Optische Rehabilitation nach Limbusstammzellinsuffizienz: aktuelle Behandlungsmöglichkeiten und Entwicklungen

Zusammenfassung

Die Behandlung der Limbusstammzellinsuffizienz (LSZI) stellt eine Herausforderung in der Augenheilkunde dar. Es handelt sich um eine Störung der Augenoberfläche, die durch eine nicht funktionale Regeneration des kornealen Epithels entsteht. Die LSZI wird sowohl von hereditären als auch erworbenen Grunderkrankungen verursacht. Je nach Ausprägung unterscheidet man dabei zwischen einer partiellen oder totalen LSZI sowie zwischen uni- oder bilateralen Fällen. Die Behandlung richtet sich nach der Ätiologie der Erkrankung. Es stehen zu diesem Zweck eine Reihe von Techniken zur Verfügung, darunter fallen die Anwendung von Amniontransplantationen, die Transplantation von Limbusgewebe oder die Anwendung von ex vivo expandierten Zellen. In dieser Übersichtsarbeit werden die aktuellen Behandlungsoptionen für die LSZI zusammengefasst sowie neue Entwicklungen auf diesem Gebiet vorgestellt.

Abstract

Limbal stem cell deficiency (LSCD) is a condition caused by the loss of corneal epithelial regenerative potential. The treatment of this condition is still a challenge. It results from various conditions both intrinsic as well as extrinsic. LSCD can be either uni- or bilateral and either partial or total. Today treatment options include a variety of techniques including transplantation of amniotic membrane and limbal tissue or tissue engineered cell sheets. This article summarizes the current techniques to treat LSCD and upcoming developments.

Schlüsselwörter

Limbusstammzellinsuffizienz - limbale Stamm- und Vorläuferzellen - Limbustransplantation - Ex-vivo-Expansion

Key words

limbal stem cell deficiency - limbal stem and progenitor cells - limbal transplantation - ex vivo expansion

• Literatur

• 1 Tseng SC. Concept and application of limbal stem cells. Eye (Lond) 1989; 3: 141-157
• 2 Schermer A, Galvin S, Sun TT. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol 1986; 103: 49-62
• 3 Cotsarelis G, Cheng SZ, Dong G. et al. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 1989; 57: 201-209
• 4 Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci 1983; 24: 1442-1443
• 5 Di Girolamo N, Bobba S, Ravira V. et al. Tracing the fate of limbal epithelial progenitor cells in the murine cornea. Stem Cells 2015; 33: 157-169
• 6 Matic M, Petrov IN, Chen S. et al. Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation 1997; 61: 251-260
• 7 Pellegrini G, Dellambra E, Golisano O. et al. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci U S A 2001; 98: 3156-3161
• 8 De Paiva CS, Chen Z, Corrales R. et al. ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells. Stem Cells 2005; 23: 63-73
• 9 Budak MT, Alpdogan O, Zhou M. et al. Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells. J Cell Sci 2005; 118: 1715-1724
• 10 De Paiva CS, Pflugfelder SC, Li DQ. Cell size correlates with phenotype and proliferative capacity in human corneal epithelial cells. Stem Cells 2006; 24: 368-375
• 11 Schlötzer-Schrehardt U, Kruse FE. Identification and characterization of limbal stem cells. Exp Eye Res 2005; 81: 247-264
• 12 Grueterich M. Klinik der Limbusstammzellinsuffizienz. Ophthalmologe 2012; 109: 850-856
• 13 Puangsricharern V, Tseng SCG. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology 1995; 102: 1476-1485
• 14 Miri A, Alomar T, Nubile M. et al. In vivo confocal microscopic findings in patients with limbal stem cell deficiency. Br J Ophthalmol 2012; 96: 523-529
• 15 Falke K, Prakasam RK, Guthoff RF. et al. [In vivo imaging of limbal epithelium and palisades of Vogt]. Klin Monatsbl Augenheilkd 2012; 229: 1185-1190
• 16 Espandar L, Steele JF, Lathrop KL. Optical coherence tomography imaging of the palisades of Vogt to assist clinical evaluation and surgical planning in a case of limbal stem-cell deficiency. Eye Contact Lens 2016;
• 17 Eberwein P, Reinhard T. Oberflächenrekonstruktion bei Limbusstammzellinsuffizienz. Ophthalmologe 2012; 109: 857-862
• 18 Miri A, Al-Deiri B, Dua HS. Long-term outcomes of autolimbal and allolimbal transplants. Ophthalmology 2010; 117: 1207-1213
• 19 Reinhard T, Kontopoulos T, Wernet P. et al. Long-term results of homologous penetrating limbokeratoplasty in total limbal stem cell insufficiency after chemical/thermal burns. Ophthalmologe 2004; 101: 682-687
• 20 Eberwein P, Böhringer D, Schwartzkopff J. et al. Allogenic limbo-keratoplasty with conjunctivoplasty, mitomycin c, and amniotic membrane for bilateral limbal stem cell deficiency. Ophthalmology 2012; 119: 930-937
• 21 Reinhard T, Sundmacher R, Spelsberg H. et al. Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal stem cell insufficiency. Acta Ophthalmol Scand 1999; 77: 663-667
• 22 Lang SJ, Böhringer D, Geerling G. et al. Long-term results of allogenic penetrating limbo-keratoplasty: 20 years of experience. Eye (Lond) 2017; 31: 372-378
• 23 Sangwan VS, Basu S, MacNeil S. et al. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol 2012; 96: 931-934
• 24 Kim HS, Jun Song X, de Paiva CS. et al. Phenotypic characterization of human corneal epithelial cells expanded ex vivo from limbal explant and single cell cultures. Exp Eye Res 2004; 79: 41-49
• 25 Loureiro RR, Cristovam PC, Martins CM. et al. Comparison of culture media for ex vivo cultivation of limbal epithelial progenitor cells. Mol Vis 2013; 19: 69-77
• 26 Meyer-Blazejewska EA, Kruse FE, Bitterer K. et al. Preservation of the limbal stem cell phenotype by appropriate culture techniques. Invest Ophthalmol Vis Sci 2010; 51: 765-774
• 27 Haagdorens M, Van Acker SI, Van Gerwen V. et al. Limbal stem cell deficiency: current treatment options and emerging therapies. Stem Cells Int 2016; 2016: 9798374
• 28 Feng Y, Borrelli M, Reichl S. et al. Review of alternative carrier materials for ocular surface reconstruction. Curr Eye Res 2014; 39: 541-552
• 29 Pellegrini G, Traverso CE, Franzi AT. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 1997; 349: 990-993
• 30 Pellegrini G, Rama P, Matuska S. et al. Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. Regen Med 2013; 8: 553-567
• 31 Rama P, Matuska S, Paganoni G. et al. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 2010; 363: 147-155
• 32 Bakker A, Langer B. Zelltherapeutika – eine innovative Therapieoption in der Ophthalmologie. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015; 58: 1259-1264
• 33 Pellegrini G, Lambiase A, Macaluso C. et al. From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU. Regen Med 2016; 11: 407-420
• 34 Mariappan I, Maddileti S, Savy S. et al. In vitro culture and expansion of human limbal epithelial cells. Nat Protoc 2010; 5: 1470-1479
• 35 Meller D, Pauklin M, Westekemper H. et al. [Autologous transplantation of cultivated limbal epithelium]. Ophthalmologe 2010; 107: 1133-1138
• 36 Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 2000; 343: 86-93
• 37 Meller D, Pires RT, Tseng SC. Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane cultures. Br J Ophthalmol 2002; 86: 463-471
• 38 Pauklin M, Fuchsluger TA, Westekemper H. et al. Midterm results of cultivated autologous and allogeneic limbal epithelial transplantation in limbal stem cell deficiency. Dev Ophthalmol 2010; 45: 57-70
• 39 Scholz S, Thomasen H, Hestermann K. et al. Langzeitergebnisse zur autologen Transplantation von ex vivo kultiviertem Limbusepithel bei limbaler Stammzellinsuffizienz. Ophthalmologe 2016; 113: 321-329
• 40 Meller D, Thomasen H, Hanet M. et al. Kurz- und Langzeitkomplikationen nach Transplantation von kultiviertem Limbusepithel. Ophthalmologe 2013; 110: 622-628
• 41 Schrage N, Hille K, Cursiefen C. Aktuelle Versorgungsmöglichkeiten mit Keratoprothesen. Ophthalmologe 2014; 111: 1010-1018
• 42 Falcinelli G, Falsini B, Taloni M. et al. Modified osteo-odonto-keratoprosthesis for treatment of corneal blindness: long-term anatomical and functional outcomes in 181 cases. Arch Ophthalmol 2005; 123: 1319-1329
• 43 Sejpal K, Yu F, Aldave AJ. The Boston keratoprosthesis in the management of corneal limbal stem cell deficiency. Cornea 2011; 30: 1187-1194
• 44 Schaub F, Hos D, Bucher F. et al. Boston-Keratoprothese: erste Erfahrungen bei 13 Hochrisikoaugen aus der Kölner Universitätsaugenklinik. Ophthalmologe 2016; 113: 492-499
• 45 Ahmad S, Stewart R, Yung S. et al. Differentiation of human embryonic stem cells into corneal epithelial-like cells by in vitro replication of the corneal epithelial stem cell niche. Stem Cells 2007; 25: 1145-1155
• 46 Zhang W, Yang X, Liu L. et al. Rapidly constructed scaffold-free embryonic stem cell sheets for ocular surface reconstruction. Scanning 2014; 36: 286-292
• 47 Zhu J, Zhang K, Sun Y. et al. Reconstruction of functional ocular surface by acellular porcine cornea matrix scaffold and limbal stem cells derived from human embryonic stem cells. Tissue Eng Part A 2013; 19: 2412-2425
• 48 Meyer-Blazejewska EA, Call M, Yamanaka KO. et al. From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell deficiency. Stem Cells 2011; 29: 57-66
• 49 Nakamura T, Kinoshita S. Ocular surface reconstruction using cultivated mucosal epithelial stem cells. Cornea 2003; 22 (Suppl. 07) S75-S80
• 50 Nakamura T, Endo K, Cooper LJ. et al. The successful culture and autologous transplantation of rabbit oral mucosal epithelial cells on amniotic membrane. Invest Ophthalmol Vis Sci 2003; 44: 106-116
• 51 Nakamura T, Inatomi T, Sotozono C. et al. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br J Ophthalmol 2004; 88: 1280-1284
• 52 Satake Y, Higa K, Tsubota K. et al. Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency. Ophthalmology 2011; 118: 1524-1530
• 53 Inatomi T, Nakamura T, Koizumi N. et al. Midterm results on ocular surface reconstruction using cultivated autologous oral mucosal epithelial transplantation. Am J Ophthalmol 2006; 141: 267-275
• 54 Nakamura T, Takeda K, Inatomi T. et al. Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. Br J Ophthalmol 2011; 95: 942-946
• 55 Ma DH, Kuo MT, Tsai YJ. et al. Transplantation of cultivated oral mucosal epithelial cells for severe corneal burn. Eye (Lond) 2009; 23: 1442-1450
• 56 Kolli S, Ahmad S, Mudhar HS. et al. Successful application of ex vivo expanded human autologous oral mucosal epithelium for the treatment of total bilateral limbal stem cell deficiency. Stem Cells 2014; 32: 2135-2146