Kidney Specific Protein-Positive Cells Derived from Embryonic Stem Cells Reproduce Tubular Structures In Vitro and Differentiate into Renal Tubular Cells
Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.
References
[1]
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156.
[2]
Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448: 313–317.
[3]
Robinton DA, Daley GQ (2012) The promise of induced pluripotent stem cells in research and therapy. Nature 481: 295–305.
[4]
Kim D, Dressler GR (2005) Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol 16: 3527–3534.
[5]
Vigneau C, Polgar K, Striker G, Elliott J, Hyink D, et al. (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.
[6]
Kobayashi T, Tanaka H, Kuwana H, Inoshita S, Teraoka H, et al. (2005) Wnt4-transformed mouse embryonic stem cells differentiate into renal tubular cells. Biochem Biophys Res Commun 336: 585–595.
[7]
Bruce SJ, Rea RW, Steptoe AL, Busslinger M, Bertram JF, et al. (2007) In vitro differentiation of murine embryonic stem cells toward a renal lineage. Differentiation 75: 337–349.
[8]
Mae S, Shirasawa S, Yoshie S, Sato F, Kanoh Y, et al. (2010) Combination of small molecules enhances differentiation of mouse embryonic stem cells into intermediate mesoderm through BMP7-positive cells. Biochem Biophys Res Commun 393: 877–882.
[9]
Batchelder CA, Lee CC, Matsell DG, Yoder MC, Tarantal AF (2009) Renal ontogeny in the rhesus monkey (Macaca mulatta) and directed differentiation of human embryonic stem cells towards kidney precursors. Differentiation 78: 45–56.
[10]
Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, et al. (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408: 92–96.
[11]
Yurugi-Kobayashi T, Itoh H, Yamashita J, Yamahara K, Hirai H, et al. (2003) Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage. Blood 101: 2675–2678.
[12]
Yurugi-Kobayashi T, Itoh H, Schroeder T, Nakano A, Narazaki G, et al. (2006) Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors. Arterioscler Thromb Vasc Biol 26: 1977–1984.
[13]
Sone M, Itoh H, Yamashita J, Yurugi-Kobayashi T, Suzuki Y, et al. (2003) Different differentiation kinetics of vascular progenitor cells in primate and mouse embryonic stem cells. Circulation 107: 2085–2088.
[14]
Morizane R, Monkawa T, Itoh H (2009) Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro. Biochem Biophys Res Commun 390: 1334–1339.
[15]
Shao X, Johnson JE, Richardson JA, Hiesberger T, Igarashi P (2002) A minimal Ksp-cadherin promoter linked to a green fluorescent protein reporter gene exhibits tissue-specific expression in the developing kidney and genitourinary tract. J Am Soc Nephrol 13: 1824–1836.
[16]
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.
[17]
Sekine M, Taya C, Shitara H, Kikkawa Y, Akamatsu N, et al. (2006) The cis-regulatory element Gsl5 is indispensable for proximal straight tubule cell-specific transcription of core 2 beta-1,6-N-acetylglucosaminyltransferase in the mouse kidney. J Biol Chem 281: 1008–1015.
[18]
Thomson RB, Aronson PS (1999) Immunolocalization of Ksp-cadherin in the adult and developing rabbit kidney. Am J Physiol 277: F146–156.
[19]
Prozialeck WC, Lamar PC, Appelt DM (2004) Differential expression of E-cadherin, N-cadherin and beta-catenin in proximal and distal segments of the rat nephron. BMC Physiol 4: 10.
[20]
Thomson RB, Igarashi P, Biemesderfer D, Kim R, Abu-Alfa A, et al. (1995) Isolation and cDNA cloning of Ksp-cadherin, a novel kidney-specific member of the cadherin multigene family. J Biol Chem 270: 17594–17601.
[21]
Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H (2006) Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 343: 159–166.
[22]
Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, et al. (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.
[23]
Rogers SA, Ryan G, Hammerman MR (1991) Insulin-like growth factors I and II are produced in the metanephros and are required for growth and development in vitro. J Cell Biol 113: 1447–1453.
[24]
Hammerman MR, Miller SB (1994) Therapeutic use of growth factors in renal failure. J Am Soc Nephrol 5: 1–11.
[25]
Taub M, Wang Y, Szczesny TM, Kleinman HK (1990) Epidermal growth factor or transforming growth factor alpha is required for kidney tubulogenesis in matrigel cultures in serum-free medium. Proc Natl Acad Sci U S A 87: 4002–4006.
[26]
Nishinakamura R, Osafune K (2006) Essential roles of Sall family genes in kidney development. J Physiol Sci 56: 131–136.
[27]
Sekine M, Monkawa T, Morizane R, Matsuoka K, Taya C, et al. (2012) Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury. Transgenic Res 21: 51–62.
[28]
Schmitt R, Ellison DH, Farman N, Rossier BC, Reilly RF, et al. (1999) Developmental expression of sodium entry pathways in rat nephron. Am J Physiol 276: F367–381.
[29]
Echevarria M, Windhager EE, Tate SS, Frindt G (1994) Cloning and expression of AQP3, a water channel from the medullary collecting duct of rat kidney. Proc Natl Acad Sci U S A 91: 10997–11001.
[30]
Bariety J, Mandet C, Hill GS, Bruneval P (2006) Parietal podocytes in normal human glomeruli. J Am Soc Nephrol 17: 2770–2780.