Skip to main content

Early Kidney Specification and Its Recapitulation by Pluripotent Stem Cells

  • Chapter
  • First Online:
Organ Regeneration Based on Developmental Biology

Abstract

Successful generation of the kidney from pluripotent stem cells is challenging because of insufficient knowledge of the underlying developmental processes. In addition to the technical difficulties of physically examining the early stages of embryogenesis, the unique features surrounding the development of the kidney from three distinct primordia hamper a more complete understanding of the relevant cell fate acquisition mechanisms. We have recently addressed these issues by combining in vivo lineage tracing experiments and ex vivo directed differentiation culture systems. Our strategy has revealed the mechanism by which the kidney morphogenic field is patterned along the anteroposterior axis and also identified the key signals which promote posteriorization, specification, and maturation of nephron progenitors from pluripotent stem cells. Importantly, these newly identified biological insights have enabled the production of three-dimensional complex nephron structure from both mouse and human pluripotent stem cells, which would be a big progress toward the realization of kidney regenerative medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aulehla A, Pourquie O (2010) Signaling gradients during paraxial mesoderm development. Cold Spring Harb Perspect Biol 2:a000869

    Article  PubMed  PubMed Central  Google Scholar 

  • Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, Bole-Feysot C, Nitschke P, Salomon R, Antignac C, Ornitz DM, Kopan R (2012) FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell 22:1191–1207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell 99:377–386

    Article  CAS  PubMed  Google Scholar 

  • Boyle SC, Kim M, Valerius MT, Mcmahon AP, Kopan R (2011) Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development 138:4245–4254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown AC, Muthukrishnan SD, Guay JA, Adams DC, Schafer DA, Fetting JL, Oxburgh L (2013) Role for compartmentalization in nephron progenitor differentiation. Proc Natl Acad Sci U S A 110:4640–4645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burn SF, Webb A, Berry RL, Davies JA, Ferrer-Vaquer A, Hadjantonakis AK, Hastie ND, Hohenstein P (2011) Calcium/NFAT signalling promotes early nephrogenesis. Dev Biol 352:288–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 9:283–292

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Brunskill EW, Potter SS, Dexheimer PJ, Salomonis N, Aronow BJ, HONG CI, Zhang T, Kopan R (2015) Intrinsic age-dependent changes and cell-cell contacts regulate nephron progenitor lifespan. Dev Cell 35:49–62

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheng HT, Miner JH, Lin M, Tansey MG, Roth K, Kopan R (2003) Gamma-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney. Development 130:5031–5042

    Article  CAS  PubMed  Google Scholar 

  • Das A, Tanigawa S, Karner CM, Xin M, Lum L, Chen C, Olson EN, Perantoni AO, Carroll TJ (2013) Stromal-epithelial crosstalk regulates kidney progenitor cell differentiation. Nat Cell Biol 15:1035–1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drawbridge J, Meighan CM, Lumpkins R, Kite ME (2003) Pronephric duct extension in amphibian embryos: migration and other mechanisms. Dev Dyn 226:1–11

    Article  PubMed  Google Scholar 

  • Dressler GR (2009) Advances in early kidney specification, development and patterning. Development 136:3863–3874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dressler GR, Wilkinson JE, Rothenpieler UW, Patterson LT, Williams-Simons L, Westphal H (1993) Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature 362:65–67

    Article  CAS  PubMed  Google Scholar 

  • Fleming BM, Yelin R, James RG, Schultheiss TM (2013) A role for Vg1/Nodal signaling in specification of the intermediate mesoderm. Development 140:1819–1829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, Mcnagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gadue P, Huber TL, Paddison PJ, Keller GM (2006) Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci U S A 103:16806–16811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gouti M, Tsakiridis A, Wymeersch FJ, Huang Y, Kleinjung J, Wilson V, Briscoe J (2014) In vitro generation of neuromesodermal progenitors reveals distinct roles for wnt signalling in the specification of spinal cord and paraxial mesoderm identity. PLoS Biol 12:e1001937

    Article  PubMed  PubMed Central  Google Scholar 

  • Grobstein C (1953) Inductive epithelio-mesenchymal interaction in cultured organ rudiments of the mouse metanephros. Science 118:52–55

    Article  CAS  PubMed  Google Scholar 

  • Grobstein C (1955) Inductive interaction in the development of the mouse metanephros. J Exp Zool 130:319–340

    Article  Google Scholar 

  • Henrique D, Abranches E, Verrier L, Storey KG (2015) Neuromesodermal progenitors and the making of the spinal cord. Development 142:2864–2875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, Mcmahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • James RG, Schultheiss TM (2003) Patterning of the avian intermediate mesoderm by lateral plate and axial tissues. Dev Biol 253:109–124

    Article  CAS  PubMed  Google Scholar 

  • James RG, Schultheiss TM (2005) Bmp signaling promotes intermediate mesoderm gene expression in a dose-dependent, cell-autonomous and translation-dependent manner. Dev Biol 288:113–125

    Article  CAS  PubMed  Google Scholar 

  • James RG, Kamei CN, Wang Q, Jiang R, Schultheiss TM (2006) Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells. Development 133:2995–3004

    Article  CAS  PubMed  Google Scholar 

  • Karner CM, Das A, Ma Z, Self M, Chen C, Lum L, Oliver G, Carroll TJ (2011) Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development 138:1247–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kispert A, Vainio S, Shen L, Rowitch DH, Mcmahon AP (1996) Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips. Development 122:3627–3637

    CAS  PubMed  Google Scholar 

  • Kispert A, Vainio S, Mcmahon AP (1998) Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Development 125:4225–4234

    CAS  PubMed  Google Scholar 

  • Kobayashi A, Valerius MT, Mugford JW, Carroll TJ, Self M, Oliver G, Mcmahon AP (2008) Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3:169–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 3:650–662

    Article  CAS  Google Scholar 

  • Kopan R, Cheng HT, Surendran K (2007) Molecular insights into segmentation along the proximal-distal axis of the nephron. J Am Soc Nephrol 18:2014–2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993) WT-1 is required for early kidney development. Cell 74:679–691

    Article  CAS  PubMed  Google Scholar 

  • Kuure S, Popsueva A, Jakobson M, Sainio K, Sariola H (2007) Glycogen synthase kinase-3 inactivation and stabilization of beta-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes. J Am Soc Nephrol 18:1130–1139

    Article  CAS  PubMed  Google Scholar 

  • Lindstrom NO, Lawrence ML, Burn SF, Johansson JA, Bakker ER, Ridgway RA, Chang CH, Karolak MJ, Oxburgh L, Headon DJ, Sansom OJ, Smits R, Davies JA, Hohenstein P (2014) Integrated beta-catenin, BMP, PTEN, and Notch signalling patterns the nephron. elife 3:e04000

    Google Scholar 

  • Majumdar A (2003) Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130:3175–3185

    Article  CAS  PubMed  Google Scholar 

  • Mauch TJ, Yang G, Wright M, Smith D, Schoenwolf GC (2000) Signals from trunk paraxial mesoderm induce pronephros formation in chick intermediate mesoderm. Dev Biol 220:62–75

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Mendjan S, Mascetti VL, Ortmann D, Ortiz M, Karjosukarso DW, Ng Y, Moreau T, Pedersen RA (2014) NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. Cell Stem Cell 15:310–325

    Article  CAS  PubMed  Google Scholar 

  • 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 33:1193–1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mugford JW, Sipila P, Kobayashi A, Behringer RR, Mcmahon AP (2008a) Hoxd11 specifies a program of metanephric kidney development within the intermediate mesoderm of the mouse embryo. Dev Biol 319:396–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mugford JW, Sipila P, Mcmahon JA, Mcmahon AP (2008b) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mugford JW, Yu J, Kobayashi A, Mcmahon AP (2009) High-resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the nephron progenitor population. Dev Biol 333:312–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murry CE, Keller G (2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132:661–680

    Article  CAS  PubMed  Google Scholar 

  • Muthukrishnan SD, Yang X, Friesel R, Oxburgh L (2015) Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nat Commun 6:10027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishinakamura R, Matsumoto Y, Nakao K, Nakamura K, Sato A, Copeland NG, Gilbert DJ, Jenkins NA, Scully S, Lacey DL, Katsuki M, Asashima M, Yokota T (2001) Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development 128:3105–3115

    CAS  PubMed  Google Scholar 

  • O’brien LL, Guo Q, Lee Y, Tran T, Benazet JD, Whitney PH, Valouev A, Mcmahon AP (2016) Differential regulation of mouse and human nephron progenitors by the six family of transcriptional regulators. Development 143:595–608

    Article  PubMed  PubMed Central  Google Scholar 

  • Osafune K, Takasato M, Kispert A, Asashima M, Nishinakamura R (2006) Identification of multipotent progenitors in the embryonic mouse kidney by a novel colony-forming assay. Development 133:151–161

    Article  CAS  PubMed  Google Scholar 

  • Park JS, Valerius MT, Mcmahon AP (2007) Wnt/ -catenin signaling regulates nephron induction during mouse kidney development. Development 134:2533–2539

    Article  CAS  PubMed  Google Scholar 

  • Perantoni AO, Dove LF, Karavanova I (1995) Basic fibroblast growth factor can mediate the early inductive events in renal development. Proc Natl Acad Sci U S A 92:4696–4700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poleev A, Fickenscher H, Mundlos S, Winterpacht A, Zabel B, Fidler A, Gruss P, Plachov D (1992) PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms’ tumors. Development 116:611–623

    CAS  PubMed  Google Scholar 

  • Psychoyos D, Stern CD (1996) Fates and migratory routes of primitive streak cells in the chick embryo. Development 122:1523–1534

    CAS  PubMed  Google Scholar 

  • Rogers SA, Ryan G, Purchio AF, Hammerman MR (1993) Metanephric transforming growth factor-beta 1 regulates nephrogenesis in vitro. Am J Phys 264:F996–1002

    CAS  Google Scholar 

  • Saxen L (1987) Organogenesis of the kidney. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • Schneider J, Arraf AA, Grinstein M, Yelin R, Schultheiss TM (2015) Wnt signaling orients the proximal-distal axis of chick kidney nephrons. Development 142:2686–2695

    Article  CAS  PubMed  Google Scholar 

  • Self M, Lagutin OV, Bowling B, Hendrix J, Cai Y, Dressler GR, Oliver G (2006) Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J 25:5214–5228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shakya R, Watanabe T, Costantini F (2005) The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev Cell 8:65–74

    Article  CAS  PubMed  Google Scholar 

  • Sharmin S, Taguchi A, Kaku Y, Yoshimura Y, Ohmori T, Sakuma T, Mukoyama M, Yamamoto T, Kurihara H, Nishinakamura R (2015) Human induced pluripotent stem cell-derived podocytes mature into vascularized glomeruli upon experimental transplantation. J Am Soc Nephrol 27(6):1778–1791

    Article  PubMed  Google Scholar 

  • Stark K, Vainio S, Vassileva G, Mcmahon AP (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372:679–683

    Article  CAS  PubMed  Google Scholar 

  • Taguchi A, Nishinakamura R (2014) Nephron reconstitution from pluripotent stem cells. Kidney Int 87(5):894–900

    Article  PubMed  Google Scholar 

  • Taguchi A, Kaku Y, Ohmori T, Sharmin S, Ogawa M, Sasaki H, Nishinakamura R (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

    Article  CAS  PubMed  Google Scholar 

  • Takada S, Stark KL, Shea MJ, Vassileva G, Mcmahon JA, Mcmahon AP (1994) Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev 8:174–189

    Article  CAS  PubMed  Google Scholar 

  • Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva De Sousa Lopes SM, Little MH (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:564–568

    Article  CAS  PubMed  Google Scholar 

  • Takemoto T, Uchikawa M, Yoshida M, Bell DM, Lovell-Badge R, Papaioannou VE, Kondoh H (2011) Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 470:394–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tam PP, Loebel DA (2007) Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet 8:368–381

    Article  CAS  PubMed  Google Scholar 

  • Tanigawa S, Wang H, Yang Y, Sharma N, Tarasova N, Ajima R, Yamaguchi TP, Rodriguez LG, Perantoni AO (2011) Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism. Dev Biol 352:58–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner DA, Hayward PC, Baillie-Johnson P, Rue P, Broome R, Faunes F, Martinez Arias A (2014) Wnt/beta-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells. Development 141:4243–4253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tzouanacou E, Wegener A, Wymeersch FJ, Wilson V, Nicolas J-F (2009) Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell 17:365–376

    Article  CAS  PubMed  Google Scholar 

  • Vega QC, Worby CA, Lechner MS, Dixon JE, Dressler GR (1996) Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc Natl Acad Sci U S A 93:10657–10661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wellik DM, Hawkes PJ, Capecchi MR (2002) Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev 16:1423–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson V, Olivera-Martinez I, Storey KG (2009) Stem cells, signals and vertebrate body axis extension. Development 136:1591–1604

    Article  CAS  PubMed  Google Scholar 

  • Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, Fine LG, Jat PS, Noble MD, Gherardi E (1995) Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros. J Cell Biol 128:171–184

    Article  CAS  PubMed  Google Scholar 

  • Xia Y, Nivet E, Sancho-Martinez I, Gallegos T, Suzuki K, Okamura D, Wu MZ, Dubova I, Esteban CR, Montserrat N, Campistol JM, Izpisua Belmonte JC (2013) Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells. Nat Cell Biol 15:1507–1515

    Article  CAS  PubMed  Google Scholar 

  • Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R (1999) Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 23:113–117

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi TP, Takada S, Yoshikawa Y, Wu N, Mcmahon AP (1999) T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Genes Dev 13:3185–3190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Carroll TJ, Rajagopal J, Kobayashi A, Ren Q, Mcmahon AP (2009) A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136:161–171

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ryuichi Nishinakamura .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Taguchi, A., Nishinakamura, R. (2017). Early Kidney Specification and Its Recapitulation by Pluripotent Stem Cells. In: Tsuji, T. (eds) Organ Regeneration Based on Developmental Biology. Springer, Singapore. https://doi.org/10.1007/978-981-10-3768-9_9

Download citation

Publish with us

Policies and ethics