128. 128

    Nasu M, Takata N, Danjo T, Sakaguchi H, Kadoshima T, Futaki S, et al. Robust formation and maintenance of continuous stratified cortical neuroepithelium by laminin-containing matrix in mouse ES cell culture. PLoS ONE. 2012;7:e53024. https://doi.org/10.1371/journal.pone.0053024

  129. 129

    Kelava I, Lancaster MA. Dishing out mini-brains: current progress and future prospects in brain organoid research. Dev Biol. 2016;420:199–209. https://doi.org/10.1016/j.ydbio.2016.06.037

  130. 130

    Savic N, Schwank G. Advances in therapeutic CRISPR/Cas9 genome editing. Transl Res. 2016;168:15–21. https://doi.org/10.1016/j.trsl.2015.09.008

  131. 131

    Hockemeyer D, Jaenisch R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell. 2016;18:573–86. https://doi.org/10.1016/j.stem.2016.04.013

  132. 132

    Wataya T, Ando S, Muguruma K, Ikeda H, Watanabe K, Eiraku M, et al. Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation. Proc Natl Acad Sci USA. 2008;105:11796–801. https://doi.org/10.1073/pnas.0803078105

  133. 133

    Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472:51–6. https://doi.org/10.1038/nature09941

  134. 134

    Sasai Y. Grow your own eye: biologists have coaxed cells to form a retina, a step toward growing replacement organs outside the body. Sci Am. 2012;307:44–9.

  135. 135

    Suga H, Kadoshima T, Minaguchi M, Ohgushi M, Soen M, Nakano T, et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature. 2011;480:57–62. https://doi.org/10.1038/nature10637

  136. 136

    Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. 2015;6:8896 https://doi.org/10.1038/ncomms9896

  137. 137

    Ozone C, Suga H, Eiraku M, Kadoshima T, Yonemura S, Takata N, et al. Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat Commun. 2016;7:10351. https://doi.org/10.1038/ncomms10351

  138. 138

    Takata N, Sakakura E, Kasukawa T, Sakuma T, Yamamoto T, Sasai Y. Establishment of functional genomics pipeline in mouse epiblast-like tissue by combining transcriptomic analysis and gene knockdown/knockin/knockout, using RNA interference and CRISPR/Cas9. Hum Gene Ther. 2016;27:436–50. https://doi.org/10.1089/hum.2015.148

  139. 139

    Takata N, Sakakura E, Sasai Y. IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro. In Vitro Cell Dev Biol Anim. 2016;52:607–15. https://doi.org/10.1007/s11626-016-0012-6

  140. 140

    Nie J, Hashino E. Organoid technologies meet genome engineering. EMBO Rep. 2017;18:367–76. https://doi.org/10.15252/embr.201643732

  141. 141

    Brookhouser N, Raman S, Potts C, Brafman DA. May I cut in? gene editing approaches in human induced pluripotent stem cells. Cells. 2017;6. https://doi.org/10.3390/cells6010005.

  142. 142

    Verma N, Zhu Z, Huangfu D. CRISPR/cas-mediated knockin in human pluripotent stem cells. Methods Mol Biol. 2017;1513:119–40. https://doi.org/10.1007/978-1-4939-6539-7_9

  143. 143

    Blair JD, Bateup HS, Hockemeyer DF. Establishment of genome-edited human pluripotent stem cell lines: from targeting to isolation. J Vis Exp. 2016;e53583. https://doi.org/10.3791/53583.

  144. 144

    Sluch VM, Davis CHO, Ranganathan V, Kerr JM, Krick K, Martin R et al. Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line. Sci Rep. 2015;5. https://doi.org/10.1038/srep16595

  145. 145

    Homma K, Usui S, Kaneda M. Knock-in strategy at 3’-end of Crx gene by CRISPR/Cas9 system shows the gene expression profiles during human photoreceptor differentiation. Genes Cells. 2017;22:250–64. https://doi.org/10.1111/gtc.12472

  146. 146

    Sasai Y. Cytosystems dynamics in self-organization of tissue architecture. Nature. 2013;493:318–26. https://doi.org/10.1038/nature11859

  147. 147

    Sasai Y, Eiraku M, Suga H. In vitro organogenesis in three dimensions: self-organising stem cells. Development. 2012;139:4111–21. https://doi.org/10.1242/dev.079590

  148. 148

    Sakakura E, Eiraku M, Takata N. Specification of embryonic stem cell-derived tissues into eye fields by Wnt signaling using rostral diencephalic tissue-inducing culture. Mech Develop. 2016;141:90–9. https://doi.org/10.1016/j.mod.2016.05.001

  149. 149

    Eiraku M, Adachi T, Sasai Y. Relaxation-expansion model for self-driven retinal morphogenesis: a hypothesis from the perspective of biosystems dynamics at the multi-cellular level. Bioessays. 2012;34:17–25. https://doi.org/10.1002/bies.201100070

  150. 150

    Hasegawa Y, Takata N, Okuda S, Kawada M, Eiraku M, Sasai Y. Emergence of dorsal-ventral polarity in ESC-derived retinal tissue. Development. 2016;143:3895–906. https://doi.org/10.1242/dev.134601

  151. 151

    Andrabi M, Kuraku S, Takata N, Sasai Y, Love NR. Comparative, transcriptome analysis of self-organizing optic tissues. Sci Data. 2015;2. https://doi.org/10.1038/sdata.2015.30.

  152. 152

    Drost J, Clevers H. Translational applications of adult stem cell-derived organoids. Development. 2017;144:968–75. https://doi.org/10.1242/dev.140566

  153. 153

    Huch M, Boj SF, Clevers H. Lgr5(+) liver stem cells, hepatic organoids and regenerative medicine. Regen Med. 2013;8:385–7. https://doi.org/10.2217/rme.13.39

  154. 154

    Huch M, Koo BK. Modeling mouse and human development using organoid cultures. Development. 2015;142:3113–25. https://doi.org/10.1242/dev.118570

  155. 155

    Boj SF, Hwang CI, Baker LA, Chio IIC, Engle DD, Corbo V, et al. Organoid models of human and mouse ductal pancreatic. Cancer Cell. 2015;160:324–38. https://doi.org/10.1016/j.cell.2014.12.021

  156. 156

    Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJM, van de Wetering M, et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 2013;32:2708–21. https://doi.org/10.1038/emboj.2013.204

  157. 157

    Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36. https://doi.org/10.1016/j.stem.2009.11.013

  158. 158

    Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H, Kujala P, et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology. 2015;148:126–136.e6. https://doi.org/10.1053/j.gastro.2014.09.042

  159. 159

    Kessler M, Hoffmann K, Brinkmann V, Thieck O, Jackisch S, Toelle B et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat Commun. 2015;6. https://doi.org/10.1038/ncomms9989

  160. 160

    Chua CW, Shibata M, Lei M, Toivanen R, Barlow LJ, Bergren SK, et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol. 2014;16:951–61. https://doi.org/10.1038/ncb3047

  161. 161

    Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 2014;159:163–75. https://doi.org/10.1016/j.cell.2014.08.017

  162. 162

    Ren W, Lewandowski BC, Watson J, Aihara E, Iwatsuki K, Bachmanov AA, et al. Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc Natl Acad Sci USA. 2014;111:16401–6. https://doi.org/10.1073/pnas.1409064111

  163. 163

    Maimets M, Rocchi C, Bron R, Pringle S, Kuipers J, Giepmans BN, et al. Long-term in vitro expansion of salivary gland stem cells driven by Wnt signals. Stem Cell Rep. 2016;6:150–62. https://doi.org/10.1016/j.stemcr.2015.11.009

  164. 164

    Clevers H. What is an adult stem cell? Science. 2015;350:1319–20. https://doi.org/10.1126/science.aad7016

  165. 165

    Dutta D, Heo I, Clevers H. Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med. 2017. https://doi.org/10.1016/j.molmed.2017.02.007.

  166. 166

    Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13:653–8. https://doi.org/10.1016/j.stem.2013.11.002

  167. 167

    Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5(+) stem cell. Nat Med. 2012;18:618–23. https://doi.org/10.1038/nm.2695

  168. 168

    Fordham RP, Yui S, Hannan NR, Soendergaard C, Madgwick A, Schweiger PJ, et al. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell. 2013;13:734–44. https://doi.org/10.1016/j.stem.2013.09.015

  169. 169

    Fukuda M, Mizutani T, Mochizuki W, Matsumoto T, Nozaki K, Sakamaki Y, et al. Small intestinal stem cell identity is maintained with functional Paneth cells in heterotopically grafted epithelium onto the colon. Gene Dev. 2014;28:1752–7. https://doi.org/10.1101/gad.245233.114

  170. 170

    Nakamura T, Watanabe M. Intestinal stem cell transplantation. J Gastroenterol. 2017;52:151–7. https://doi.org/10.1007/s00535-016-1288-8

  171. 171

    Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481–4. https://doi.org/10.1038/nature12271

  172. 172

    Takebe T, Zhang RR, Koike H, Kimura M, Yoshizawa E, Enomura M, et al. Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nat Protoc. 2014;9:396–409. https://doi.org/10.1038/nprot.2014.020

  173. 173

    Takebe T, Enomura M, Yoshizawa E, Kimura M, Koike H, Ueno Y, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell. 2015;16:556–65. https://doi.org/10.1016/j.stem.2015.03.004

  174. 174

    Ottone C, Krusche B, Whitby A, Clements M, Quadrato G, Pitulescu ME, et al. Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. Nat Cell Biol. 2014;16:1045–+. https://doi.org/10.1038/ncb3045

  175. 175

    Goldberg JS, Hirschi KK. Diverse roles of the vasculature within the neural stem cell niche. Regen Med. 2009;4:879–97. https://doi.org/10.2217/Rme.09.61

  176. 176

    Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 2008;3:279–88. https://doi.org/10.1016/j.stem.2008.07.025

  177. 177

    Rafii S, Butler JM, Ding BS. Angiocrine functions of organ-specific endothelial cells. Nature. 2016;529:316–25. https://doi.org/10.1038/nature17040

  178. 178

    Whitelaw CB, Sheets TP, Lillico SG, Telugu BP. Engineering large animal models of human disease. J Pathol. 2016;238:247–56. https://doi.org/10.1002/path.4648

  179. 179

    Le Douarin NM. The ontogeny of the neural crest in avian embryo chimaeras. Nature. 1980;286:663–9.

  180. 180

    Gardner RL, Johnson MH. Investigation of early mammalian development using interspecific chimaeras between rat and mouse. Nat New Biol. 1973;246:86–9.

  181. 181

    Fehilly CB, Willadsen SM, Tucker EM. Interspecific chimaerism between sheep and goat. Nature. 1984;307:634–6. https://doi.org/10.1038/307634a0

  182. 182

    Williams TJ, Munro RK, Shelton JN. Production of interspecies chimeric calves by aggregation of Bos indicus and Bos taurus demi-embryos. Reprod Fertil Dev. 1990;2:385–94.

  183. 183

    Rossant J, Frels WI. Interspecific chimeras in mammals - successful production of live chimeras between mus-musculus and mus-caroli. Science. 1980;208:419–21. https://doi.org/10.1126/science.7367871

  184. 184

    Rossant J, Croy BA, Chapman VM, Siracusa L, Clark DA. Interspecific chimeras in mammals: a new experimental system. J Anim Sci. 1982;55:1241–8.

  185. 185

    Rossant J, Mauro VM, Croy BA. Importance of trophoblast genotype for survival of interspecific murine chimaeras. J Embryol Exp Morphol. 1982;69:141–9.

  186. 186

    Suchy F, Nakauchi H. Lessons from interspecies mammalian chimeras. Annu Rev Cell Dev Biol. 2017. https://doi.org/10.1146/annurev-cellbio-100616-060654.

  187. 187

    Aigner B, Renner S, Kessler B, Klymiuk N, Kurome M, Wunsch A, et al. Transgenic pigs as models for translational biomedical research. J Mol Med. 2010;88:653–64. https://doi.org/10.1007/s00109-010-0610-9

  188. 188

    Prather RS, Lorson M, Ross JW, Whyte JJ, Walters E. Genetically engineered pig models for human diseases. Annu Rev Anim Biosci. 2013;1:203–19. https://doi.org/10.1146/annurev-animal-031412-103715

  189. 189

    Flisikowska T, Kind A, Schnieke A. Genetically modified pigs to model human diseases. J Appl Genet. 2014;55:53–64. https://doi.org/10.1007/s13353-013-0182-9

  190. 190

    Feng W, Dai Y, Mou L, Cooper DK, Shi D, Cai Z. The potential of the combination of CRISPR/Cas9 and pluripotent stem cells to provide human organs from chimaeric pigs. Int J Mol Sci. 2015;16:6545–56. https://doi.org/10.3390/ijms16036545

  191. 191

    Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell. 2010;142:787–99. https://doi.org/10.1016/j.cell.2010.07.039

  192. 192

    Usui J, Kobayashi T, Yamaguchi T, Knisely AS, Nishinakamura R, Nakauchi H. Generation of kidney from pluripotent stem cells via blastocyst complementation. Am J Pathol. 2012;180:2417–26. https://doi.org/10.1016/j.ajpath.2012.03.007

  193. 193

    Yamaguchi T, Sato H, Kato-Itoh M, Goto T, Hara H, Sanbo M, et al. Interspecies organogenesis generates autologous functional islets. Nature. 2017;542:191–6. https://doi.org/10.1038/nature21070

  194. 194

    Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc Natl Acad Sci USA. 2013;110:4557–62. https://doi.org/10.1073/pnas.1222902110

  195. 195

    Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, et al. Interspecies chimerism with mammalian pluripotent stem cells. Cell. 2017;168:473–486.e415. https://doi.org/10.1016/j.cell.2016.12.036

  196. 196

    Lee K, Kwon DN, Ezashi T, Choi YJ, Park C, Ericsson AC, et al. Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. Proc Natl Acad Sci USA. 2014;111:7260–5. https://doi.org/10.1073/pnas.1406376111

  197. 197

    Rashid T, Kobayashi T, Nakauchi H. Revisiting the flight of Icarus: making human organs from PSCs with large animal chimeras. Cell Stem Cell. 2014;15:406–9. https://doi.org/10.1016/j.stem.2014.09.013

  198. 198

    Sheets TP, Park CH, Park KE, Powell A, Donovan DM, Telugu BP. Somatic cell nuclear transfer followed by CRIPSR/Cas9 microinjection results in highly efficient genome editing in cloned pigs. Int J Mol Sci. 2016;17. https://doi.org/10.3390/ijms17122031.

  199. 199

    Hai T, Teng F, Guo R, Li W, Zhou Q. One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Res. 2014;24:372–5. https://doi.org/10.1038/cr.2014.11

  200. 200

    Whitworth KM, Lee K, Benne JA, Beaton BP, Spate LD, Murphy SL, et al. Use of the CRISPR/Cas9 system to produce genetically engineered pigs from in vitro-derived oocytes and embryos. Biol Reprod. 2014;91. https://doi.org/10.1095/biolreprod.114.121723 doi:ARTN 7810.1095/biolreprod.114.121723.

  201. 201

    Casal M, Haskins M. Large animal models and gene therapy. Eur J Hum Genet. 2006;14:266–72. https://doi.org/10.1038/sj.ejhg.5201535

  202. 202

    Camus S, Ko WK, Pioli E, Bezard E. Why bother using non-human primate models of cognitive disorders in translational research? Neurobiol Learn Mem. 2015;124:123–9. https://doi.org/10.1016/j.nlm.2015.06.012

  203. 203

    Yao J, Huang J, Zhao J. Genome editing revolutionize the creation of genetically modified pigs for modeling human diseases. Hum Genet. 2016;135:1093–105. https://doi.org/10.1007/s00439-016-1710-6

  204. 204

    Yum SY, Yoon KY, Lee CI, Lee BC, Jang G. Transgenesis for pig models. J Vet Sci. 2016;17:261–8. https://doi.org/10.4142/jvs.2016.17.3.261

  205. 205

    Butler JR, Ladowski JM, Martens GR, Tector M, Tector AJ. Recent advances in genome editing and creation of genetically modified pigs. Int J Surg. 2015;23:217–22. https://doi.org/10.1016/j.ijsu.2015.07.684

  206. 206

    Zhou X, Xin J, Fan N, Zou Q, Huang J, Ouyang Z, et al. Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer. Cell Mol Life Sci. 2015;72:1175–84. https://doi.org/10.1007/s00018-014-1744-7

  207. 207

    Tan WS, Carlson DF, Walton MW, Fahrenkrug SC, Hackett PB. Precision editing of large animal genomes. Adv Genet. 2012;80:37–97. https://doi.org/10.1016/B978-0-12-404742-6.00002-8

  208. 208

    Tanihara F, Takemoto T, Kitagawa E, Rao S, Do LT, Onishi A, et al. Somatic cell reprogramming-free generation of genetically modified pigs. Sci Adv. 2016;2:e1600803. https://doi.org/10.1126/sciadv.1600803

  209. 209

    Shaw D, Dondorp W, Geijsen N, de Wert G. Creating human organs in chimaera pigs: an ethical source of immunocompatible organs? J Med Ethics. 2015;41:970–4. https://doi.org/10.1136/medethics-2014-102224

Download references

Acknowledgements

We thank Dr. G. Oliver for the informative knowledge. We also thank M. Oxendine for his careful English proofreading. This work was supported by JSPS KAKENHI Grant Number 26112723 (to M.E.).

Author information

Affiliations

  1. Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University, 303 East Superior Street, Chicago, IL, 60611, USA

    • Nozomu Takata
  2. Laboratory for In Vitro Histogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    • Nozomu Takata
    •  & Mototsugu Eiraku
  3. Laboratory of Developmental Systems, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan

    • Mototsugu Eiraku

Authors

  1. Search for Nozomu Takata in:

  2. Search for Mototsugu Eiraku in:

Contributions

N.T. prepared the figures and wrote the manuscript. M.E. supervised the figure preparation and the manuscript writing.

Conflict of interest

The authors declare that they have no competing interests.

Corresponding authors

Correspondence to Nozomu Takata or Mototsugu Eiraku.