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Understanding kidney morphogenesis to guide renal tissue regeneration

Key Points

  • Directing the differentiation of stem cells to kidney tissues requires an understanding of kidney morphogenesis

  • The kidney is a mesodermal organ and hence is derived from the primitive streak

  • The primitive streak-derived intermediate mesoderm gives rise to both the ureteric bud and the metanephric mesenchyme

  • The anterior intermediate mesoderm forms the mesonephric duct, which gives rise to the ureteric bud whereas the posterior intermediate mesoderm gives rise to the metanephric mesenchyme; both regions are required to recreate the entire kidney

  • Using their understanding of kidney development, a number of groups have developed approaches to generate nephrons or whole kidney organoids from human pluripotent stem cells

  • Kidney tissues generated in vitro are now being investigated as tools for disease modelling, drug screening, cell therapy and bioengineering of replacement renal tissue

Abstract

The treatment of renal failure has seen little change in the past 70 years. Patients with end-stage renal disease (ESRD) are treated with renal replacement therapy, including dialysis or organ transplantation. The growing imbalance between the availability of donor organs and prevalence of ESRD is pushing an increasing number of patients to undergo dialysis. Although the prospect of new treatment options for patients through regenerative medicine has long been suggested, advances in the generation of human kidney cell types through the directed differentiation of human pluripotent stem cells over the past 2 years have brought this prospect closer to delivery. These advances are the result of careful research into mammalian embryogenesis. By understanding the decision points made within the embryo to pattern the kidney, it is now possible to recreate self-organizing kidney tissues in vitro. In this Review, we describe the key decision points in kidney development and how these decisions have been mimicked experimentally. Recreation of human nephrons from human pluripotent stem cells opens the door to patient-derived disease models and personalized drug and toxicity screening. In the long term, we hope that these efforts will also result in the generation of bioengineered organs for the treatment of kidney disease.

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Figure 1: Key embryogenic decision points during kidney development.
Figure 2: Comparison of the developing mouse kidney and a kidney organoid generated from human pluripotent stem cells.
Figure 3: Potential applications of kidney tissue generated from stem cells in nephrology.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Hentze, H. et al. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2, 198–210 (2009).

    PubMed  Google Scholar 

  3. Lin, S. A. et al. Subfractionation of differentiating human embryonic stem cell populations allows the isolation of a mesodermal population enriched for intermediate mesoderm and renal progenitors. Stem Cells Dev. 19, 1637–1648 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Takasato, M. & Little, M. H. Generating a self-organising kidney from pluripotent cells. Curr. Opin. Organ. Transplant. 20, 178–186 (2015).

    PubMed  Google Scholar 

  7. Takasato, M. et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16, 118–126 (2014).

    CAS  PubMed  Google Scholar 

  8. Taguchi, A. et al. 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 (2014).

    CAS  PubMed  Google Scholar 

  9. Mae, S.-I. et al. Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nat. Commun. 4, 1367 (2013).

    PubMed  Google Scholar 

  10. Lam, A. Q. et al. Rapid and efficient differentiation of human pluripotent stem cells into intermediate mesoderm that forms tubules expressing kidney proximal tubular markers. J. Am. Soc. Nephrol. 25, 1211–1225 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33, 1193–1200 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Tam, P. P. L. & Loebel, D. A. F. Gene function in mouse embryogenesis: get set for gastrulation. Nat. Rev. Genet. 8, 368–381 (2007).

    CAS  PubMed  Google Scholar 

  16. Takaoka, K. & Hamada, H. Cell fate decisions and axis determination in the early mouse embryo. Development 139, 3–14 (2012).

    CAS  PubMed  Google Scholar 

  17. Perea-Gomez, A. et al. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3, 745–756 (2002).

    CAS  PubMed  Google Scholar 

  18. Ben-Haim, N. et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev. Cell 11, 313–323 (2006).

    CAS  PubMed  Google Scholar 

  19. Funa, N. S. et al. β-Catenin regulates primitive streak induction through collaborative interactions with SMAD2/SMAD3 and OCT4. Cell Stem Cell 16, 639–652 (2015).

    CAS  PubMed  Google Scholar 

  20. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nat. Genet. 22, 361–365 (1999).

    CAS  PubMed  Google Scholar 

  21. Mizutani, A. et al. Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4α in HepG2 cells. J. Biol. Chem. 286, 29848–29860 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Conlon, F. L. et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919–1928 (1994).

    CAS  PubMed  Google Scholar 

  23. Lu, C. C. & Robertson, E. J. Multiple roles for Nodal in the epiblast of the mouse embryo in the establishment of anterior-posterior patterning. Dev. Biol. 273, 149–159 (2004).

    CAS  PubMed  Google Scholar 

  24. Bachiller, D. et al. The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 403, 658–661 (2000).

    CAS  PubMed  Google Scholar 

  25. Winnier, G., Blessing, M., Labosky, P. A. & Hogan, B. L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).

    CAS  PubMed  Google Scholar 

  26. Beppu, H. et al. BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev. Biol. 221, 249–258 (2000).

    CAS  PubMed  Google Scholar 

  27. Vincent, S. D., Dunn, N. R., Hayashi, S., Norris, D. P. & Robertson, E. J. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes Dev. 17, 1646–1662 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pereira, L. A., Wong, M. S., Mei Lim, S., Stanley, E. G. & Elefanty, A. G. The Mix family of homeobox genes-Key regulators of mesendoderm formation during vertebrate development. Dev. Biol. 367, 163–177 (2012).

    CAS  PubMed  Google Scholar 

  29. Hart, A. H. et al. Mixl1 is required for axial mesendoderm morphogenesis and patterning in the murine embryo. Development 129, 3597–3608 (2002).

    CAS  PubMed  Google Scholar 

  30. Sumi, T., Tsuneyoshi, N., Nakatsuji, N. & Suemori, H. Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/β-catenin, Activin/Nodal and BMP signaling. Development 135, 2969–2979 (2008).

    CAS  PubMed  Google Scholar 

  31. Davis, R. P. et al. 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, 1876–1884 (2008).

    CAS  PubMed  Google Scholar 

  32. Burridge, P. W., Keller, G., Gold, J. D. & Wu, J. C. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10, 16–28 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jackson, S. A., Schiesser, J., Stanley, E. G. & Elefanty, A. G. Differentiating embryonic stem cells pass through 'temporal windows' that mark responsiveness to exogenous and paracrine mesendoderm inducing signals. PLoS ONE. 5, e10706 (2010).

    PubMed  PubMed Central  Google Scholar 

  34. Gertow, K. et al. WNT3A promotes hematopoietic or mesenchymal differentiation from hESCs depending on the time of exposure. Stem Cell Reports 1, 53–65 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peng, G. et al. Spatial transcriptome for the molecular annotation of lineage fates and cell identity in mid-gastrula mouse embryo. Dev. Cell 36, 681–697 (2016).

    CAS  PubMed  Google Scholar 

  36. James, R. G. & Schultheiss, T. M. Patterning of the avian intermediate mesoderm by lateral plate and axial tissues. Dev. Biol. 253, 109–124 (2003).

    CAS  PubMed  Google Scholar 

  37. Sweetman, D., Wagstaff, L., Cooper, O., Weijer, C. & Münsterberg, A. The migration of paraxial and lateral plate mesoderm cells emerging from the late primitive streak is controlled by different Wnt signals. BMC Dev. Biol. 8, 63 (2008).

    PubMed  PubMed Central  Google Scholar 

  38. Obara-Ishihara, T., Kuhlman, J., Niswander, L. & Herzlinger, D. The surface ectoderm is essential for nephric duct formation in intermediate mesoderm. Development 126, 1103–1108 (1999).

    CAS  PubMed  Google Scholar 

  39. James, R. G. & Schultheiss, T. M. Bmp signaling promotes intermediate mesoderm gene expression in a dose-dependent, cell-autonomous and translation-dependent manner. Dev. Biol. 288, 113–125 (2005).

    CAS  PubMed  Google Scholar 

  40. Wijgerde, M., Karp, S., McMahon, J. & McMahon, A. P. Noggin antagonism of BMP4 signaling controls development of the axial skeleton in the mouse. Dev. Biol. 286, 149–157 (2005).

    CAS  PubMed  Google Scholar 

  41. Biben, C. et al. Murine cerberus homologue mCer-1: a candidate anterior patterning molecule. Dev. Biol. 194, 135–151 (1998).

    CAS  PubMed  Google Scholar 

  42. Fleming, B. M., Yelin, R., James, R. G. & Schultheiss, T. M. A role for Vg1/Nodal signaling in specification of the intermediate mesoderm. Development 140, 1819–1829 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Colvin, J. S., Feldman, B., Nadeau, J. H., Goldfarb, M. & Ornitz, D. M. Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev. Dyn. 216, 72–88 (1999).

    CAS  PubMed  Google Scholar 

  44. Little, M. H., & McMahon, A. P. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb. Perspect. Biol. 4, a008300 (2012).

    PubMed  PubMed Central  Google Scholar 

  45. Xu, J. et al. Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Dev. Cell 31, 434–447 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Takasato, M. & Little, M. H. The origin of the mammalian kidney: implications for recreating the kidney in vitro. Development 142, 1937–1947 (2015).

    CAS  PubMed  Google Scholar 

  47. Deng, C., Lewandoski, M. & Pourquié, O. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development 134, 4033–4041 (2007).

    PubMed  Google Scholar 

  48. Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sakai, Y. et al. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 15, 213–225 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sajithlal, G., Zou, D., Silvius, D. & Xu, P. Eya 1 acts as a critical regulator for specifying the metanephric mesenchyme. Dev. Biol. 284, 323–336 (2005).

    CAS  PubMed  Google Scholar 

  51. Dressler, G. R. Advances in early kidney specification, development and patterning. Development 136, 3863–3874 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Mugford, J. W., Sipilä, P., McMahon, J. A. & McMahon, A. P. Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Dev. Biol. 324, 88–98 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bouchard, M., Souabni, A., Mandler, M., Neubüser, A. & Busslinger, M. Nephric lineage specification by Pax2 and Pax8. Genes Dev. 16, 2958–2970 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kobayashi, A. et al. Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development 132, 2809–2823 (2005).

    CAS  PubMed  Google Scholar 

  55. Grote, D., Souabni, A., Busslinger, M. & Bouchard, M. Pax 2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney. Development 133, 53–61 (2006).

    CAS  PubMed  Google Scholar 

  56. Chi, X. et al. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev. Cell 17, 199–209 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. & Pachnis, V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994).

    CAS  PubMed  Google Scholar 

  58. Moore, M. W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    CAS  PubMed  Google Scholar 

  59. Enomoto, H. et al. GFRα1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21, 317–324 (1998).

    CAS  PubMed  Google Scholar 

  60. Costantini, F. Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system. Wiley Interdiscip. Rev. Dev. Biol. 1, 693–713 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Costantini, F. & Kopan, R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev. Cell 18, 698–712 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Majumdar, A., Vainio, S., Kispert, A., McMahon, J. & McMahon, A. P. Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130, 3175–3185 (2003).

    CAS  PubMed  Google Scholar 

  63. Lu, B. C. et al. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat. Genet. 41, 1295–1302 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao, H. et al. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev. Biol. 276, 403–415 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Burn, S. F. et al. Calcium/NFAT signalling promotes early nephrogenesis. Dev. Biol. 352, 288–298 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Marose, T. D., Merkel, C. E., McMahon, A. P., Carroll, T. J. β-Catenin is necessary to keep cells of ureteric bud/Wolffian duct epithelium in a precursor state. Dev. Biol. 314, 112–126 (2008).

    CAS  PubMed  Google Scholar 

  67. Carroll, T. J., Park, J. S., Hayashi, S., Majumdar, A. & McMahon, A. P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev. Cell 9, 283–292 (2005).

    CAS  PubMed  Google Scholar 

  68. Yu, J. et al. Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136, 161–171 (2009).

    CAS  PubMed  Google Scholar 

  69. Mendelsohn, C., Batourina, E., Fung, S., Gilbert, T. & Dodd, J. Stromal cells mediate retinoid-dependent functions essential for renal development. Development 126, 1139–1148 (1999).

    CAS  PubMed  Google Scholar 

  70. Batourina, E. et al. Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nat. Genet. 27, 74–78 (2001).

    CAS  PubMed  Google Scholar 

  71. Rosselot, C. et al. Non-cell-autonomous retinoid signaling is crucial for renal development. Development 137, 283–292 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Caruana, G. et al. Spatial gene expression in the T-stage mouse metanephros. Gene Expr. Patterns 6, 807–825 (2006).

    CAS  PubMed  Google Scholar 

  73. Song, B. et al. The directed differentiation of human iPS cells into kidney podocytes. PloS ONE 7, e46453 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang, J. et al. Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Exp. Nephrol. 121, e23–e27 (2012).

    CAS  PubMed  Google Scholar 

  75. Vetter, M. R. & Gibley, C. W. Morphogenesis and histochemistry of the developing mouse kidney. J. Morphol. 120, 135–155 (1966).

    CAS  PubMed  Google Scholar 

  76. Georgas, K. M., Chiu, H. S., Lesieur, E., Rumballe, B. A. & Little, M. H. Expression of metanephric nephron-patterning genes in differentiating mesonephric tubules. Dev. Dyn. 240, 1600–1612 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Woolf, A. S., Gnudi, L., Long, D. A., Roles of angiopoietins in kidney development and disease. J. Am. Soc. Nephrol. 20, 239–244 (2009).

    CAS  PubMed  Google Scholar 

  78. Schoenwolf, G. Larsen's Human Embryology 5th Edition Ch. 3,4,15 (Churchill Livingstone, 2014).

    Google Scholar 

  79. Kobayashi, A. et al. Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis. Stem Cell Reports 3, 650–662 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kobayashi, A. et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3, 169–181 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Self, M. et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J. 25, 5214–5228 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Boyle, S. et al. 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, 234–245 (2008).

    CAS  PubMed  Google Scholar 

  83. Cebrian, C., Asai, N., D'Agati, V. & Costantini, F. The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment. Cell Rep. 7, 127–137 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Karner, C. M. et al. Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development 138, 1247–1257 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Barak, H. et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22, 1191–1207 (2010).

    Google Scholar 

  86. Dudley, A. T., Godin, R. E. & Robertson, E. J. Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme. Genes Dev. 13, 1601–1613 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Brown, A. C. et al. Role for compartmentalization in nephron progenitor differentiation. Proc. Natl. Acad. Sci. USA 110, 4640–4645 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Brown, A. C., Muthukrishnan, S. D. & Oxburgh, L. A synthetic niche for nephron progenitor cells. Dev. Cell 34, 229–241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Park, J. S. et al. Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev. Cell 23, 637–651 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tanigawa, S. et al. Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism. Dev. Biol. 352, 58–69 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Perantoni, A. O. et al. Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development 132, 3859–3871 (2005).

    CAS  PubMed  Google Scholar 

  92. Little, M. et al. Kidney development: two tales of tubulogenesis. Curr. Top. Dev. Biol. 90, 193–229 (2010).

    CAS  PubMed  Google Scholar 

  93. Cheng, H. T. et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134, 801–811 (2007).

    CAS  PubMed  Google Scholar 

  94. Wingert, R. A. & Davidson, A. J. Zebrafish nephrogenesis involves dynamic spatiotemporal expression changes in renal progenitors and essential signals from retinoic acid and irx3b. Dev. Dyn. 240, 2011–2027 (2011).

    CAS  PubMed  Google Scholar 

  95. Schneider, J., Arraf, A. A., Grinstein, M., Yelin, R. & Schultheiss, T. M. Wnt signaling orients the proximal-distal axis of chick kidney nephrons. Development 142, 2686–2695 (2015).

    CAS  PubMed  Google Scholar 

  96. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Sequeira-Lopez, M. L. et al. The earliest metanephric arteriolar progenitors and their role in kidney vascular development. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R138–R149 (2015).

    CAS  PubMed  Google Scholar 

  98. Hu, Y., Li, M., Göthert, J. R., Gomez, R. A. & Sequeira-Lopez, M. L. Hemovascular progenitors in the kidney require sphingosine-1-phosphate receptor 1 for vascular development. J. Am. Soc. Nephrol. 27, 1984–1995 (2016).

    CAS  PubMed  Google Scholar 

  99. Xu, J., Nie, X., Cai, X., Cai, C. L. & Xu, P. X. Tbx18 is essential for normal development of vasculature network and glomerular mesangium in the mammalian kidney. Dev. Biol. 391, 17–31 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sharmin, S. et al. Human induced pluripotent stem cell-derived podocytes mature into vascularized glomeruli upon experimental transplantation. J. Am. Soc. Nephrol. 27, 1778–1791 (2016).

    CAS  PubMed  Google Scholar 

  101. Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 156, 1032–1044 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Roost, M. S. et al. KeyGenes, a tool to probe tissue differentiation using a human fetal transcriptional atlas. Stem Cell Reports 4, 1112–1124 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, Y. et al. Identification of nephrotoxic compounds with embryonic stem-cell-derived human renal proximal tubular-like cells. Mol. Pharm. 11, 1982–1990 (2014).

    CAS  PubMed  Google Scholar 

  104. Araoka, T. et al. Efficient and rapid induction of human iPSCs/ESCs into nephrogenic intermediate mesoderm using small molecule-based differentiation methods. PloS ONE 9, e84881 (2014).

    PubMed  PubMed Central  Google Scholar 

  105. Toyohara, T. et al. Cell therapy using human induced pluripotent stem cell-derived renal progenitors ameliorates acute kidney injury in mice. Stem Cells Transl Med. 4, 980–992 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Rabelink, T. J. & Little, M. H. Stromal cells in tissue homeostasis: balancing regeneration and fibrosis. Nat. Rev. Nephrol. 9, 747–753 (2013).

    CAS  PubMed  Google Scholar 

  107. Imberti, B. et al. Renal progenitors derived from human iPSCs engraft and restore function in a mouse model of acute kidney injury. Sci. Rep. 5, 8826 (2015).

    PubMed  PubMed Central  Google Scholar 

  108. Koulouridis, E. & Koulouridis, I. The loop of Henle as the milestone of mammalian kindey concentrating ability: a historical review. Acta Med. Hist. Adriat. 12, 413–428 (2014).

    PubMed  Google Scholar 

  109. Jansen, J. et al. Bioengineered kidney tubules efficiently excrete uremic toxins. Sci. Rep. 6, 26715 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Roessger, A., Denk, L. & Minuth, W. W. Potential of stem/progenitor cell cultures within polyester fleeces to regenerate renal tubules. Biomaterials 30, 3723–3732 (2009).

    CAS  PubMed  Google Scholar 

  111. Song, J. J. et al. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat. Med. 19, 646–651 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Bonandrini, B. et al. Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells. Tissue Eng. Part A 20, 1486–1498, (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Caralt, M. et al. Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am. J. Transplant. 15, 64–75, (2015).

    CAS  PubMed  Google Scholar 

  114. Little, M. H. Improving our resolution of kidney morphogenesis across time and space. Curr. Opin. Genet. Dev. 32, 135–143 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

M.H.L. is a Senior Principal Research Fellow of the National Health and Medical Research Council (ID1042093). A.N.C. is an Australian Research Council (ARC) DECRA Postdoctoral Fellow (DE150100652). The laboratory is supported by funding from the NHMRC (ID1041277), NIH (DK107344-01) and the ARC (DP130102939).

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All authors made substantial contributions to discussing the article's content, writing the article and reviewing or editing the article before submission.

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Correspondence to Melissa H. Little.

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Competing interests

M.H.L. has previously (2014) received research funding from Organovo Inc.

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Glossary

Human embryonic stem cells

Pluripotent stem cells derived from the early preimplantation embryo; they are thought to arise from the epiblast.

Induced pluripotent stem cell

Pluripotent stem cell generated from a somatic cell via transcriptional reprogramming. The approach was pioneered in mice in 2006 and can also be performed in human somatic cells.

Pluripotent stem cells

Cells that have the potential to differentiate into any cell type of the body.

Epiblast

One of two distinct layers of the inner cell mass of the preimplantation embryo. The epiblast can give rise to all three germ layers: ectoderm, mesoderm and endoderm; the kidneys are derived from the mesoderm.

Primitive streak

Elongated region of cells along the axis of the embryo that represents the site of gastrulation. It arises via the movement of lateral cells toward the medial axis and gives rise to the endoderm and mesoderm of the embryo with the rostro-caudal and medial-lateral axes of the embryo defined by its position.

Visceral endoderm

Extra-embryonic tissue that surrounds the epiblast before gastrulation.

Node

Site where gastrulation occurs in the developing embryo.

Paraxial mesoderm

Region of the trunk mesoderm that lies along the spinal cord and gives rise to bone, cartilage, skeletal muscle and dermis via somitogenesis. It is characterized by the expression of Tcf15, Tbx6 and Pax3.

Lateral plate mesoderm

Region of the trunk mesoderm that is located most distally from the spinal cord and gives rise to the heart, smooth muscles, blood cells, endothelium, the spleen and limbs. It is characterized by the expression of Osr1, Foxf1 and Nkx2-5.

Intermediate mesoderm

Region of the trunk mesoderm that develops between the paraxial mesoderm and the lateral plate mesoderm. It differentiates into the nephric duct and the nephrogenic mesenchyme, which give rise to the urogenital system including the kidney, the gonads, and the adrenal cortex. It is marked by the expression of Pax2, Lhx1 (anterior) and Hoxd11, Eya1 (posterior).

Notochord

Midline structure along the axis of the embryo located ventrally to the neural tube that has a critical role in patterning during development.

Nephrogenic cord

Non-epithelial mesodermal mass alongside the nephric duct that originates from the intermediary mesoderm and is marked by Osr1 and Wt1 expression. It gives rise to the mesonephric and metanephric mesenchyme that form the mesonephric tubules of the mesonephros and the nephrons of the kidney.

Nephric duct

Epithelial tube structure derived from the intermediary mesoderm in both the pronephros and mesonephros that gives rise to the ureteric bud, which forms the collecting ducts and the ureter of the metanephros. It also contributes to the male reproductive tract but regresses in the female. Marked by Gata3, Lhx1, Pax2 and Ecad expression.

Pronephros

First and most rostral excretory organ to form along the mammalian embryo axis. The pronephros degenerates as the mesonephros is formed.

Mesonephros

Second excretory organ to form along the mammalian embryo axis. It is composed of mesonephric tubules and degenerates during fetal development with sexually dimorphic regression (some tubules are retained in males to form the rete testis).

Metanephros

Final and permanent excretory organ to form in mammals. It arises as an interaction between the ureteric bud and the metanephric mesenchyme and its excretory function commences before birth.

Anterior intermediate mesoderm

The most rostral portion of the forming intermediate mesoderm from which the nephric duct and the pronephric tubules arise. It is formed by the first cells to migrate from the primitive streak.

Ureteric epithelium

Tissue derived from the ureteric bud that invades the metanephric mesenchyme and then branches dichotomously to form the ureteric tree.

Posterior intermediate mesoderm

Most caudal portion of the forming intermediary mesoderm from which the nephrogenic mesenchyme arises. It is formed by cells that migrate out of the primitive streak at a later time point than cells that give rise to the anterior intermediate mesoderm.

Metanephric mesenchyme

Caudal part of the nephrogenic mesenchyme that gives rise to the nephrons, the stromal interstitium and some vascular elements within the final metanephric kidney. Marked by the expression of Osr1, Six1, Six2, Eya1, Wt1 and Gdnf.

Tailbud

This proliferating mass of cells at the caudal end of the embryo, sometimes referred to as the caudal cell mass or caudal eminence, is the source of cells that contribute to the elongating body axis.

Ureteric bud

Epithelial bud that arises from the caudal nephric duct adjacent to the metanephric mesenchyme in response to GDNF, a chemoattractant secreted by the metanephric mesenchyme.

Ureteric tree

Tree-like structure derived from the dichotomous branching of the ureteric epithelium that gives rise to the collecting ducts in the metanephros. The ends of each branch are called 'ureteric tips' and express Ret, Gfra1 and Wnt11.

Cap mesenchyme

Derivative of the metanephric mesenchyme adjacent to the tips of the branching ureteric bud that gives rise to all of the cell types of the nephron via mesenchymal-to-epithelial transition; it is hence also referred to as the nephrogenic mesenchyme. It is marked by the expression of Osr1, Six2, Cited1, Eya1, Wt1, Pax2 and Gdnf.

Organ-on-a-chip

Microfluidic cell culture chip that houses various cell types to mimic the 3D physiology (multicellular architecture, tissue-tissue interfaces, physicochemical and mechanical environment) of an organ.

Artificial scaffolds

Structural element or framework used to hold cells or tissues together.

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Little, M., Combes, A. & Takasato, M. Understanding kidney morphogenesis to guide renal tissue regeneration. Nat Rev Nephrol 12, 624–635 (2016). https://doi.org/10.1038/nrneph.2016.126

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