Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Expression Analyses Revealed Thymic Stromal Co-Transporter/Slc46A2 Is in Stem Cell Populations and Is a Putative Tumor Suppressor

  • Kim, Ki Yeon (Department of Biological Sciences, Inha University) ;
  • Lee, Gwanghee (Department of Cell Biology and Physiology, Washington University School of Medicine) ;
  • Yoon, Minsang (Department of Biological Sciences, Inha University) ;
  • Cho, Eun Hye (Department of Biological Sciences, Inha University) ;
  • Park, Chan-Sik (Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Kim, Moon Gyo (Department of Biological Sciences, Inha University)
  • Received : 2015.02.12
  • Accepted : 2015.03.10
  • Published : 2015.06.30
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Abstract

By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the $CD31^+$endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-$1^+$ fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation.

Keywords

References

  1. Ahn, S., Lee, G., Yang, S.J., Lee, D., Lee, S., Shin, H.S., Kim, M.C., Lee, K.N., Palmer, D.C., Theoret, M.R., et al. (2008). TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation. PLos Biol. 6, e191. https://doi.org/10.1371/journal.pbio.0060191
  2. Alves, N.L., Takahama, Y., Ohigashi, I., Ribeiro, A.R., Baik, S., Anderson, G., and Jenkinson, W.E. (2014). Serial progression of cortical and medullary thymic epithelial microenvironments. Eur. J. Immunol. 44, 16-22. https://doi.org/10.1002/eji.201344110
  3. Balciunaite, G., Keller, M.P., Balciunaite, E., Piali, L., Zuklys, S., Mathieu, Y.D., Gill, J., Boyd, R., Sussman, D.J., and Hollander, G.A. (2002). Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat. Immunol. 3, 1102-1108. https://doi.org/10.1038/ni850
  4. Bellavia, D., Checquolo, S., Campese, A.F., Felli, M.P., Gulino, A., and Screpanti, I. (2008). Notch3: from subtle structural differences to functional diversity. Oncogene 27, 5092-5098. https://doi.org/10.1038/onc.2008.230
  5. Bennett, A.R., Farley, A., Blair, N.F., Gordon, J., Sharp, L., and Blackburn, C.C. (2002). Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803-814. https://doi.org/10.1016/S1074-7613(02)00321-7
  6. Berzins, S.P., Uldrich, A.P., Sutherland, J.S., and Gill, J. (2002). Thymic regeneration: teaching an old immune system new tricks. Trends Mol. Med. 8, 469-476. https://doi.org/10.1016/S1471-4914(02)02415-2
  7. Blackburn, C.C., and Manley, N.R. (2004). Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4, 278-289. https://doi.org/10.1038/nri1331
  8. Blackburn, C.C., Augustine, C.L., Li, R., Harvey, R.P., Malin, M.A., Boyd, R.L., Miller, J.F., and Morahan, G. (1996). The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl. Acad. Sci. USA 93, 5742-5746. https://doi.org/10.1073/pnas.93.12.5742
  9. Blackburn, C.C., Manley, N.R., Palmer, D.B., Boyd, R.L., Anderson, G., and Ritter, M.A. (2002). One for all and all for one: thymic epithelial stem cells and regeneration. Trends Immunol. 23, 391-395. https://doi.org/10.1016/S1471-4906(02)02265-2
  10. Bleul, C.C., and Boehm, T. (2005). BMP signaling is required for normal thymus development. J. Immunol. 175, 5213-5221. https://doi.org/10.4049/jimmunol.175.8.5213
  11. Bleul, C.C., Corbeaux, T., Reuter, A., Fisch, P., Monting, J.S., and Boehm, T. (2006). Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992-996. https://doi.org/10.1038/nature04850
  12. Boehm, T. (2008). Thymus development and function. Curr. Opin. Immunol. 20, 178-184. https://doi.org/10.1016/j.coi.2008.03.001
  13. Bonfanti, P., Claudinot, S., Amici, A.W., Farley, A., Blackburn, C.C., and Barrandon, Y. (2010). Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466, 978-982. https://doi.org/10.1038/nature09269
  14. Botti, E., Spallone, G., Moretti, F., Marinari, B., Pinetti, V., Galanti, S., De Meo, P.D., De Nicola, F., Ganci, F., Castrignano, T., et al. (2011). Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas. Proc. Natl. Acad. Sci. USA 108, 13710-13715. https://doi.org/10.1073/pnas.1110931108
  15. Bredenkamp, N., Nowell, C.S., and Blackburn, C.C. (2014). Regeneration of the aged thymus by a single transcription factor. Development 141, 1627-1637. https://doi.org/10.1242/dev.103614
  16. Brems, H., Park, C., Maertens, O., Pemov, A., Messiaen, L., Upadhyaya, M., Claes, K., Beert, E., Peeters, K., Mautner, V. (2009). Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 69, 7393-7401. https://doi.org/10.1158/0008-5472.CAN-09-1752
  17. Chen, C., Kim, M.G., Soo Lyu, M., Kozak, C.A., Schwartz, R.H., and Flomerfelt, F.A. (2000). Characterization of the mouse gene, human promoter and human cDNA of TSCOT reveals strong interspecies homology. Biochim. Biophys. Acta 1493, 159-169. https://doi.org/10.1016/S0167-4781(00)00177-9
  18. Chen, L., Xiao, S., and Manley, N.R. (2009). Foxn1 is required to maintain the postnatal thymic microenvironment in a dosagesensitive manner. Blood 113, 567-574. https://doi.org/10.1182/blood-2008-05-156265
  19. Cheng, L., Guo, J., Sun, L., Fu, J., Barnes, P.F., Metzger, D., Chambon, P., Oshima, R.G., Amagai, T., and Su, D.M. (2010). Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J. Biol. Chem. 285, 5836-5847. https://doi.org/10.1074/jbc.M109.072124
  20. Chinn, I.K., Blackburn, C.C., Manley, N.R., and Sempowski, G.D. (2012). Changes in primary lymphoid organs with aging. Semin. Immunol. 24 309-320. https://doi.org/10.1016/j.smim.2012.04.005
  21. Chu, G., Qi, S., Yang, G., Dou, K., Du, J., and Lu, Z. (2012). Gastrointestinal tract specific gene GDDR inhibits the progression of gastric cancer in a TFF1 dependent manner. Mol. Cell. Biochem. 359, 369-374. https://doi.org/10.1007/s11010-011-1030-z
  22. Cimpean, A.M., Encica, S., Raica, M., and Ribatti, D. (2011). SOX2 gene expression in normal human thymus and thymoma. Clin. Exp. Med. 11, 251-254. https://doi.org/10.1007/s10238-010-0127-0
  23. Corbeaux, T., Hess, I., Swann, J.B., Kanzler, B., Haas-Assenbaum, A., and Boehm, T. (2010). Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc. Natl. Acad. Sci. USA 107, 16613-16618. https://doi.org/10.1073/pnas.1004623107
  24. de la Garza, G., Schleiffarth, J.R., Dunnwald, M., Mankad, A., Weirather, J.L., Bonde, G., Butcher, S., Mansour, T.A., Kousa, Y.A., Fukazawa, C.F., et al. (2012). Interferon regulatory factor 6 promotes differentiation of the periderm by activating expression of grainyhead-Like 3. J. Invest. Dermatol. 133, 68-77.
  25. Diop-Bove, N., Jain, M., Scaglia, F., and Goldman, I.D. (2013). A novel deletion mutation in the proton-coupled folate transporter (PCFT, SLC46A1) in a Nicaraguan child with hereditary folate malabsorption. Gene 527, 673-74. https://doi.org/10.1016/j.gene.2013.06.039
  26. Dooley, J., Erickson, M., Roelink, H., and Farr, A.G. (2005). Nude thymic rudiment lacking functional foxn1 resembles respiratory epithelium. Dev. Dyn. 233, 1605-1612. https://doi.org/10.1002/dvdy.20495
  27. Dudakov, J.A., Hanash, A.M., Jenq, R.R., Young, L.F., Ghosh, A., Singer, N.V., West, M.L., Smith, O.M., Holland, A.M., Tsai, J.J., et al. (2012). Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91-95. https://doi.org/10.1126/science.1218004
  28. Engelmark, M.T., Ivansson, E.L., Magnusson, J.J., Gustavsson, I.M., Beskow, A.H., Magnusson, P.K.E., and Gyllensten, U.B. (2006). Identification of susceptibility loci for cervical carcinoma by genome scan of affected sib-pairs. Hum. Mol. Genet. 15, 3351-3360. https://doi.org/10.1093/hmg/ddl411
  29. Engelmark, M.T., Ivansson, E.L., Magnusson, J.J., Gustavsson, I.M., Wyoni, P.I., Ingman, M., Magnusson, P.K., and Gyllensten, U.B. (2008). Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis. Hum. Genet. 123, 437-443. https://doi.org/10.1007/s00439-008-0494-8
  30. Gill, J., Malin, M., Hollander, G.A., and Boyd, R. (2002). Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat. Immunol. 3, 635-642.
  31. Gill, J., Malin, M., Sutherland, J., Gray, D., Hollander, G., and Boyd, R. (2003). Thymic generation and regeneration. Immunol. Rev. 195, 28-50. https://doi.org/10.1034/j.1600-065X.2003.00077.x
  32. Golebiewska, A., Brons, N.H., Bjerkvig, R., and Niclou, S.P. (2011). Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell 8, 136-147. https://doi.org/10.1016/j.stem.2011.01.007
  33. Gordon, J., and Manley, N.R. (2011). Mechanisms of thymus organogenesis and morphogenesis. Development 138, 3865- 3878. https://doi.org/10.1242/dev.059998
  34. Gordon, J., Patel, S.R., Mishina, Y., and Manley, N.R. (2010). Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev. Biol. 339, 141-154. https://doi.org/10.1016/j.ydbio.2009.12.026
  35. Graf, U., Casanova, E.A., and Cinelli, P. (2011). The role of the leukemia inhibitory factor (LIF) - pathway in derivation and maintenance of murine pluripotent stem cells. Genes 2, 280-297. https://doi.org/10.3390/genes2010280
  36. Hetzer-Egger, C., Schorpp, M., Haas-Assenbaum, A., Balling, R., Peters, H., and Boehm, T. (2002). Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175- 1181. https://doi.org/10.1002/1521-4141(200204)32:4<1175::AID-IMMU1175>3.0.CO;2-U
  37. Hirayama, T., Asano, Y., Iida, H., Watanabe, T., Nakamura, T., and Goitsuka, R. (2014). Meis1 is required for the maintenance of postnatal thymic epithelial cells. PLoS One 9, e89885. https://doi.org/10.1371/journal.pone.0089885
  38. Hollander, G., Gill, J., Zuklys, S., Iwanami, N., Liu, C., and Takahama, Y. (2006). Cellular and molecular events during early thymus development. Immunol. Rev. 209, 28-46. https://doi.org/10.1111/j.0105-2896.2006.00357.x
  39. Huang, J., and Muegge, K. (2001). Control of chromatin accessibility for V(D)J recombination by interleukin-7. J. Leukoc. Biol. 69, 907-911.
  40. Imaoka, S., Yoneda, Y., Sugimoto, T., Hiroi, T., Yamamoto, K., Nakatani, T., and Funae, Y. (2000). CYP4B1 is a possible risk factor for bladder cancer in humans. Biochem. Biophys. Res. Commun. 277, 776-780. https://doi.org/10.1006/bbrc.2000.3740
  41. Jerome, L.A., and Papaioannou, V.E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet. 27, 286-291. https://doi.org/10.1038/85845
  42. Jiang, W., Swiggard, W.J., Heufler, C., Peng, M., Mirza, A., Steinman, R.M., and Nussenzweig, M.C. (1995). The receptor DEC- 205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 375, 151-155. https://doi.org/10.1038/375151a0
  43. Kho, A.T., Bhattacharya, S., Tantisira, K.G., Carey, V.J., Gaedigk, R., Leeder, J.S., Kohane, I.S., Weiss, S.T., and Mariani, T.J. (2010). Transcriptomic analysis of human lung development. Am. J. Respir. Crit. Care Med. 181, 54-63. https://doi.org/10.1164/rccm.200907-1063OC
  44. Kim, M.G., Chen, C., Flomerfelt, F.A., Germain, R.N., and Schwartz, R.H. (1998). A subtractive PCR-based cDNA library made from fetal thymic stromal cells. J. Immunol. Methods 213, 169-182. https://doi.org/10.1016/S0022-1759(98)00031-3
  45. Kim, M.G., Flomerfelt, F.A., Lee, K.N., Chen, C., and Schwartz, R.H. (2000). A putative 12 transmembrane domain cotransporter expressed in thymic cortical epithelial cells. J. Immunol. 164, 3185-3192. https://doi.org/10.4049/jimmunol.164.6.3185
  46. Kirchner, J., Forbush, K.A., and Bevan, M.J. (2001). Identification and Characterization of thymus LIM Protein: targeted disruption reduces thymus cellularity. Mol. Cell. Biol. 21, 8592-8604. https://doi.org/10.1128/MCB.21.24.8592-8604.2001
  47. Klug, D.B., Carter, C., Crouch, E., Roop, D., Conti, C.J., and Richie, E.R. (1998). Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl. Acad. Sci. USA 95, 11822-11827. https://doi.org/10.1073/pnas.95.20.11822
  48. Klug, D.B., Carter, C., Gimenez-Conti, I.B., and Richie, E.R. (2002). Cutting edge: thymocyte-independent and thymocytedependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842-2845. https://doi.org/10.4049/jimmunol.169.6.2842
  49. Lee, G., Kim, K.Y., Chang, C.H., and Kim, M.G. (2012). Thymic epithelial requirement for ${\gamma}{\delta}$ T cell development revealed in the cell ablation transgenic system with TSCOT promoter. Mol. Cells 34, 481-493. https://doi.org/10.1007/s10059-012-0246-4
  50. Liang, H., Coles, A.H., Zhu, Z., Zayas, J., Jurecic, R., Kang, J., and Jones, S.N., (2007). Noncanonical Wnt signaling promotes apoptosis in thymocyte development. J. Exp. Med. 204, 3077-3084. https://doi.org/10.1084/jem.20062692
  51. Liu, J., Hadjokas, N., Mosley, B., Estrov, Z., Spence, M.J., and Vestal, R.E. (1998). Oncostatin M-specific receptor expression and function in regulating cell proliferation of normal and malignant mammary epithelial cells. Cytokine 10, 295-302. https://doi.org/10.1006/cyto.1997.0283
  52. Liu, K., Lin, B., Zhao, M., Yang, X., Chen, M., Gao, A., Que, J., and Lan, X. (2013). The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cell. Signal. 25, 1264-1271. https://doi.org/10.1016/j.cellsig.2013.02.013
  53. Liu, G., Wang, L., Pang, T., Zhu, D., Xu, Y., Wang, H., Cong, X., and Liu, Y. (2014). Umbilical cord-derived mesenchymal stem cells regulate thymic epithelial cell development and function in Foxn1-/- mice. Cell. Mol. Immunol. 11, 275-284. https://doi.org/10.1038/cmi.2013.69
  54. Lynch, H.E., Goldberg, G.L., Chidgey, A., Van den Brink, M.R., Boyd, R., and Sempowski, G.D. (2009). Thymic involution and immune reconstitution. Trends Immunol. 30, 366-373. https://doi.org/10.1016/j.it.2009.04.003
  55. Malik, S., Kakar, N., Hasnain, S., Ahmad, J., Wilcox, E.R., and Naz, S. (2010). Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Clin. Genet. 78, 247-256. https://doi.org/10.1111/j.1399-0004.2010.01375.x
  56. Manley, N.R., and Capecchi, M.R. (1995). The role of Hoxa-3 in mouse thymus and thyroid development. Development 121, 1989-2003.
  57. Manley, N.R., and Condie, B.G. (2010). Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog. Mol. Biol. Transl. Sci. 92, 103-120.
  58. Manley, N.R., Selleri, L., Brendolan, A., Gordon, J., and Cleary, M.L. (2004). Abnormalities of caudal pharyngeal pouch development in Pbx1 knockout mice mimic loss of Hox3 paralogs. Dev. Biol. 276, 301-312. https://doi.org/10.1016/j.ydbio.2004.08.030
  59. Moore-Scott, B.A., and Manley, N.R. (2005). Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm- derived organs. Dev. Biol. 278, 323-335. https://doi.org/10.1016/j.ydbio.2004.10.027
  60. Murata, S., Sasaki, K., Kishimoto, T., Niwa, S., Hayashi, H., Takahama, Y., and Tanaka, K. (2007). Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349-1353. https://doi.org/10.1126/science.1141915
  61. Nehls, M., Kyewski, B., Messerle, M., Waldschutz, R., Schuddekopf, K., Smith, A.J., and Boehm, T. (1996). Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886-889. https://doi.org/10.1126/science.272.5263.886
  62. Nowell, C.S., Bredenkamp, N., Tetelin, S., Jin, X., Tischner, C., Vaidya, H., Sheridan, J.M., Stenhouse, F.H., Heussen, R., Smith, A.J., et al. (2011). Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but Is dispensable for medullary sublineage divergence. PLoS Genet. 7, e1002348. https://doi.org/10.1371/journal.pgen.1002348
  63. Obermann, H., Wingbermuhle, A., Munz, S., and Kirchhoff, C. (2003). A putative 12-transmembrane domain cotransporter associated with apical membranes of the epididymal duct. J. Androl. 24, 542-556. https://doi.org/10.1002/j.1939-4640.2003.tb02706.x
  64. Park, D. (1997). Cloning, sequencing, and overexpression of SH2/SH3 adaptor protein Nck from mouse thymus. Mol. Cells 7, 231-236.
  65. Park, C.S., Lee, G., Yang, S.J., Ahn, S., Kim, K.Y., Shin, H., and Kim, M.G. (2013). Differential lineage specification of thymic epithelial cells from bipotent precursors revealed by TSCOT promoter activities. Genes Immun. 14, 401-406. https://doi.org/10.1038/gene.2013.30
  66. Potter, C.S., Pruett, N.D., Kern, M.J., Baybo, M.A., Godwin, A.R., Potter, K.A., Peterson, R.L., Sundberg, J.P., and Awgulewitsch, A. (2010). The nude mutant gene Foxn1 Is a HOXC13 regulatory target during hair follicle and nail differentiation. J. Invest. Dermatol. 131, 828-837.
  67. Richardson, R.J., Dixon, J., Malhotra, S., Hardman, M.J., Knowles, L., Boot-Handford, R.P., Shore, P., Whitmarsh, A., and Dixon, M.J. (2006). Irf6 is a key determinant of the keratinocyte proliferation- differentiation switch. Nat. Genet. 38, 1329-1334. https://doi.org/10.1038/ng1894
  68. Roberts, N.A., White, A.J., Jenkinson, W.E., Turchinovich, G., Nakamura, K., Withers, D.R., McConnell, F.M., Desanti, G.E., Benezech, C., Parnell, S.M., et al. (2012). Rank signaling links the development of invariant ${\gamma}{\delta}$ T cell progenitors and Aire(+) medullary epithelium. Immunity 36, 427-437. https://doi.org/10.1016/j.immuni.2012.01.016
  69. Rodewald, H.R. (2008). Thymus organogenesis. Annu. Rev. Immunol. 26, 355-388. https://doi.org/10.1146/annurev.immunol.26.021607.090408
  70. Rodewald, H.R., Paul, S., Haller, C., Bluethmann, H., and Blum, C. (2001). Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763-768. https://doi.org/10.1038/414763a
  71. Rossi, S.W., Jenkinson, W.E., Anderson, G., and Jenkinson, E.J. (2006). Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988-991. https://doi.org/10.1038/nature04813
  72. Sahin, U., Koslowski, M., Dhaene, K., Usener, D., Brandenburg, G., Seitz, G., Huber, C., and Tureci, O. (2008). Claudin-18 splice variant 2 is a Pan-cancer target suitable for therapeutic antibody development. Clin. Cancer Res. 14, 7624-7634. https://doi.org/10.1158/1078-0432.CCR-08-1547
  73. Saunders-Pullman, R., Barrett, M.J., Stanley, K.M., Luciano, M.S., Shanker, V., Severt, L., Hunt, A., Raymond, D., Ozelius, L.J., and Bressman, S.B. (2010). LRRK2G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov. Disord. 25, 2536-2541. https://doi.org/10.1002/mds.23314
  74. Shakib, S., Desanti, G.E., Jenkinson, W.E., Parnell, S.M., Jenkinson, E.J., and Anderson, G. (2009). Checkpoints in the development of thymic cortical epithelial cells. J. Immunol. 182, 130-137. https://doi.org/10.4049/jimmunol.182.1.130
  75. Shen, M.M., and Leder, P. (1992). Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro. Proc. Natl. Acad. Sci. USA 89, 8240-8244. https://doi.org/10.1073/pnas.89.17.8240
  76. Su, D., Ellis, S., Napier, A., Lee, K., and Manley, N.R. (2001). Hoxa3 and Pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev. Biol. 236, 316-329. https://doi.org/10.1006/dbio.2001.0342
  77. Sun, L., Luo, H., Li, H., and Zhao, Y. (2013). Thymic epithelial cell development and differentiation: cellular and molecular regulation. Protein Cell 4, 342-355. https://doi.org/10.1007/s13238-013-3014-0
  78. Sutherland, J.S., Goldberg, G.L., Hammett, M.V., Uldrich, A.P., Berzins, S.P., Heng, T.S., Blazar, B.R., Millar, J.L., Malin, M.A., Chidgey, A.P., et al. (2005). Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175, 2741-2753. https://doi.org/10.4049/jimmunol.175.4.2741
  79. Swann, J.B., and Boehm, T. (2007). Back to the beginning - the quest for thymic epithelial stem cells. Eur. J. Immunol. 37, 2364- 2366. https://doi.org/10.1002/eji.200737709
  80. Ucar, A., Ucar, O., Klug, P., Matt, S., Brunk, F., Hofmann, T.G., and Kyewski, B. (2014). Adult thymus Contains FoxN1- epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41, 257-269. https://doi.org/10.1016/j.immuni.2014.07.005
  81. Wallin, J., Eibel, H., Neubuser, A., Wilting, J., Koseki, H., and Balling, R. (1996). Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23-30.
  82. Watson, A.P., Evans, R.L., and Egland, K.A. (2013). Multiple functions of sushi domain containing 2 (SUSD2) in breast tumorigenesis. Mol. Cancer Res. 11, 74-85. https://doi.org/10.1158/1541-7786.MCR-12-0501-T
  83. Wei, Q., and Condie, B.G. (2011). A focused in situ hybridization screen identifies candidate transcriptional regulators of thymic epithelial cell development and function. PLoS One 6, e26795. https://doi.org/10.1371/journal.pone.0026795
  84. Wong, K., Lister, N.L., Barsanti, M., Lim, J.M., Hammett, M.V., Khong, D.M., Siatskas, C., Gray, D.H., Boyd, R.L., and Chidgey, A.P. (2014). Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep. 8, 1198-1209. https://doi.org/10.1016/j.celrep.2014.07.029
  85. Yang, S.J., Ahn, S., Park, C.S., Choi, S., and Kim, M.G. (2005). Identifying subpopulations of thymic epithelial cells by flow cytometry using a new specific thymic epithelial marker, Ly110. J. Immunol. Methods 297, 265-270. https://doi.org/10.1016/j.jim.2004.12.021
  86. Yu, Z., Bhandari, A., Mannik, J., Pham, T., Xu, X., and Andersen, B. (2008). Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Dev. Biol. 319, 56-67. https://doi.org/10.1016/j.ydbio.2008.04.001
  87. Zamisch, M., Moore-Scott, B., Su, D.M., Lucas, P.J., Manley, N., and Richie, E.R. (2005). Ontogeny and regulation of IL-7- expressing thymic epithelial cells. J. Immunol. 174, 60-67. https://doi.org/10.4049/jimmunol.174.1.60
  88. Zhou, S., Schuetz, J.D., Bunting, K.D., Colapietro, A.M., Sampath, J., Morris, J.J., Lagutina, I., Grosveld, G.C., Osawa, M., Nakauchi, H., et al. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat. Med. 7, 1028-1034. https://doi.org/10.1038/nm0901-1028

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