Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
권호 표지
DOI QR코드

DOI QR Code

Characterization of the expression of cytokeratins 5, 8, and 14 in mouse thymic epithelial cells during thymus regeneration following acute thymic involution

  • Lee, Eun-Na (Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University) ;
  • Park, Jin-Kyeong (Department of Anatomy, School of Medicine, Pusan National University) ;
  • Lee, Ja-Rang (Department of Anatomy, School of Medicine, Pusan National University) ;
  • Oh, Sae-Ock (Department of Anatomy, School of Medicine, Pusan National University) ;
  • Baek, Sun-Yong (Department of Anatomy, School of Medicine, Pusan National University) ;
  • Kim, Bong-Seon (Department of Anatomy, School of Medicine, Pusan National University) ;
  • Yoon, Sik (Department of Anatomy, School of Medicine, Pusan National University)
  • Published : 2011.03.31
⟨ Previous Next ⟩

Abstract

The thymus is a central lymphoid organ for T cell development. Thymic epithelial cells (TECs) constitute a major component of the thymic stroma, which provides a specialized microenvironment for survival, proliferation, and differentiation of immature T cells. In this study, subsets of TECs were examined immunohistochemically to investigate their cytokeratin (CK) expression patterns during thymus regeneration following thymic involution induced by cyclophosphamide treatment. The results demonstrated that both normal and regenerating mouse thymuses showed a similar CK expression pattern. The major medullary TECs (mTEC) subset, which is stellate in appearance, exhibited CK5 and CK14 staining, and the minor mTEC subset, which is globular in appearance, exhibited CK8 staining, whereas the vast majority of cortical TECs (cTECs) expressed CK8 during thymus regeneration. Remarkably, the levels of CK5 and CK14 expression were enhanced in mTECs, and CK8 expression was upregulated in cTECs during mouse thymus regeneration after cyclophosphamide-induced acute thymic involution. Of special interest, a relatively high number of $CK5^{+}CK8^{+}$ TEC progenitors occurred in the thymic cortex during thymus regeneration. Taken together, these findings shed more light on the role of CK5, CK8, and CK14 in the physiology of TECs during mouse thymus regeneration, and on the characterization of TEC progenitors for restoration of the epithelial network and for concomitant regeneration of the adult thymus.

Keywords

References

  1. Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, Davidson NJ, Bean AG, Ladyman HM, Ritter MA, Hugo P. The thymic microenvironment. Immunol Today 1993;14:445-59. https://doi.org/10.1016/0167-5699(93)90248-J
  2. Savage PA, Davis MM. A kinetic window constricts the T cell receptor repertoire in the thymus. Immunity 2001;14:243-52. https://doi.org/10.1016/S1074-7613(01)00106-6
  3. Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 2006;6:127-35. https://doi.org/10.1038/nri1781
  4. Osada M, Jardine L, Misir R, Andl T, Millar SE, Pezzano M. DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLoS One 2010;5:e9062. https://doi.org/10.1371/journal.pone.0009062
  5. Barclay AN, Mayrhofer G. Bone marrow origin of Ia-positive cells in the medulla rat thymus. J Exp Med 1981;153:1666-71. https://doi.org/10.1084/jem.153.6.1666
  6. De Waal EJ, Rademakers LH. Heterogeneity of epithelial cells in the rat thymus. Microsc Res Tech 1997;38:227-36. https://doi.org/10.1002/(SICI)1097-0029(19970801)38:3<227::AID-JEMT4>3.0.CO;2-J
  7. Schuurman HJ, Kuper CF, Kendall MD. Thymic microenvironment at the light microscopic level. Microsc Res Tech 1997;38:216-26. https://doi.org/10.1002/(SICI)1097-0029(19970801)38:3<216::AID-JEMT3>3.0.CO;2-K
  8. Von Gaudecker B, Kendall MD, Ritter MA. Immuno-electron microscopy of the thymic epithelial microenvironment. Microsc Res Tech 1997;38:237-49. https://doi.org/10.1002/(SICI)1097-0029(19970801)38:3<237::AID-JEMT5>3.0.CO;2-J
  9. van de Wijngaert FP, Kendall MD, Schuurman HJ, Rademakers LH, Kater L. Heterogeneity of epithelial cells in the human thymus: an ultrastructural study. Cell Tissue Res 1984;237:227-37. https://doi.org/10.1007/BF00217140
  10. Haynes BF. The human thymic microenvironment. Adv Immunol 1984;36:87-142.
  11. Rouse RV, Bolin LM, Bender JR, Kyewski BA. Monoclonal antibodies reactive with subsets of mouse and human thymic epithelial cells. J Histochem Cytochem 1988;36:1511-7. https://doi.org/10.1177/36.12.2461413
  12. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31:11-24. https://doi.org/10.1016/0092-8674(82)90400-7
  13. Heid HW, Moll I, Franke WW. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. II. Concomitant and mutually exclusive synthesis of trichocytic and epithelial cytokeratins in diverse human and bovine tissues (hair follicle, nail bed and matrix, lingual papilla, thymic reticulum). Differentiation 1988;37:215-30. https://doi.org/10.1111/j.1432-0436.1988.tb00724.x
  14. Banks-Schlegel SP. Keratin alterations during embryonic epidermal differentiation: a presage of adult epidermal maturation. J Cell Biol 1982;93:551-9. https://doi.org/10.1083/jcb.93.3.551
  15. Linder S. Cytokeratin markers come of age. Tumour Biol 2007;28:189-95. https://doi.org/10.1159/000107582
  16. Laster AJ, Itoh T, Palker TJ, Haynes BF. The human thymic microenvironment: thymic epithelium contains specific keratins associated with early and late stages of epidermal keratinocyte maturation. Differentiation 1986;31:67-77. https://doi.org/10.1111/j.1432-0436.1986.tb00385.x
  17. Savino W, Dardenne M. Immunohistochemical studies on a human thymic epithelial cell subset defined by the anti-cytokeratin 18 monoclonal antibody. Cell Tissue Res 1988;254:225-31.
  18. Shezen E, Okon E, Ben-Hur H, Abramsky O. Cytokeratin expression in human thymus: immunohistochemical mapping. Cell Tissue Res 1995;279:221-31. https://doi.org/10.1007/BF00300707
  19. Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A 1998;95:11822-7. https://doi.org/10.1073/pnas.95.20.11822
  20. Klug DB, Carter C, Gimenez-Conti IB, Richie ER. Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 2002;169:2842-5.
  21. Kuraguchi M, Wang XP, Bronson RT, Rothenberg R, Ohene-Baah NY, Lund JJ, Kucherlapati M, Maas RL, Kucherlapati R. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet 2006;2:e146. https://doi.org/10.1371/journal.pgen.0020146
  22. Liepinsh DJ, Kruglov AA, Galimov AR, Shakhov AN, Shebzukhov YV, Kuchmiy AA, Grivennikov SI, Tumanov AV, Drutskaya MS, Feigenbaum L, Kuprash DV, Nedospasov SA. Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus. Eur J Immunol 2009;39:2906-15. https://doi.org/10.1002/eji.200839191
  23. Milicevic NM, Milicevic Z, Piletic O, Mujovic S, Ninkov V. Patterns of thymic regeneration in rats after single or divided doses of cyclophosphamide. J Comp Pathol 1984;94:197-202. https://doi.org/10.1016/0021-9975(84)90040-9
  24. Yoon S, Yoo YH, Kim BS, Kim JJ. Ultrastructural alterations of the cortical epithelial cells of the rat thymus after cyclophosphamide treatment. Histol Histopathol 1997;12:401-13.
  25. Yoon S, Lee HW, Baek SY, Kim BS, Kim JB, Lee SA. Upregulation of TrkA neurotrophin receptor expression in the thymic subcapsular, paraseptal, perivascular, and cortical epithelial cells during thymus regeneration. Histochem Cell Biol 2003;119:55-68.
  26. Lee HW, Kim BS, Kim HJ, Lee CW, Yoo HJ, Kim JB, Yoon S. Upregulation of receptor activator of nuclear factor-kappaB ligand expression in the thymic subcapsular, paraseptal, perivascular, and medullary epithelial cells during thymus regeneration. Histochem Cell Biol 2005;123:491-500. https://doi.org/10.1007/s00418-005-0751-z
  27. Lee HW, Kim SM, Shim NR, Bae SK, Jung IG, Kwak JY, Kim BS, Kim JB, Moon JO, Chung JS, Yoon S. Expression of nerve growth factor is upregulated in the rat thymic epithelial cells during thymus regeneration following acute thymic involution. Regul Pept 2007;141:86-95. https://doi.org/10.1016/j.regpep.2006.12.015
  28. Kim YM, Kim HK, Kim HJ, Lee HW, Ju SA, Choi BK, Kwon BS, Kim BS, Kim JB, Lim YT, Yoon S. Expression of 4-1BB and 4-1BBL in thymocytes during thymus regeneration. Exp Mol Med 2009;41:896-911. https://doi.org/10.3858/emm.2009.41.12.095
  29. Lavialle C, Modjtahedi N, Lamonerie T, Frebourg T, Landin RM, Fossar N, Lhomond G, Cassingena R, Brison O. The human breast carcinoma cell line SW 613-S: an experimental system to study tumor heterogeneity in relation to c-myc amplification, growth factor production and other markers (review). Anticancer Res 1989;9:1265-79.
  30. Tsubokawa F, Nishisaka T, Takeshima Y, Inai K. Heterogeneity of expression of cytokeratin subtypes in squamous cell carcinoma of the lung: with special reference to CK14 overexpression in cancer of high-proliferative and lymphogenous metastatic potential. Pathol Int 2002;52:286-93. https://doi.org/10.1046/j.1440-1827.2002.01353.x
  31. He QY, Cheung YH, Leung SY, Yuen ST, Chu KM, Chiu JF. Diverse proteomic alterations in gastric adenocarcinoma. Proteomics 2004;4:3276-87. https://doi.org/10.1002/pmic.200300916
  32. Lau AT, Chiu JF. The possible role of cytokeratin 8 in cadmium-induced adaptation and carcinogenesis. Cancer Res 2007;67:2107-13. https://doi.org/10.1158/0008-5472.CAN-06-3771
  33. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 2007;7:134. https://doi.org/10.1186/1471-2407-7-134
  34. Kabos P, Haughian JM, Wang X, Dye WW, Finlayson C, Elias A, Horwitz KB, Sartorius CA. Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat 2010 Jul 28[Epub]. DOI: 10.1007/s10549-010-1078-6.
  35. Caulin C, Ware CF, Magin TM, Oshima RG. Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. J Cell Biol 2000;149:17-22. https://doi.org/10.1083/jcb.149.1.17
  36. Inada H, Izawa I, Nishizawa M, Fujita E, Kiyono T, Takahashi T, Momoi T, Inagaki M. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol 2001;155:415-26. https://doi.org/10.1083/jcb.200103078
  37. Roop DR, Cheng CK, Titterington L, Meyers CA, Stanley JR, Steinert PM, Yuspa SH. Synthetic peptides corresponding to keratin subunits elicit highly specific antibodies. J Biol Chem 1984;259:8037-40.
  38. Kemler R, Brulet P, Schnebelen MT, Gaillard J, Jacob F. Reactivity of monoclonal antibodies against intermediate filament proteins during embryonic development. J Embryol Exp Morphol 1981;64:45-60.
  39. Farr AG, Anderson SK. Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 1985;134:2971-7.
  40. Surh CD, Gao EK, Kosaka H, Lo D, Ahn C, Murphy DB, Karlsson L, Peterson P, Sprent J. Two subsets of epithelial cells in the thymic medulla. J Exp Med 1992;176:495-505. https://doi.org/10.1084/jem.176.2.495
  41. Zhang L, Sun L, Zhao Y. Thymic epithelial progenitor cells and thymus regeneration: an update. Cell Res 2007;17:50-5. https://doi.org/10.1038/sj.cr.7310114
  42. Garcia-Ceca J, Jimenez E, Alfaro D, Cejalvo T, Munoz JJ, Zapata AG. Cell-autonomous role of EphB2 and EphB3 receptors in the thymic epithelial cell organization. Eur J Immunol 2009;39:2916-24. https://doi.org/10.1002/eji.200939437
  43. Su DM, Navarre S, Oh WJ, Condie BG, Manley NR. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol 2003;4:1128-35. https://doi.org/10.1038/ni983
  44. Sano S, Takahama Y, Sugawara T, Kosaka H, Itami S, Yoshikawa K, Miyazaki J, van Ewijk W, Takeda J. Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 2001;15:261-73. https://doi.org/10.1016/S1074-7613(01)00180-7
  45. Osada M, Ito E, Fermin HA, Vazquez-Cintron E, Venkatesh T, Friedel RH, Pezzano M. The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clin Dev Immunol 2006;13:299-319. https://doi.org/10.1080/17402520600935097
  46. Popa I, Zubkova I, Medvedovic M, Romantseva T, Mostowski H, Boyd R, Zaitseva M. Regeneration of the adult thymus is preceded by the expansion of $K5^{+}K8^{+}$ epithelial cell progenitors and by increased expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma. Int Immunol 2007;19:1249-60. https://doi.org/10.1093/intimm/dxm092

Cited by

  1. Evaluation of cloned cells, animal model, and ATRA sensitivity of human testicular yolk sac tumor vol.10, pp.None, 2011, https://doi.org/10.1186/1479-5876-10-46
  2. Intrathymic progenitor cell transplantation across histocompatibility barriers results in the persistence of early thymic progenitors and T-cell differentiation vol.121, pp.11, 2011, https://doi.org/10.1182/blood-2012-08-447417
  3. Terminally Differentiated Epithelial Cells of the Thymic Medulla and Skin Express Nicotinic Acetylcholine Receptor Subunit α 3 vol.2014, pp.None, 2011, https://doi.org/10.1155/2014/757502
  4. Cholinergic epithelial cell with chemosensory traits in murine thymic medulla vol.358, pp.3, 2011, https://doi.org/10.1007/s00441-014-2002-x
  5. Bioengineering mini functional thymic units with EAK16-II/EAKIIH6 self-assembling hydrogel vol.160, pp.1, 2011, https://doi.org/10.1016/j.clim.2015.03.010
  6. Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function vol.11, pp.2, 2011, https://doi.org/10.1371/journal.pone.0149430
  7. Effect of orally administered zinc oxide nanoparticles on albino rat thymus and spleen : Effect of Orally Administered ZO NPs on Albino Rats vol.69, pp.7, 2011, https://doi.org/10.1002/iub.1638
  8. Acute Thymic Involution and Mechanisms for Recovery vol.65, pp.5, 2017, https://doi.org/10.1007/s00005-017-0462-x
  9. RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice vol.12, pp.2, 2011, https://doi.org/10.1371/journal.pone.0171510
  10. In mice transgenic for IGF1 under keratin-14 promoter, lifespan is decreased and the rates of aging and thymus involution are accelerated vol.11, pp.7, 2011, https://doi.org/10.18632/aging.101903
  11. Histopathologic assessment of cultured human thymus vol.15, pp.3, 2011, https://doi.org/10.1371/journal.pone.0230668
  12. Immunohistochemical Characteristics of Thymomas and Hyperplastic Lesions in Wistar Hannover Rats vol.48, pp.5, 2011, https://doi.org/10.1177/0192623320922849
  13. Potential impact of SARS-CoV-2 infection on the thymus vol.67, pp.1, 2011, https://doi.org/10.1139/cjm-2020-0170
  14. Defective dystrophic thymus determines degenerative changes in skeletal muscle vol.12, pp.1, 2011, https://doi.org/10.1038/s41467-021-22305-x