Skip to main content
SpringerLink
Log in

Perspektiven und aktueller Stand der Limbusstammzelltransplantation

Perspectives and current state in limbal stem cell transplantation

  • Leitthema
  • Published:
Der Ophthalmologe Aims and scope Submit manuscript

Zusammenfassung

Die Limbusstammzelltransplantation stellt eine der größten Herausforderungen in der chirurgischen Therapie von Oberflächenerkrankungen dar. Während Patienten mit einseitiger oder partieller Limbusstammzellinsuffizienz (LSI) mit autologen lamellären Limbustransplantaten vom Partnerauge versorgt werden, kann bei fortgeschrittener beidseitiger, aber noch partieller LSI eine Ex-vivo-Expansion autologer Limbusstammzellen auf Amnionmembran durchgeführt werden. Dagegen kann die beidseitige komplette LSI nur durch Transplantation allogenen Limbusgewebes mit großen immunologischen Risiken behandelt werden. Die allogene Limbusstammzelltransplantation wurde in den letzten Jahren durch Kombination mit Mitomycin C und Amnionmembrantransplantation erfolgreich weiterentwickelt. Während grundlagenwissenschaftlich zunächst an einer Transdifferenzierung von Knochenmarksstammzellen zu epithelialen Zellen gearbeitet wurde, gab es zuletzt vielversprechende Ansätze zur Verwendung von Haarfollikelstammzellen als Zellquelle. Die Erforschung der Limbusstammzellnische schließlich führt zu einem besseren Verständnis der natürlichen Wachstumsbedingungen von Limbusstammzellen, ein entscheidender Baustein in der Verbesserung der Ex-vivo-Kultur.

Abstract

The transplantation of limbal stem cells is one of the most challenging surgical approaches in ocular surface reconstruction. Partial and unilateral limbal stem cell insufficiency (LSCI) can be treated by fractionated abrasion or autologous limbal stem cell transplantation from the fellow eye. In cases of advanced bilateral and partial LSCI, ex vivo expansion of limbal stem cells on amniotic membranes or fibrin can be performed but all patients with complete bilateral LSCI must rely on allogenic limbal stem cell transplantation with high immunological risks. Attempts to combine allogenic limbal stem cell transplantation with mitomycin C and amniotic membrane transplantation are promising. In the laboratory, attempts to transdifferentiate bone marrow stem cells into corneal epithelial cells have been without success. Nonetheless, transdifferentiation of hair follicle stem cells into corneal epithelial cells looks promising. In parallel, research on the limbal stem cell niche is ongoing to elucidate the natural environment of limbal stem cells in order to improve ex vivo culture.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5
Abb. 6

Literatur

  1. Baradaran-Rafii A, Ebrahimi M, Kanavi MR et al (2010) Midterm outcomes of autologous cultivated limbal stem cell transplantation with or without penetrating keratoplasty. Cornea 29:502–509

    Article  PubMed  Google Scholar 

  2. Blazejewska EA, Schlotzer-Schrehardt U, Zenkel M et al (2009) Corneal limbal microenvironment can induce transdifferentiation of hair follicle stem cells into corneal epithelial-like cells. Stem Cells (Dayton, Ohio) 27:642–652

    Google Scholar 

  3. Chen JJ, Tseng SC (1990) Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci 31:1301–1314

    PubMed  CAS  Google Scholar 

  4. Chen JJ, Tseng SC (1991) Abnormal corneal epithelial wound healing in partial-thickness removal of limbal epithelium. Invest Ophthalmol Vis Sci 32:2219–2233

    PubMed  CAS  Google Scholar 

  5. Cotsarelis G, Cheng SZ, Dong G et al (1989) Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57:201–209

    Article  PubMed  CAS  Google Scholar 

  6. Discher DE, Janmey P, Wang YL (2005) Tissue cells feel and respond to the stiffness of their substrate. Science 310:1139–1143

    Article  PubMed  CAS  Google Scholar 

  7. Dua HS (1998) The conjunctiva in corneal epithelial wound healing. Br J Ophthalmol 82:1407–1411

    Article  PubMed  CAS  Google Scholar 

  8. Dua HS, Azuara-Blanco A (2000) Limbal stem cells of the corneal epithelium. Surv Ophthalmol 44:415–425

    Article  PubMed  CAS  Google Scholar 

  9. Dua HS, Saini JS, Azuara-Blanco A et al (2000) Limbal stem cell deficiency: concept, aetiology, clinical presentation, diagnosis and management. Indian J Ophthalmol 48:83–92

    PubMed  CAS  Google Scholar 

  10. Dua HS, Shanmuganathan VA, Powell-Richards AO et al (2005) Limbal epithelial crypts: a novel anatomical structure and a putative limbal stem cell niche. Br J Ophthalmol 89:529–532

    Article  PubMed  CAS  Google Scholar 

  11. Espana EM, Kawakita T, Romano A et al (2003) Stromal niche controls the plasticity of limbal and corneal epithelial differentiation in a rabbit model of recombined tissue. Invest Ophthalmol Vis Sci 44:5130–5135

    Article  PubMed  Google Scholar 

  12. Grueterich M, Espana EM, Tseng SC (2003) Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv Ophthalmol 48:631–646

    Article  PubMed  Google Scholar 

  13. Grueterich M, Tseng SC (2002) Human limbal progenitor cells expanded on intact amniotic membrane ex vivo. Arch Ophthalmol 120:783–790

    PubMed  Google Scholar 

  14. Huang AJ, Tseng SC (1991) Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci 32:96–105

    PubMed  CAS  Google Scholar 

  15. Jiang TS, Cai L, Ji WY et al (2010) Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol Vis 16:1304–1316

    PubMed  Google Scholar 

  16. Kawakita T, Shimmura S, Hornia A et al (2008) Stratified epithelial sheets engineered from a single adult murine corneal/limbal progenitor cell. J Cell Mol Med 12:1303–1316

    Article  PubMed  CAS  Google Scholar 

  17. Kolli S, Lako M, Figueiredo F et al (2008) Loss of corneal epithelial stem cell properties in outgrowths from human limbal explants cultured on intact amniotic membrane. Regen Med 3:329–342

    Article  PubMed  CAS  Google Scholar 

  18. Kruse FE, Tseng SC (1991) The limbus epithelium in vitro. Fortschr Ophthalmol 88:107–112

    PubMed  CAS  Google Scholar 

  19. Li W, Hayashida Y, Chen YT et al (2007) Niche regulation of corneal epithelial stem cells at the limbus. Cell Res 17:26–36

    Article  PubMed  Google Scholar 

  20. Li W, Hayashida Y, He H et al (2007) The fate of limbal epithelial progenitor cells during explant culture on intact amniotic membrane. Invest Ophthalmol Vis Sci 48:605–613

    Article  PubMed  Google Scholar 

  21. Meller D, Kruse F (2001) Ex-vivo expansion of cornea stem cells. Experimental principles and initial clinical results. Ophthalmologe 98:811–817

    Article  PubMed  CAS  Google Scholar 

  22. Meller D, Dabul V, Tseng SC (2002) Expansion of conjunctival epithelial progenitor cells on amniotic membrane. Exp Eye Res 74:537–545

    Article  PubMed  CAS  Google Scholar 

  23. Meller D, Pires RT, Tseng SC (2002) Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane cultures. Br J Ophthalmol 86:463–471

    Article  PubMed  CAS  Google Scholar 

  24. Meller D, Fuchsluger T, Pauklin M et al (2009) Ocular surface reconstruction in graft-versus-host disease with HLA-identical living-related allogeneic cultivated limbal epithelium after hematopoietic stem cell transplantation from the same donor. Cornea 28:233–236

    Article  PubMed  Google Scholar 

  25. Meller D, Pauklin M, Westekemper H et al (2010) Autologous transplantation of cultivated limbal epithelium. Ophthalmologe 107:1133–1138

    Article  PubMed  CAS  Google Scholar 

  26. Meyer-Blazejewska EA, Kruse FE, Bitterer K et al (2010) Preservation of the limbal stem cell phenotype by appropriate culture techniques. Invest Ophthalmol Vis Sci 51:765–774

    Article  PubMed  Google Scholar 

  27. Meyer-Blazejewska EA, Call MK, Yamanaka O et al (2011) From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell deficiency. Stem Cells (Dayton, Ohio) 29:57–66

    Google Scholar 

  28. Miri A, Al-Deiri B, Dua HS (2010) Long-term outcomes of autolimbal and allolimbal transplants. Ophthalmology 117:1207–1213

    Article  PubMed  Google Scholar 

  29. Pauklin M, Fuchsluger TA, Westekemper H et al (2010) Midterm results of cultivated autologous and allogeneic limbal epithelial transplantation in limbal stem cell deficiency. Dev Ophthalmol 45:57–70

    Article  PubMed  Google Scholar 

  30. Rama P, Bonini S, Lambiase A et al (2001) Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 72:1478–1485

    Article  PubMed  CAS  Google Scholar 

  31. Rama P, Matuska S, Paganoni G et al (2010) Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363:147–155

    Article  PubMed  CAS  Google Scholar 

  32. Reinhard T, Sundmacher R, Heering P (1996) Systemic ciclosporin A in high-risk keratoplasties. Graefes Arch Clin Exp Ophthalmol 234(Suppl 1):S115–S121

    Article  PubMed  CAS  Google Scholar 

  33. Reinhard T, Sundmacher R, Spelsberg H et al (1999) Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal stem cell insufficiency. Acta Ophthalmol Scand 77:663–667

    Article  PubMed  CAS  Google Scholar 

  34. Reinhard T, Kontopoulos T, Wernet P et al (2004) Long-term results of homologous penetrating limbokeratoplasty in total limbal stem cell insufficiency after chemical/thermal burns. Ophthalmologe 101:682–687

    Article  PubMed  Google Scholar 

  35. Reinhard T, Spelsberg H, Henke L et al (2004) Long-term results of allogeneic penetrating limbo-keratoplasty in total limbal stem cell deficiency. Ophthalmology 111:775–782

    Article  PubMed  Google Scholar 

  36. Reinshagen H, Auw-Haedrich C, Sorg RV et al (2009) Corneal surface reconstruction using adult mesenchymal stem cells in experimental limbal stem cell deficiency in rabbits. Acta Ophthalmol [Epub ahead of print]

  37. Schermer A, Galvin S, Sun TT (1986) Differentiation-related expression of a major 64 K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol 103:49–62

    Article  PubMed  CAS  Google Scholar 

  38. Schlotzer-Schrehardt U, Kruse FE (2005) Identification and characterization of limbal stem cells. Exp Eye Res 81:247–264

    Article  PubMed  Google Scholar 

  39. Schlotzer-Schrehardt U, Dietrich T, Saito K et al (2007) Characterization of extracellular matrix components in the limbal epithelial stem cell compartment. Exp Eye Res 85:845–860

    Article  PubMed  CAS  Google Scholar 

  40. Selver OB, Barash A, Ahmed M et al (2011) ABCG2-dependent dye exclusion activity and clonal potential in epithelial cells continuously growing for 1 month from limbal explants. Invest Ophthalmol Vis Sci 52:4330–4337

    Article  PubMed  CAS  Google Scholar 

  41. Shanmuganathan VA, Foster T, Kulkarni BB et al (2007) Morphological characteristics of the limbal epithelial crypt. Br J Ophthalmol 91:514–519

    Article  PubMed  Google Scholar 

  42. Spelsberg H, Reinhard T, Henke L et al (2004) Penetrating limbo-keratoplasty for granular and lattice corneal dystrophy: survival of donor limbal stem cells and intermediate-term clinical results. Ophthalmology 111:1528–1533

    Article  PubMed  Google Scholar 

  43. Stepp MA, Zieske JD (2005) The corneal epithelial stem cell niche. Ocul Surf 3:15–26

    PubMed  Google Scholar 

  44. Sundmacher R, Reinhard T (1996) Central corneolimbal transplantation under systemic ciclosporin A cover for severe limbal stem cell insufficiency. Graefes Arch Clin Exp Ophthalmol 234(Suppl 1):S122–S125

    Article  PubMed  Google Scholar 

  45. Thoft RA, Wiley LA, Sundarraj N (1989) The multipotential cells of the limbus. Eye (Lond) 3(Pt 2):109–113

    Google Scholar 

  46. Tsai RJ, Tsai RY (2010) Ex vivo expansion of corneal stem cells on amniotic membrane and their outcome. Eye Contact Lens 36:305–309

    Article  PubMed  Google Scholar 

  47. Tseng SC (1989) Concept and application of limbal stem cells. Eye (Lond) 3(Pt 2):141–157

  48. Tseng SC, Tsai RJ (1991) Limbal transplantation for ocular surface reconstruction – a review. Fortschr Ophthalmol 88:236–242

    PubMed  CAS  Google Scholar 

  49. Tseng SC, Meller D, Anderson DF et al (2002) Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane for treating corneal diseases with total limbal stem cell deficiency. Adv Exp Med Biol 506:1323–1334

    PubMed  Google Scholar 

  50. Yeung AM, Schlotzer-Schrehardt U, Kulkarni B et al (2008) Limbal epithelial crypt: a model for corneal epithelial maintenance and novel limbal regional variations. Arch Ophthalmol 126:665–669

    Article  PubMed  Google Scholar 

  51. Eberwein P Steinberg T, Schulz S et al (2011) Expression of corneal keratinocyte biomarkers is governed by environmental biomechanics. Eur J Biol (im Druck)

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Universitäts-Augenklinik Freiburg, Killianstr. 5, 79106, Freiburg, Deutschland

    P. Eberwein & T. Reinhard

Authors
  1. P. Eberwein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Reinhard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Eberwein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eberwein, P., Reinhard, T. Perspektiven und aktueller Stand der Limbusstammzelltransplantation. Ophthalmologe 108, 840–845 (2011). https://doi.org/10.1007/s00347-011-2332-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00347-011-2332-y

Schlüsselwörter

Keywords

Search

Navigation