Thymic Involution: A Barrier or Opportunity for Cell Replacement Therapy?

  • Simon Hackett
  • Paul J. Fairchild
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Although regenerative medicine offers prospects for cell replacement therapies relevant to many disease states, research has mainly focused on regenerating major organ systems such as the heart, kidney and lungs. The thymus, however, undergoes natural age-related involution and its ability to sustain a functional T cell repertoire therefore declines throughout life. While in healthy adults this process has no significant immunological impact, in immunocompromised patients, the involuted thymus is unable to rescue immune homeostasis which leads to increased risk of infection. Regenerating the thymus using stem cell technology, may, therefore, provide a viable option for rescuing immune function in immune compromised or elderly patients. Furthermore, thymic regeneration offers the prospect of influencing the acceptance of allogeneic tissues through the induction of central tolerance. Here, we explore the rationale behind thymic transplantation and current efforts in the stem cell field aiming to derive functional thymic tissue.


Cell Repertoire DiGeorge Syndrome Mixed Chimerism Pharyngeal Pouch EpCAM1 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are indebted to Kate Silk, Naoki Ichiryu, Alison Leishman, Tim Davies and Patty Sachamitr for helpful discussions. SH holds an MRC Capacity Building Studentship awarded to the Oxford Stem Cell Institute. Work on thymic involution in the authors' laboratory was supported by Pfizer Regenerative Medicine.


  1. 1.
    Anderson G, Jenkinson E (2001) Lymphostromal interactions in thymus development and function. Nat Rev Immunol 1:31–40PubMedCrossRefGoogle Scholar
  2. 2.
    Nishino M, Ashiku SK, Kocher ON, Thurer RL, Boiselle PM, Hatabu H (2006) The thymus: a comprehensive review. Radiographics 26:336–348CrossRefGoogle Scholar
  3. 3.
    Miller JF (1961) Immunological basis of the thymus. Lancet 2:748–749PubMedCrossRefGoogle Scholar
  4. 4.
    Baldwin TA, Hogquist KA, Jameson SC (2004) The fourth way? Harnessing aggressive tendencies in the thymus. J Immunol 173:6515–6520PubMedGoogle Scholar
  5. 5.
    Steinmann GG, Klaus B, Muller-Hermelink HK (1985) The involution of the ageing human thymic epithelium is independent of puberty. Scand J Immunol 22:563–575PubMedCrossRefGoogle Scholar
  6. 6.
    Sobhon P, Jirasattham C (1974) Effect of sex hormones on the thymus and lymphoid tissue of ovariectomized rats. Acta Anat 89:211–225PubMedCrossRefGoogle Scholar
  7. 7.
    Yajima N, Sakamaki K, Yonehara S (2004) Age related thymic involution is mediated by Fas on thymic epithelial cells. Jap Soc Immunol 16:027–1035Google Scholar
  8. 8.
    Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175:2741–2753PubMedGoogle Scholar
  9. 9.
    Sakaguchi S, Sakaguchi N (1988) Thymus and autoimmunity: transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice. J Exp Med 167:1479–1485PubMedCrossRefGoogle Scholar
  10. 10.
    George AJT, Ritter MA (1999) Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 17:267–272CrossRefGoogle Scholar
  11. 11.
    Kirkwood TBL (1977) Evolution of ageing. Nature 270:301–304PubMedCrossRefGoogle Scholar
  12. 12.
    Manley N, Gordon J (2011) Mechanisms of thymus organogenesis and morphogenesis. Development 138:3685–3878Google Scholar
  13. 13.
    Blackburn CC, Manley NR (2004) Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4:278–289PubMedCrossRefGoogle Scholar
  14. 14.
    Manley NR, Bryson JL, Griffith AV, Takahama Y, Richie ER (2009) Foxn1 is required for thymic vascularisation. J Immunol 182:86–90Google Scholar
  15. 15.
    Corbeaux T, Hess I, Swann J, Kanzler B, Haas-Assenbaum A, Boehm T (2010) Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. PNAS 107:16613–16618PubMedCrossRefGoogle Scholar
  16. 16.
    Cordier AC, Heremans JF (1975) Nude mouse embyro: ectodermal nature of the primordial thymic defect. Scan J Immunol 4:193–196CrossRefGoogle Scholar
  17. 17.
    Le Dourain NM, Jotereau FV (1975) Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J Exp Med 142:17–39CrossRefGoogle Scholar
  18. 18.
    Moore MAS, Owen JJT (1967) Experimental studies on the development of the thymus. J Exp Med 126:715–726PubMedCrossRefGoogle Scholar
  19. 19.
    Gordon J, Wilson VA, Blaire FN, Sheridan J, Farley A, Wilson L, Manley NR, Blackburn CC (2004) Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol 5:546–553PubMedCrossRefGoogle Scholar
  20. 20.
    Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T (2006) Formation of a functional thymus initiated by a post natal epithelial progenitor cell. Nature 441:992–996PubMedCrossRefGoogle Scholar
  21. 21.
    Gordon J, Wilson VA, Blair NF (2004) Functional evidence for a single endodermal origin of the thymic epithelium. Nat Immunol 5:546–553PubMedCrossRefGoogle Scholar
  22. 22.
    Rossi WW, Jenkinson E, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:988–991PubMedCrossRefGoogle Scholar
  23. 23.
    Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC (2002) Identification and characterisation of thymic epithelial progenitor cells. Immunity 16:803–814PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of immunological self shadow by Aire protein. Science 298:1395–1401PubMedCrossRefGoogle Scholar
  25. 25.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during treatment of HIV infection. Nature 396:690–695PubMedCrossRefGoogle Scholar
  26. 26.
    Livak F, Schatz DG (1996) T cell receptor alpha locus V(D) J recombination by-products are abundant in thymocytes and mature T cell. Mol Cell Biol 16:609–618PubMedGoogle Scholar
  27. 27.
    Markert ML, Boeck A, Hale LP, Kloster AL, McLaughlin TM, Rice HE, Mahaffey SM (1999) Transplantation of thymus tissue in complete DiGeorge syndrome. New Engl J Med 341:1180–1189PubMedCrossRefGoogle Scholar
  28. 28.
    Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexeiff MJ, Li J, Hauser ER, Haynes BF, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR (2003) Thymus transplantation in complete DiGeorge syndrome: immunological and safety evaluations in 12 patients. Blood 102:1121–1130PubMedCrossRefGoogle Scholar
  29. 29.
    Liesveld JL, Rothberg PG (2008) Mixed chimerism in SCT: conflict or peaceful coexistence? Bone Marrow Transplant 42:297–310PubMedCrossRefGoogle Scholar
  30. 30.
    Wekerle T, Sykes M (2001) Mixed chimerism and transplantation tolerance. Ann Rev Med 52:353–370PubMedCrossRefGoogle Scholar
  31. 31.
    Lai L, Jin J (2009) Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27:3012–302PubMedGoogle Scholar
  32. 32.
    Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T, Nishikawa S (2005) Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23:1542–1550PubMedCrossRefGoogle Scholar
  33. 33.
    Gill J, Malin M, Hollander G, Boyd R (2002) Generation of a complete thymic microenvironment by MTS24 + thymic epithelial cells. Nat Immunol 7:635–642CrossRefGoogle Scholar
  34. 34.
    Seach N, Mattesich M, Abberton K, Matsuda K, Tilkorn DJ, Rophael J, Boyd RL, Morrison WA (2010) Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng 16:543–551CrossRefGoogle Scholar
  35. 35.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  36. 36.
    Inami Y, Yoshikai T, Ito S, Nishio N, Suzuki H, Sakurai H, Isobe K (2010) Differentiation of induced pluripotent stem cells to thymic epithelial cells by phenotype. Immunol Cell Biol 89:314–321PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Sir William Dunn School of PathologyUniversity of OxfordOxfordUK

Personalised recommendations