1932

Abstract

Human kidney tissue can now be generated via the directed differentiation of human pluripotent stem cells. This advance is anticipated to facilitate the modeling of human kidney diseases, provide platforms for nephrotoxicity screening, enable cellular therapy, and potentially generate tissue for renal replacement. All such applications will rely upon the accuracy and reliability of the model and the capacity for stem cell–derived kidney tissue to recapitulate both normal and diseased states. In this review, we discuss the models available, how well they recapitulate the human kidney, and how far we are from application of these cells for use in cellular therapies.

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2019-02-10
2024-06-23
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Literature Cited

  1. 1.  Martin GR. 1981. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. PNAS 78:7634–38
    [Google Scholar]
  2. 2.  Evans MJ, Kaufman MH 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–56
    [Google Scholar]
  3. 3.  Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ et al. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145–47
    [Google Scholar]
  4. 4.  Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–72
    [Google Scholar]
  5. 5.  Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL et al. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–20
    [Google Scholar]
  6. 6.  Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE 2011. Human nephron number: implications for health and disease. Pediatr. Nephrol. 26:1529–33
    [Google Scholar]
  7. 7.  Boyle S, Misfeldt A, Chandler KJ, Deal KK, Southard-Smith EM et al. 2008. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev. Biol. 313:234–45
    [Google Scholar]
  8. 8.  Brunskill EW, Aronow BJ, Georgas K, Rumballe B, Valerius MT et al. 2008. Atlas of gene expression in the developing kidney at microanatomic resolution. Dev. Cell 15:781–91
    [Google Scholar]
  9. 9.  Kobayashi A, Valerius MT, Mugford JW, Carroll TJ, Self M et al. 2008. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3:169–81
    [Google Scholar]
  10. 10.  Short KM, Combes AN, Lefevre J, Ju AL, Georgas KM et al. 2014. Global quantification of tissue dynamics in the developing mouse kidney. Dev. Cell 29:188–202
    [Google Scholar]
  11. 11.  Little MH. 2015. Improving our resolution of kidney morphogenesis across time and space. Curr. Opin. Genet. Dev. 32:135–43
    [Google Scholar]
  12. 12.  Ryan D, Sutherland MR, Flores TJ, Kent AL, Dahlstrom JE et al. 2018. Development of the human fetal kidney from mid to late gestation in male and female infants. EBioMedicine 27:275–83
    [Google Scholar]
  13. 13.  Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D 1991. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab. Investig. 64:777–84
    [Google Scholar]
  14. 14.  Hammerman MR. 2011. Xenotransplantation of embryonic pig kidney or pancreas to replace the function of mature organs. J. Transplant. 2011:501749
    [Google Scholar]
  15. 15.  Rumballe BA, Georgas KM, Combes AN, Ju AL, Gilbert T, Little MH 2011. Nephron formation adopts a novel spatial topology at cessation of nephrogenesis. Dev. Biol. 360:110–22
    [Google Scholar]
  16. 16.  Park J, Shrestha R, Qiu C, Kondo A, Huang S et al. 2018. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758–63
    [Google Scholar]
  17. 17.  Little MH, Brennan J, Georgas K, Davies JA, Davidson DR et al. 2007. A high-resolution anatomical ontology of the developing murine genitourinary tract. Gene Expr. Patterns 7:680–99
    [Google Scholar]
  18. 18.  Takasato M, Little MH 2015. The origin of the mammalian kidney: implications for recreating the kidney in vitro. Development 142:1937–47
    [Google Scholar]
  19. 19.  Torres M, Gómez-Pardo E, Dressler GR, Gruss P 1995. Pax-2 controls multiple steps of urogenital development. Development 121:4057–65
    [Google Scholar]
  20. 20.  Georgas KM, Chiu HS, Lesieur E, Rumballe BA, Little MH 2011. Expression of metanephric nephron-patterning genes in differentiating mesonephric tubules. Dev. Dyn. 240:1600–12
    [Google Scholar]
  21. 21.  Vazquez MD, Bouchet P, Mallet JL, Foliguet B, Gerard H, LeHeup B 1998. 3D reconstruction of the mouse's mesonephros. Anat. Histol. Embryol. 27:283–87
    [Google Scholar]
  22. 22.  Little MH, McMahon AP 2012. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb. Perspect. Biol. 4:a008300
    [Google Scholar]
  23. 23.  Georgas K, Rumballe B, Valerius MT, Chiu HS, Thiagarajan RD et al. 2009. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment. Dev. Biol. 332:273–86
    [Google Scholar]
  24. 24.  Sequeira-Lopez ML, Lin EE, Li M, Hu Y, Sigmund CD, Gomez RA 2015. The earliest metanephric arteriolar progenitors and their role in kidney vascular development. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308:R138–49
    [Google Scholar]
  25. 25.  Rae F, Woods K, Sasmono T, Campanale N, Taylor D et al. 2007. Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev. Biol. 308:232–46
    [Google Scholar]
  26. 26.  Kobayashi A, Mugford JW, Krautzberger AM, Naiman N, Liao J, McMahon AP 2014. Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis. Stem Cell Rep 3:650–62
    [Google Scholar]
  27. 27.  Bohnenpoll T, Bettenhausen E, Weiss AC, Foik AB, Trowe MO et al. 2013. Tbx18 expression demarcates multipotent precursor populations in the developing urogenital system but is exclusively required within the ureteric mesenchymal lineage to suppress a renal stromal fate. Dev. Biol. 380:25–36
    [Google Scholar]
  28. 28.  Karner CM, Das A, Ma Z, Self M, Chen C et al. 2011. Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development 138:1247–57
    [Google Scholar]
  29. 29.  Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP 2005. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev. Cell 9:283–92
    [Google Scholar]
  30. 30.  Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J et al. 2012. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22:1191–207
    [Google Scholar]
  31. 31.  Brown AC, Muthukrishnan SD, Oxburgh L 2015. A synthetic niche for nephron progenitor cells. Dev. Cell 34:229–41
    [Google Scholar]
  32. 32.  Li Z, Araoka T, Wu J, Liao HK, Li M et al. 2016. 3D culture supports long-term expansion of mouse and human nephrogenic progenitors. Cell Stem Cell 19:516–29
    [Google Scholar]
  33. 33.  Tanigawa S, Taguchi A, Sharma N, Perantoni AO, Nishinakamura R 2016. Selective in vitro propagation of nephron progenitors derived from embryos and pluripotent stem cells. Cell Rep 15:801–13
    [Google Scholar]
  34. 34.  Costantini F, Kopan R 2010. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev. Cell 18:698–712
    [Google Scholar]
  35. 35.  Lindström NO, Guo J, Kim AD, Tran T, Guo Q et al. 2018. Conserved and divergent features of mesenchymal progenitor cell types within the cortical nephrogenic niche of the human and mouse kidney. J. Am. Soc. Nephrol. 29:806–24
    [Google Scholar]
  36. 36.  Lindström NO, McMahon JA, Guo J, Tran T, Guo Q et al. 2018. Conserved and divergent features of human and mouse kidney organogenesis. J. Am. Soc. Nephrol. 29:785–805
    [Google Scholar]
  37. 37.  Lindström NO, Tran T, Guo J, Rutledge E, Parvez RK et al. 2018. Conserved and divergent molecular and anatomic features of human and mouse nephron patterning. J. Am. Soc. Nephrol. 29:825–40
    [Google Scholar]
  38. 38.  Lin SA, Kolle G, Grimmond SM, Zhou Q, Doust E et al. 2010. Subfractionation of differentiating human embryonic stem cell populations allows the isolation of a mesodermal population enriched for intermediate mesoderm and putative renal progenitors. Stem Cells Dev 19:1637–48
    [Google Scholar]
  39. 39.  Odorico JS, Kaufman DS, Thomson JA 2001. Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19:193–204
    [Google Scholar]
  40. 40.  Murry CE, Keller G 2008. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132:661–80
    [Google Scholar]
  41. 41.  Taguchi A, Kaku Y, Ohmori T, Sharmin S, Ogawa M et al. 2014. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell 14:53–67
    [Google Scholar]
  42. 42.  Takasato M, Er PX, Becroft M, Vanslambrouck JM, Stanley EG et al. 2014. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16:118–26
    [Google Scholar]
  43. 43.  Takasato M, Er PX, Chiu HS, Little MH 2016. Generation of kidney organoids from human pluripotent stem cells. Nat. Protoc. 11:1681–92
    [Google Scholar]
  44. 44.  Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ et al. 2015. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:564–68
    [Google Scholar]
  45. 45.  Ader M, Tanaka EM 2014. Modeling human development in 3D culture. Curr. Opin. Cell Biol. 31:23–28
    [Google Scholar]
  46. 46.  Morizane R, Lam AQ, Freedman BS, Kishi S, Valerius MT, Bonventre JV 2015. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33:1193–200
    [Google Scholar]
  47. 47.  Morizane R, Bonventre JV 2017. Generation of nephron progenitor cells and kidney organoids from human pluripotent stem cells. Nat. Protoc. 12:195–207
    [Google Scholar]
  48. 48.  Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R et al. 2015. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat. Commun. 6:8715
    [Google Scholar]
  49. 49.  Taguchi A, Nishinakamura R 2017. Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21:730–46.e6
    [Google Scholar]
  50. 50.  O'Brien LL, Guo Q, Lee Y, Tran T, Benazet JD et al. 2016. Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators. Development 143:595–608
    [Google Scholar]
  51. 51.  Davis RP, Ng ES, Costa M, Mossman AK, Sourris K et al. 2008. Targeting a GFP reporter gene to the MIXL1 locus of human embryonic stem cells identifies human primitive streak-like cells and enables isolation of primitive hematopoietic precursors. Blood 111:1876–84
    [Google Scholar]
  52. 52.  Mae SI, Shono A, Shiota F, Yasuno T, Kajiwara M et al. 2013. Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nat. Commun. 4:1367
    [Google Scholar]
  53. 53.  Combes AN, Phipson B, Zappia L, Lawlor KT, Er PX et al. 2017. High throughput single cell RNA-seq of developing mouse kidney and human kidney organoids reveal a roadmap for recreating the kidney. bioRxiv 235499. https://doi.org/10.1101/235499
    [Crossref]
  54. 54.  Wu H, Uchimura K, Donnelly E, Kirita Y, Morris SA, Humphreys BD 2017. Comparative analysis of kidney organoid and adult human kidney single cell and single nucleus transcriptomes. bioRxiv 232561. https://doi.org/10.1101/232561
    [Crossref]
  55. 55.  Phipson B, Er PX, Hale L, Yen D, Lawlor K et al. 2017. Transcriptional evaluation of the developmental accuracy, reproducibility and robustness of kidney organoids derived from human pluripotent stem cells. bioRxiv 238428. https://doi.org/10.1101/238428
    [Crossref]
  56. 56.  Song B, Smink AM, Jones CV, Callaghan JM, Firth SD et al. 2012. The directed differentiation of human iPS cells into kidney podocytes. PLOS ONE 7:e46453
    [Google Scholar]
  57. 57.  Narayanan K, Schumacher KM, Tasnim F, Kandasamy K, Schumacher A et al. 2013. Human embryonic stem cells differentiate into functional renal proximal tubular-like cells. Kidney Int 83:593–603
    [Google Scholar]
  58. 58.  Perazella MA. 2009. Renal vulnerability to drug toxicity. Clin. J. Am. Soc. Nephrol. 4:1275–83
    [Google Scholar]
  59. 59.  Hagenbuch B, Stieger B 2013. The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34:396–412
    [Google Scholar]
  60. 60.  Bernard AM, Collette C, Lauwerys R 1992. Renal effects of in utero exposure to mercuric chloride in rats. Arch. Toxicol. 66:508–13
    [Google Scholar]
  61. 61.  Steinhardt G, Salinas-Madrigal L, Phillips R, DeMello D 1992. Fetal nephrotoxicity. J. Urol. 148:760–63
    [Google Scholar]
  62. 62.  Graham FL, Smiley J, Russell WC, Nairn R 1977. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 36:59–74
    [Google Scholar]
  63. 63.  Jin H, Yin S, Song X, Zhang E, Fan L, Hu H 2016. p53 activation contributes to patulin-induced nephrotoxicity via modulation of reactive oxygen species generation. Sci. Rep. 6:24455
    [Google Scholar]
  64. 64.  Kandasamy K, Chuah JK, Su R, Huang P, Eng KG et al. 2015. Prediction of drug-induced nephrotoxicity and injury mechanisms with human induced pluripotent stem cell-derived cells and machine learning methods. Sci. Rep. 5:12337
    [Google Scholar]
  65. 65.  Li Y, Kandasamy K, Chuah JK, Lam YN, Toh WS et al. 2014. Identification of nephrotoxic compounds with embryonic stem-cell-derived human renal proximal tubular-like cells. Mol. Pharm. 11:1982–90
    [Google Scholar]
  66. 66.  Kaminski MM, Tosic J, Kresbach C, Engel H, Klockenbusch J et al. 2016. Direct reprogramming of fibroblasts into renal tubular epithelial cells by defined transcription factors. Nat. Cell Biol. 18:1269–80
    [Google Scholar]
  67. 67.  van den Berg CW, Ritsma L, Avramut MC, Wiersma LE, van den Berg BM et al. 2018. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem Cell Rep 10:751–65
    [Google Scholar]
  68. 68.  Levey AS, Coresh J 2012. Chronic kidney disease. Lancet 379:165–80
    [Google Scholar]
  69. 69.  Dowell RD. 2011. The similarity of gene expression between human and mouse tissues. Genome Biol 12:101
    [Google Scholar]
  70. 70.  Perlman RL. 2016. Mouse models of human disease: an evolutionary perspective. Evol. Med. Public Health 2016:170–76
    [Google Scholar]
  71. 71.  Akkerman N, Defize LH 2017. Dawn of the organoid era: 3D tissue and organ cultures revolutionize the study of development, disease, and regeneration. Bioessays 39:1600244
    [Google Scholar]
  72. 72.  Sánchez-Romero N, Schophuizen CM, Giménez I, Masereeuw R 2016. In vitro systems to study nephropharmacology: 2D versus 3D models. Eur. J. Pharmacol. 790:36–45
    [Google Scholar]
  73. 73.  Devuyst O. 2018. Genetics of kidney diseases in 2017: unveiling the genetic architecture of kidney disease. Nat. Rev. Nephrol. 14:80–82
    [Google Scholar]
  74. 74.  Lee SH, Somlo S 2014. Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease. Kidney Res. Clin. Pract. 33:73–78
    [Google Scholar]
  75. 75.  Cruz NM, Song X, Czerniecki SM, Gulieva RE, Churchill AJ et al. 2017. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat. Mater. 16:1112–19
    [Google Scholar]
  76. 76.  Mallett AJ, McCarthy HJ, Ho G, Holman K, Farnsworth E et al. 2017. Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders. Kidney Int 92:1493–506
    [Google Scholar]
  77. 77.  Forbes TA, Howden SE, Lawlor K, Phipson B, Maksimovic J et al. 2018. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am. J. Hum. Genet. 102:816–31
    [Google Scholar]
  78. 78.  Miller KA, Ah-Cann CJ, Welfare MF, Tan TY, Pope K et al. 2013. Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome. PLOS Genet 9:e1003746
    [Google Scholar]
  79. 79.  Krtil J, Platenik J, Kazderova M, Tesar V, Zima T 2007. Culture methods of glomerular podocytes. Kidney Blood Press. Res 30:162–74
    [Google Scholar]
  80. 80.  Ni L, Saleem M, Mathieson PW 2012. Podocyte culture: tricks of the trade. Nephrology 17:525–31
    [Google Scholar]
  81. 81.  Sekine Y, Nishibori Y, Akimoto Y, Kudo A, Ito N et al. 2009. Amino acid transporter LAT3 is required for podocyte development and function. J. Am. Soc. Nephrol. 20:1586–96
    [Google Scholar]
  82. 82.  Musah S, Mammoto A, Ferrante TC, Jeanty SSF, Hirano-Kobayashi M et al. 2017. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat. Biomed. Eng. 1:0069
    [Google Scholar]
  83. 83.  Sharmin S, Taguchi A, Kaku Y, Yoshimura Y, Ohmori T et al. 2016. Human induced pluripotent stem cell-derived podocytes mature into vascularized glomeruli upon experimental transplantation. J. Am. Soc. Nephrol. 27:1778–91
    [Google Scholar]
  84. 84.  Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE et al. 2017. Gene-edited human kidney organoids reveal mechanisms of disease in podocyte development. Stem Cells 35:2366–78
    [Google Scholar]
  85. 85.  Barua M, Shieh E, Schlondorff J, Genovese G, Kaplan BS, Pollak MR 2014. Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis. Kidney Int 85:124–33
    [Google Scholar]
  86. 86.  Kang HG, Lee M, Lee KB, Hughes M, Kwon BS et al. 2017. Loss of podocalyxin causes a novel syndromic type of congenital nephrotic syndrome. Exp. Mol. Med. 49:e414
    [Google Scholar]
  87. 87.  Doyonnas R, Kershaw DB, Duhme C, Merkens H, Chelliah S et al. 2001. Anuria, omphalocele, and perinatal lethality in mice lacking the CD34-related protein podocalyxin. J. Exp. Med. 194:13–27
    [Google Scholar]
  88. 88.  Bierzynska A, Saleem M 2017. Recent advances in understanding and treating nephrotic syndrome. F1000Research 6:121
    [Google Scholar]
  89. 89.  Ulinski T. 2010. Recurrence of focal segmental glomerulosclerosis after kidney transplantation: strategies and outcome. Curr. Opin. Organ Transplant. 15:628–32
    [Google Scholar]
  90. 90.  Bantounas I, Ranjzad P, Tengku F, Silajdzic E, Forster D et al. 2018. Generation of functioning nephrons by implanting human pluripotent stem cell-derived kidney progenitors. Stem Cell Rep 10:766–79
    [Google Scholar]
  91. 91.  Mironov V, Drake C, Wen X 2006. Research project: Charleston Bioengineered Kidney Project. Biotechnol. J. 1:903–5
    [Google Scholar]
  92. 92.  Humes HD, Weitzel WF, Bartlett RH, Swaniker FC, Paganini EP et al. 2004. Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. Kidney Int 66:1578–88
    [Google Scholar]
  93. 93.  Dekel B, Burakova T, Arditti FD, Reich-Zeliger S, Milstein O et al. 2003. Human and porcine early kidney precursors as a new source for transplantation. Nat. Med. 9:53–60
    [Google Scholar]
  94. 94.  Howden SE, Thomson JA, Little MH 2018. Simultaneous reprogramming and gene editing of human fibroblasts. Nat. Protoc. 13:875–98
    [Google Scholar]
  95. 95.  Ng ES, Azzola L, Bruveris FF, Calvanese V, Phipson B et al. 2016. Differentiation of human embryonic stem cells to HOXA+ hemogenic vasculature that resembles the aorta-gonad-mesonephros. Nat. Biotechnol. 34:1168–79
    [Google Scholar]
  96. 96.  Drawnel FM, Boccardo S, Prummer M, Delobel F, Graff A et al. 2014. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep 9:810–21
    [Google Scholar]
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