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Stem cell marker TRA-1-60 is expressed in foetal and adult kidney and upregulated in tubulo-interstitial disease

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Abstract

The kidney has an intrinsic ability to repair itself when injured. Epithelial cells of distal tubules may participate in regeneration. Stem cell marker, TRA-1-60 is linked to pluripotency in human embryonic stem cells and is lost upon differentiation. TRA-1-60 expression was mapped and quantified in serial sections of human foetal, adult and diseased kidneys. In 8- to 10-week human foetal kidney, the epitope was abundantly expressed on ureteric bud and structures derived therefrom including collecting duct epithelium. In adult kidney inner medulla/papilla, comparisons with reactivity to epithelial membrane antigen, aquaporin-2 and Tamm–Horsfall protein, confirmed extensive expression of TRA-1-60 in cells lining collecting ducts and thin limb of the loop of Henle, which may be significant since the papillae were proposed to harbour slow cycling cells involved in kidney homeostasis and repair. In the outer medulla and cortex there was rare, sporadic expression in tubular cells of the collecting ducts and nephron, with positive cells confined to the thin limb and thick ascending limb and distal convoluted tubules. Remarkably, in cortex displaying tubulo-interstitial injury, there was a dramatic increase in number of TRA-1-60 expressing individual cells and in small groups of cells in distal tubules. Dual staining showed that TRA-1-60 positive cells co-expressed Pax-2 and Ki-67, markers of tubular regeneration. Given the localization in foetal kidney and the distribution patterns in adults, it is tempting to speculate that TRA-1-60 may identify a population of cells contributing to repair of distal tubules in adult kidney.

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References

  • Alvarez-Buylla A, Seri B, Doetsch F (2002) Identification of neural stem cells in the adult vertebrate brain. Brain Res Bull 57:751–758

    Article  PubMed  Google Scholar 

  • Andrews PW, Banting G, Damjanov I, Arnaud D, Avner P (1984) Three monoclonal antibodies defining distinct differentiation antigens associated with different high molecular weight polypeptides on the surface of human embryonal carcinoma cells. Hybridoma 3:347–361

    Article  PubMed  CAS  Google Scholar 

  • Badcock G, Pigott C, Goepel J, Andrews PW (1999) The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratan sulfate proteoglycan. Cancer Res 59:4715–4719

    PubMed  CAS  Google Scholar 

  • Bonventre JV (2003) Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol 14(Suppl 1):S55–S61

    Article  PubMed  Google Scholar 

  • Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D, Camussi G (2005) Isolation of renal progenitor cells from adult human kidney. Am J Pathol 166:545–555

    PubMed  CAS  Google Scholar 

  • Cantz T, Manns MP, Ott M (2008) Stem cells in liver regeneration and therapy. Cell Tissue Res 331:271–282

    Article  PubMed  Google Scholar 

  • Cheng HY, Lin YY, Yu CY, Chen JY, Shen KF, Lin WL, Liao HK, Chen YJ, Liu CH, Pang VF, Jou TS (2005) Molecular identification of canine podocalyxin-like protein 1 as a renal tubulogenic regulator. J Am Soc Nephrol 16:1612–1622

    Article  PubMed  CAS  Google Scholar 

  • Cordell J, Richardson TC, Pulford KA, Ghosh AK, Gatter KC, Heyderman E, Mason DY (1985) Production of monoclonal antibodies against human epithelial membrane antigen for use in diagnostic immunocytochemistry. Br J Cancer 52:347–354

    PubMed  CAS  Google Scholar 

  • Davies JA, Bard JB (1998) The development of the kidney. Curr Top Dev Biol 39:245–301

    Article  PubMed  CAS  Google Scholar 

  • Deen PM, Knoers NV (1998) Physiology and pathophysiology of the aquaporin-2 water channel. Curr Opin Nephrol Hypertens 7:37–42

    PubMed  CAS  Google Scholar 

  • Dressler GR (2006) The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529

    Article  PubMed  CAS  Google Scholar 

  • Dressler GR, Douglass EC (1992) Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms tumor. Proc Natl Acad Sci USA 89:1179–1183

    Article  PubMed  CAS  Google Scholar 

  • Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, Bonventre JV (2005) Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest 115:1743–1755

    Article  PubMed  CAS  Google Scholar 

  • Eccles MR, He S, Legge M, Kumar R, Fox J, Zhou C, French M, Tsai RW (2002) PAX genes in development and disease: the role of PAX2 in urogenital tract development. Int J Dev Biol 46:535–544

    PubMed  CAS  Google Scholar 

  • Funderburgh JL (2000) Keratan sulfate: structure, biosynthesis, and function. Glycobiology 10:951–958

    Article  PubMed  CAS  Google Scholar 

  • Gerdes J, Schwab U, Lemke H, Stein H (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 31:13–20

    Article  PubMed  CAS  Google Scholar 

  • Gobe GC, Johnson DW (2007) Distal tubular epithelial cells of the kidney: potential support for proximal tubular cell survival after renal injury. Int J Biochem Cell Biol 39:1551–1561

    Article  PubMed  CAS  Google Scholar 

  • Gubhaju L, Laslett A, Bertram JF, Zulli A, Black MJ (2008) Immunohistochemical localisation of TRA-1-60, TRA-1-81, GCTM-2 and podocalyxin in the developing baboon kidney. Histochem Cell Biol 129:651–657

    Article  PubMed  CAS  Google Scholar 

  • Haycock GB (1998) Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn. Br J Urol 81(Suppl 2):33–38

    PubMed  Google Scholar 

  • Heyderman E, Steele K, Ormerod MG (1979) A new antigen on the epithelial membrane: its immunoperoxidase localisation in normal and neoplastic tissue. J Clin Pathol 32:35–39

    Article  PubMed  CAS  Google Scholar 

  • Hopkins C, Li J, Rae F, Little MH (2009) Stem cell options for kidney disease. J Pathol 217:265–281

    Article  PubMed  CAS  Google Scholar 

  • Humphreys BD, Bonventre JV (2007) The contribution of adult stem cells to renal repair. Nephrol Ther 3:3–10

    PubMed  CAS  Google Scholar 

  • Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV (2008) Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2:284–291

    Article  PubMed  CAS  Google Scholar 

  • Imgrund M, Grone E, Grone HJ, Kretzler M, Holzman L, Schlondorff D, Rothenpieler UW (1999) Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1. Kidney Int 56:1423–1431

    Article  PubMed  CAS  Google Scholar 

  • Kerjaschki D, Sharkey DJ, Farquhar MG (1984) Identification and characterization of podocalyxin—the major sialoprotein of the renal glomerular epithelial cell. J Cell Biol 98:1591–1596

    Article  PubMed  CAS  Google Scholar 

  • Kim D, Dressler GR (2005) Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol 16:3527–3534

    Article  PubMed  CAS  Google Scholar 

  • Knepper MA, Wade JB, Terris J, Ecelbarger CA, Marples D, Mandon B, Chou CL, Kishore BK, Nielsen S (1996) Renal aquaporins. Kidney Int 49:1712–1717

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Lazzeri E, Crescioli C, Ronconi E, Mazzinghi B, Sagrinati C, Netti GS, Angelotti ML, Parente E, Ballerini L, Cosmi L, Maggi L, Gesualdo L, Rotondi M, Annunziato F, Maggi E, Lasagni L, Serio M, Romagnani S, Vannelli GB, Romagnani P (2007) Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol 18:3128–3138

    Article  PubMed  CAS  Google Scholar 

  • Lieberthal W, Nigam SK (1998) Acute renal failure. I. Relative importance of proximal vs. distal tubular injury. Am J Physiol 275:F623–F631

    PubMed  CAS  Google Scholar 

  • Maeshima A, Maeshima K, Nojima Y, Kojima I (2002) Involvement of Pax-2 in the action of activin A on tubular cell regeneration. J Am Soc Nephrol 13:2850–2859

    Article  PubMed  CAS  Google Scholar 

  • Meder D, Shevchenko A, Simons K, Fullekrug J (2005) Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells. J Cell Biol 168:303–313

    Article  PubMed  CAS  Google Scholar 

  • Nielsen JS, Graves ML, Chelliah S, Vogl AW, Roskelley CD, McNagny KM (2007) The CD34-related molecule podocalyxin is a potent inducer of microvillus formation. PLoS One 2:e237

    Article  PubMed  CAS  Google Scholar 

  • Ojakian GK, Nelson WJ, Beck KA (1997) Mechanisms for de novo biogenesis of an apical membrane compartment in groups of simple epithelial cells surrounded by extracellular matrix. J Cell Sci 110:2781–2794

    PubMed  CAS  Google Scholar 

  • Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q (2004) The renal papilla is a niche for adult kidney stem cells. J Clin Invest 114:795–804

    PubMed  CAS  Google Scholar 

  • Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q (2009) Proliferation and migration of label-retaining cells of the kidney papilla. J Am Soc Nephrol 20(11):2315–2327

    Article  PubMed  Google Scholar 

  • Pollack AL, Runyan RB, Mostov KE (1998) Morphogenetic mechanisms of epithelial tubulogenesis: MDCK cell polarity is transiently rearranged without loss of cell–cell contact during scatter factor/hepatocyte growth factor-induced tubulogenesis. Dev Biol 204:64–79

    Article  PubMed  CAS  Google Scholar 

  • Ribes D, Fischer E, Calmont A, Rossert J (2003) Transcriptional control of epithelial differentiation during kidney development. J Am Soc Nephrol 14(Suppl 1):S9–S15

    Article  PubMed  CAS  Google Scholar 

  • Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M, Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani S, Romagnani P (2006) Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol 17:2443–2456

    Article  PubMed  CAS  Google Scholar 

  • Schopperle WM, DeWolf WC (2007) The TRA-1-60 and TRA-1-81 human pluripotent stem cell markers are expressed on podocalyxin in embryonal carcinoma. Stem Cells 25:723–730

    Article  PubMed  CAS  Google Scholar 

  • Silva FG, Nadasdy T, Laszik Z (1993) Immunohistochemical and lectin dissection of the human nephron in health and disease. Arch Pathol Lab Med 117:1233–1239

    PubMed  CAS  Google Scholar 

  • Stayner C, Iglesias DM, Goodyer PR, Ellis L, Germino G, Zhou J, Eccles MR (2006) Pax2 gene dosage influences cystogenesis in autosomal dominant polycystic kidney disease. Hum Mol Genet 15:3520–3528

    Article  PubMed  CAS  Google Scholar 

  • Stripp BR, Reynolds SD (2008) Maintenance and repair of the bronchiolar epithelium. Proc Am Thorac Soc 5:328–333

    Article  PubMed  Google Scholar 

  • Takeda T, Go WY, Orlando RA, Farquhar MG (2000) Expression of podocalyxin inhibits cell-cell adhesion and modifies junctional properties in Madin-Darby canine kidney cells. Mol Biol Cell 11:3219–3232

    PubMed  CAS  Google Scholar 

  • Torres M, Gomez-Pardo E, Dressler GR, Gruss P (1995) Pax-2 controls multiple steps of urogenital development. Development 121:4057–4065

    PubMed  CAS  Google Scholar 

  • Vigneau C, Polgar K, Striker G, Elliott J, Hyink D, Weber O, Fehling HJ, Keller G, Burrow C, Wilson P (2007) Mouse embryonic stem cell-derived embryoid bodies generate progenitors that integrate long term into renal proximal tubules in vivo. J Am Soc Nephrol 18:1709–1720

    Article  PubMed  CAS  Google Scholar 

  • Wang AZ, Ojakian GK, Nelson WJ (1990) Steps in the morphogenesis of a polarized epithelium. II. Disassembly and assembly of plasma membrane domains during reversal of epithelial cell polarity in multicellular epithelial (MDCK) cysts. J Cell Sci 95:153–165

    PubMed  Google Scholar 

  • Winyard PJ, Risdon RA, Sams VR, Dressler GR, Woolf AS (1996) The PAX2 transcription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations. J Clin Invest 98:451–459

    Article  PubMed  CAS  Google Scholar 

  • Witzgall R, Brown D, Schwarz C, Bonventre JV (1994) Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 93:2175–2188

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

J.E.C. and S.K.C. would like to thank the The University of Southampton and Wessex Renal Research and Transplant Unit, Queen Alexandra Hospital, Cosham, Portsmouth, UK, for project funding. N.H. would like to acknowledge the support of the Medical Research Council and the Wellcome Trust. We would like to thank Ron Lee and Susan Wilson from the University of Southampton Medical School Histochemistry Research Unit for technical support and Anton Page from the Southampton Medical School Bioimaging Unit for help with figures.

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Authors and Affiliations

  1. Infection, Inflammation and Immunity Division, School of Medicine, University of Southampton, Southampton, UK

    Irina Fesenko, Danielle Franklin, Paul Garnett, Paul Bass, Sara Campbell, Michelle Hardyman & Jane Collins

  2. Human Genetics Division, School of Medicine, University of Southampton, Southampton, UK

    David Wilson & Neil Hanley

  3. Wessex Renal and Transplant Unit, Queen Alexandra Hospital, Portsmouth, UK

    Danielle Franklin & Sara Campbell

  4. Endocrinology and Diabetes, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    Neil Hanley

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  1. Irina Fesenko
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Correspondence to Jane Collins.

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Fesenko, I., Franklin, D., Garnett, P. et al. Stem cell marker TRA-1-60 is expressed in foetal and adult kidney and upregulated in tubulo-interstitial disease. Histochem Cell Biol 134, 355–369 (2010). https://doi.org/10.1007/s00418-010-0741-7

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