Background Conditions that destroy the limbal area of the peripheralcornea, such as the StevensJohnson syndrome, ocular pemphigoid,and chemical and thermal injuries, can deplete stem cells ofthe corneal epithelium. The result is scarring and opacificationof the normally clear cornea. Standard corneal transplantationcannot treat this form of functional blindness.
Methods We performed and evaluated 70 transplantations of cornealepithelial stem cells from cadaveric eyes into 43 eyes of 39patients with severe ocular-surface disorders and limbal dysfunction.Medical treatment had failed in all patients. The patients hada mean preoperative visual acuity of 0.004 (only being ableto count the number of fingers presented by the examiner) inthe affected eyes, which satisfies the criteria for legal blindnessin most countries. In 28 eyes, we also performed standard cornealtransplantation. Stem-cell transplantations were performed asmany as four times on 1 eye if the initial results were notsatisfactory; 19 eyes had multiple transplantations. Patientswere followed for at least one year after transplantation.
Results A mean of 1163 days after stem-cell transplantation,22 of the 43 eyes (51 percent) had corneal epithelialization;of the 22 eyes, 7 eyes had corneal stromal edema and 15 eyeshad clear corneas. Mean visual acuity improved from 0.004 to0.02 (vision sufficient to distinguish the largest symbol onthe visual-acuity chart from a distance of 1 m) (P<0.001).The 15 eyes in which the cornea remained clear had a final meanvisual acuity of 0.11 (the ability to distinguish the largestsymbol from a distance of 5 m). Complications of the first transplantationincluded persistent defects in the corneal epithelium in 26eyes, ocular hypertension in 16 eyes, and rejection of the cornealgraft in 13 of 28 eyes. The epithelial defects eventually healedin all but two of the eyes.
Conclusions Transplantation of corneal epithelial stem cellscan restore useful vision in some patients with severe ocular-surfacedisorders.
Source Information
From the Department of Ophthalmology, Tokyo Dental College, Chiba (K.T., Y.S., M.K., N.S., S.S., H.B.-M., J.S.); and the Department of Ophthalmology, Keio University School of Medicine, Tokyo (K.T., S.S., H.B.-M.) both in Japan.
Address reprint requests to Dr. Tsubota at the Department of Ophthalmology, Tokyo Dental College, 11-13 Sugano 5 Chome, Ichikawa-shi, Chiba 272-8513, Japan, or at kazuo{at}eyebank.or.jp.
Arnalich-Montiel, F., Pastor, S., Blazquez-Martinez, A., Fernandez-Delgado, J., Nistal, M., Alio, J. L., De Miguel, M. P.
(2008). Adipose-Derived Stem Cells Are a Source for Cell Therapy of the Corneal Stroma. Stem Cells
26: 570-579
[Abstract][Full Text]
Li, S., Nikulina, K., DeVoss, J., Wu, A. J., Strauss, E. C., Anderson, M. S., McNamara, N. A.
(2008). Small Proline-Rich Protein 1B (SPRR1B) Is a Biomarker for Squamous Metaplasia in Dry Eye Disease. IOVS
49: 34-41
[Abstract][Full Text]
Satake, Y., Dogru, M., Yamane, G.-Y., Kinoshita, S., Tsubota, K., Shimazaki, J.
(2008). Barrier Function and Cytologic Features of the Ocular Surface Epithelium After Autologous Cultivated Oral Mucosal Epithelial Transplantation. Arch Ophthalmol
126: 23-28
[Abstract][Full Text]
Kawashima, M., Kawakita, T., Satake, Y., Higa, K., Shimazaki, J.
(2007). Phenotypic Study After Cultivated Limbal Epithelial Transplantation for Limbal Stem Cell Deficiency. Arch Ophthalmol
125: 1337-1344
[Abstract][Full Text]
Saw, V. P J, Minassian, D., Dart, J. K G, Ramsay, A., Henderson, H., Poniatowski, S., Warwick, R. M, Cabral, S., and the Amniotic Membrane Tissue User Group (AMTUG,
(2007). Amniotic membrane transplantation for ocular disease: a review of the first 233 cases from the UK user group. Br. J. Ophthalmol.
91: 1042-1047
[Abstract][Full Text]
Vajpayee, R. B., Sharma, N., Jhanji, V., Titiyal, J. S., Tandon, R.
(2007). One Donor Cornea for 3 Recipients: A New Concept for Corneal Transplantation Surgery. Arch Ophthalmol
125: 552-554
[Abstract][Full Text]
Higa, K., Shimmura, S., Kato, N., Kawakita, T., Miyashita, H., Itabashi, Y., Fukuda, K., Shimazaki, J., Tsubota, K.
(2007). Proliferation and Differentiation of Transplantable Rabbit Epithelial Sheets Engineered with or without an Amniotic Membrane Carrier. IOVS
48: 597-604
[Abstract][Full Text]
Zhou, M., Li, X.-m., Lavker, R. M.
(2006). Transcriptional Profiling of Enriched Populations of Stem Cells Versus Transient Amplifying Cells: A COMPARISON OF LIMBAL AND CORNEAL EPITHELIAL BASAL CELLS. J. Biol. Chem.
281: 19600-19609
[Abstract][Full Text]
Shanmuganathan, V A, Rotchford, A P, Tullo, A B, Joseph, A, Zambrano, I, Dua, H S
(2006). Epithelial proliferative potential of organ cultured corneoscleral rims; implications for allo-limbal transplantation and eye banking. Br. J. Ophthalmol.
90: 55-58
[Abstract][Full Text]
Hayashida, Y., Nishida, K., Yamato, M., Watanabe, K., Maeda, N., Watanabe, H., Kikuchi, A., Okano, T., Tano, Y.
(2005). Ocular Surface Reconstruction Using Autologous Rabbit Oral Mucosal Epithelial Sheets Fabricated Ex Vivo on a Temperature-Responsive Culture Surface. IOVS
46: 1632-1639
[Abstract][Full Text]
Sangwan, V. S., Matalia, H. P., Vemuganti, G. K., Ifthekar, G., Fatima, A., Singh, S., Rao, G. N.
(2005). Early Results of Penetrating Keratoplasty After Cultivated Limbal Epithelium Transplantation. Arch Ophthalmol
123: 334-340
[Abstract][Full Text]
Wilson, S. E., Netto, M. V.
(2005). Refractive Surgery and Cornea: The Never-Ending Spiral of Technology. Arch Ophthalmol
123: 265-266
[Full Text]
Homma, R., Yoshikawa, H., Takeno, M., Kurokawa, M. S., Masuda, C., Takada, E., Tsubota, K., Ueno, S., Suzuki, N.
(2004). Induction of Epithelial Progenitors In Vitro from Mouse Embryonic Stem Cells and Application for Reconstruction of Damaged Cornea in Mice. IOVS
45: 4320-4326
[Abstract][Full Text]
Nakamura, T, Inatomi, T, Sotozono, C, Amemiya, T, Kanamura, N, Kinoshita, S
(2004). Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br. J. Ophthalmol.
88: 1280-1284
[Abstract][Full Text]
Nishida, K., Yamato, M., Hayashida, Y., Watanabe, K., Yamamoto, K., Adachi, E., Nagai, S., Kikuchi, A., Maeda, N., Watanabe, H., Okano, T., Tano, Y.
(2004). Corneal Reconstruction with Tissue-Engineered Cell Sheets Composed of Autologous Oral Mucosal Epithelium. NEJM
351: 1187-1196
[Abstract][Full Text]
Nakamura, T., Yoshitani, M., Rigby, H., Fullwood, N. J., Ito, W., Inatomi, T., Sotozono, C., Nakamura, T., Shimizu, Y., Kinoshita, S.
(2004). Sterilized, Freeze-Dried Amniotic Membrane: A Useful Substrate for Ocular Surface Reconstruction. IOVS
45: 93-99
[Abstract][Full Text]
Wang, D.-Y., Hsueh, Y.-J., Yang, V. C., Chen, J.-K.
(2003). Propagation and Phenotypic Preservation of Rabbit Limbal Epithelial Cells on Amniotic Membrane. IOVS
44: 4698-4704
[Abstract][Full Text]
Maruyama, K., Yamada, J., Sano, Y., Kinoshita, S.
(2003). Th2-Biased Immune System Promotion of Allogeneic Corneal Epithelial Cell Survival after Orthotopic Limbal Transplantation. IOVS
44: 4736-4741
[Abstract][Full Text]
Gomes, J. A. P., Santos, M. S., Ventura, A. S., Donato, W. B. C., Cunha, M. C., Hofling-Lima, A. L.
(2003). Amniotic Membrane With Living Related Corneal Limbal/Conjunctival Allograft for Ocular Surface Reconstruction in Stevens-Johnson Syndrome. Arch Ophthalmol
121: 1369-1374
[Abstract][Full Text]
Shimmura, S, Ueno, R, Matsumoto, Y, Goto, E, Higuchi, A, Shimazaki, J, Tsubota, K
(2003). Albumin as a tear supplement in the treatment of severe dry eye. Br. J. Ophthalmol.
87: 1279-1283
[Abstract][Full Text]
Gaudreault, M., Carrier, P., Larouche, K., Leclerc, S., Giasson, M., Germain, L., Guerin, S. L.
(2003). Influence of Sp1/Sp3 Expression on Corneal Epithelial Cells Proliferation and Differentiation Properties in Reconstructed Tissues. IOVS
44: 1447-1457
[Abstract][Full Text]
Nakamura, T., Endo, K.-I., Cooper, L. J., Fullwood, N. J., Tanifuji, N., Tsuzuki, M., Koizumi, N., Inatomi, T., Sano, Y., Kinoshita, S.
(2003). The Successful Culture and Autologous Transplantation of Rabbit Oral Mucosal Epithelial Cells on Amniotic Membrane. IOVS
44: 106-116
[Abstract][Full Text]
Tsujimura, A., Koikawa, Y., Salm, S., Takao, T., Coetzee, S., Moscatelli, D., Shapiro, E., Lepor, H., Sun, T.-T., Wilson, E. L.
(2002). Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J. Cell Biol.
157: 1257-1265
[Abstract][Full Text]
Nakamura, T., Nishida, K., Dota, A., Kinoshita, S.
(2002). Changes in Conjunctival Clusterin Expression in Severe Ocular Surface Disease. IOVS
43: 1702-1707
[Abstract][Full Text]
Meller, D, Pires, R T F, Tseng, S C G
(2002). Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane cultures. Br. J. Ophthalmol.
86: 463-471
[Abstract][Full Text]
Mills, R. A. D., Coster, D. J., Williams, K. A.
(2002). Effect of Immunosuppression on Outcome Measures in a Model of Rat Limbal Transplantation. IOVS
43: 647-655
[Abstract][Full Text]
Anderson, D. F, Ellies, P., Pires, R. T F, Tseng, S. C G
(2001). Amniotic membrane transplantation for partial limbal stem cell deficiency. Br. J. Ophthalmol.
85: 567-575
[Abstract][Full Text]
Nakamura, T., Nishida, K., Dota, A., Matsuki, M., Yamanishi, K., Kinoshita, S.
(2001). Elevated Expression of Transglutaminase 1 and Keratinization-Related Proteins in Conjunctiva in Severe Ocular Surface Disease. IOVS
42: 549-556
[Abstract][Full Text]
Dunaief, J. L., Ng, E. W. M., Goldberg, M. F.
(2001). Corneal Dystrophies of Epithelial Genesis: The Possible Therapeutic Use of Limbal Stem Cell Transplantation. Arch Ophthalmol
119: 120-122
[Full Text]
Hauswirth, W. W., Beaufrere, L.
(2000). Ocular Gene Therapy: Quo Vadis?. IOVS
41: 2821-2826
[Full Text]
Chen, H.-J., Pires, R. T F, Tseng, S. C G
(2000). Amniotic membrane transplantation for severe neurotrophic corneal ulcers. Br. J. Ophthalmol.
84: 826-833
[Abstract][Full Text]
Tsai, R. J.-F., Li, L.-M., Chen, J.-K.
(2000). Reconstruction of Damaged Corneas by Transplantation of Autologous Limbal Epithelial Cells. NEJM
343: 86-93
[Abstract][Full Text]
Iglesia, D. D. S., Gala, P. H., Qiu, T., Stepp, M. A.
(2000). Integrin Expression During Epithelial Migration and Restratification in the Tenascin-C-deficient Mouse Cornea. J. Histochem. Cytochem.
48: 363-376
[Abstract][Full Text]
(2000). Treatment of Severe Ocular-Surface Disorders With Corneal Epithelial Stem Cell Transplantation. Arch Ophthalmol
118: 123-124
[Full Text]
Holland, E. J., Schwartz, G. S.
(1999). Epithelial Stem-Cell Transplantation for Severe Ocular-Surface Disease. NEJM
340: 1752-1753
[Full Text]