Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

Advances in Cell Transplantation Therapy for Limbal Stem Cell Deficiency

Author(s): Yujia Gui, Yuxi He, Di Wang, Shurong Wang and Yan Zhang*

Volume 19, Issue 7, 2024

Published on: 26 October, 2023

Page: [933 - 941] Pages: 9

DOI: 10.2174/1574888X18666230821102450

Price: $65

Abstract

Background: Limbal stem cells (LSCs) are essential for maintaining corneal transparency and ocular surface integrity. Many external factors or genetic diseases can lead to corneal limbal stem cell deficiency (LSCD), resulting in the loss of barrier and corneal epithelial cell renewal functions. Stem cell transplantation is one of the primary treatments for LSCD, including limbal transplantation and cultivated limbal epithelial transplantation. In addition, a variety of non-limbal stem cell lines have been experimented with for LSCD treatment. Biological scaffolds are also used to support in vitro stem cell culture and transplantation. Here, we review the mechanisms of corneal maintenance by LSCs, the clinical stage and surgical treatment of LSCD, the source of stem cells, and the biological scaffolds required for in vitro culture.

Methods: This study is a narrative retrospective study aimed at collecting available information on various aspects of surgical treatments for LSCD. Relevant literature was searched in a range of online databases, including Web of Science, Scopus, and PubMed from 2005 to March, 2023.

Results: A total of 397 relevant articles were found, and 49 articles with strong relevance to the studies in this paper were obtained and analyzed. Moreover, 11 of these articles were on the concept of LSCD and the mechanism of LESCs maintaining the corneal epithelium, 3 articles on the staging and grading of LSCD, 17 articles on cell transplantation methods and donor cell sources, and 18 articles on scaffolds for delivering stem cells. We also summarized the advantages and disadvantages of different cell transplantation methods and the benefits and limitations of scaffolds based on the above literature.

Conclusion: The treatment of LSCD is determined by the clinical stage and whether it involves monocular or binocular eyes. Appropriate surgical techniques should be taken for LSCD patients in order to reconstruct the ocular surface, relieve symptoms, and restore visual function. Meanwhile, biological scaffolds assist in the ex vivo culture and implantation of stem cells.

[1]
Singh V, Tiwari A, Kethiri AR, Sangwan VS. Current perspectives of limbal-derived stem cells and its application in ocular surface regeneration and limbal stem cell transplantation. Stem Cells Transl Med 2021; 10(8): 1121-8.
[http://dx.doi.org/10.1002/sctm.20-0408] [PMID: 33951336]
[2]
Bonnet C, Roberts JS, Deng SX. Limbal stem cell diseases. Exp Eye Res 2021; 205: 108437.
[http://dx.doi.org/10.1016/j.exer.2021.108437] [PMID: 33571530]
[3]
Yazdanpanah G, Haq Z, Kang K, Jabbehdari S, Rosenblatt M, Djalilian AR. Strategies for reconstructing the limbal stem cell niche. Ocul Surf 2019; 17(2): 230-40.
[http://dx.doi.org/10.1016/j.jtos.2019.01.002] [PMID: 30633966]
[4]
Polisetti N, Zenkel M, Menzel-Severing J, Kruse FE, Schlötzer-Schrehardt U. Cell adhesion molecules and stem cell-niche-interactions in the limbal stem cell niche. Stem Cells 2016; 34(1): 203-19.
[http://dx.doi.org/10.1002/stem.2191] [PMID: 26349477]
[5]
Deng SX, Borderie V, Chan CC, et al. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency. Cornea 2019; 38(3): 364-75.
[http://dx.doi.org/10.1097/ICO.0000000000001820] [PMID: 30614902]
[6]
Gonzalez G, Sasamoto Y, Ksander BR, Frank MH, Frank NY. Limbal stem cells: Identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol 2018; 7(2)
[http://dx.doi.org/10.1002/wdev.303] [PMID: 29105366]
[7]
Burillon C, Huot L, Justin V, et al. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. Invest Ophthalmol Vis Sci 2012; 53(3): 1325-31.
[http://dx.doi.org/10.1167/iovs.11-7744] [PMID: 22064987]
[8]
Masood F, Chang JH, Akbar A, et al. Therapeutic strategies for restoring perturbed corneal epithelial homeostasis in limbal stem cell deficiency: Current trends and future directions. Cells 2022; 11(20): 3247.
[http://dx.doi.org/10.3390/cells11203247] [PMID: 36291115]
[9]
Lehrer MS, Sun TT, Lavker RM. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation. J Cell Sci 1998; 111(19): 2867-75.
[http://dx.doi.org/10.1242/jcs.111.19.2867] [PMID: 9730979]
[10]
Beebe DC, Masters BR. Cell lineage and the differentiation of corneal epithelial cells. Invest Ophthalmol Vis Sci 1996; 37(9): 1815-25.
[PMID: 8759349]
[11]
Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci 1983; 24(10): 1442-3.
[PMID: 6618809]
[12]
Aravena C, Bozkurt K, Chuephanich P, Supiyaphun C, Yu F, Deng SX. Classification of limbal stem cell deficiency using clinical and confocal grading. Cornea 2019; 38(1): 1-7.
[http://dx.doi.org/10.1097/ICO.0000000000001799] [PMID: 30371569]
[13]
Deng SX, Kruse F, Gomes JAP, et al. Global consensus on the management of limbal stem cell deficiency. Cornea 2020; 39(10): 1291-302.
[http://dx.doi.org/10.1097/ICO.0000000000002358] [PMID: 32639314]
[14]
Kim BY, Riaz KM, Bakhtiari P, et al. Medically reversible limbal stem cell disease: Clinical features and management strategies. Ophthalmology 2014; 121(10): 2053-8.
[http://dx.doi.org/10.1016/j.ophtha.2014.04.025] [PMID: 24908203]
[15]
Le Q, Chauhan T, Yung M, Tseng CH, Deng SX. Outcomes of limbal stem cell transplant. JAMA Ophthalmol 2020; 138(6): 660-70.
[http://dx.doi.org/10.1001/jamaophthalmol.2020.1120] [PMID: 32324211]
[16]
Yin J, Jurkunas U. Limbal stem cell transplantation and complications. Semin Ophthalmol 2018; 33(1): 134-41.
[http://dx.doi.org/10.1080/08820538.2017.1353834] [PMID: 29172876]
[17]
Sehic A, Utheim Ø, Ommundsen K, Utheim T. Pre-clinical cell-based therapy for limbal stem cell deficiency. J Funct Biomater 2015; 6(3): 863-88.
[http://dx.doi.org/10.3390/jfb6030863] [PMID: 26343740]
[18]
Nieto-Miguel T, Galindo S, Reinoso R, et al. In vitro simulation of corneal epithelium microenvironment induces a corneal epithelial-like cell phenotype from human adipose tissue mesenchymal stem cells. Curr Eye Res 2013; 38(9): 933-44.
[http://dx.doi.org/10.3109/02713683.2013.802809] [PMID: 23767776]
[19]
Meyer-Blazejewska EA, Call MK, Yamanaka O, 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(1): 57-66.
[http://dx.doi.org/10.1002/stem.550] [PMID: 20957740]
[20]
Ouyang H, Xue Y, Lin Y, et al. WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. Nature 2014; 511(7509): 358-61.
[http://dx.doi.org/10.1038/nature13465] [PMID: 25030175]
[21]
Gomes JÁP, Geraldes Monteiro B, Melo GB, et al. Corneal reconstruction with tissue-engineered cell sheets composed of human immature dental pulp stem cells. Invest Ophthalmol Vis Sci 2010; 51(3): 1408-14.
[http://dx.doi.org/10.1167/iovs.09-4029] [PMID: 19892864]
[22]
Zhang C, Du L, Pang K, Wu X. Differentiation of human embryonic stem cells into corneal epithelial progenitor cells under defined conditions. PLoS One 2017; 12(8): e0183303.
[http://dx.doi.org/10.1371/journal.pone.0183303] [PMID: 28813511]
[23]
Ueno H, Kurokawa MS, Kayama M, et al. Experimental transplantation of corneal epithelium-like cells induced by Pax6 gene transfection of mouse embryonic stem cells. Cornea 2007; 26(10): 1220-7.
[http://dx.doi.org/10.1097/ICO.0b013e31814fa814] [PMID: 18043180]
[24]
Reinshagen H, Auw-Haedrich C, Sorg RV, et al. Corneal surface reconstruction using adult mesenchymal stem cells in experimental limbal stem cell deficiency in rabbits. Acta Ophthalmol 2011; 89(8): 741-8.
[http://dx.doi.org/10.1111/j.1755-3768.2009.01812.x] [PMID: 20039850]
[25]
Yu D, Chen M, Sun X, Ge J. Differentiation of mouse induced pluripotent stem cells into corneal epithelial-like cells. Cell Biol Int 2013; 37(1): 87-94.
[http://dx.doi.org/10.1002/cbin.10007] [PMID: 23339091]
[26]
Keivyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96(5): 709-23.
[http://dx.doi.org/10.1016/S0161-6420(89)32833-8] [PMID: 2748125]
[27]
Cheung AY, Sarnicola E, Holland EJ. Long-term ocular surface stability in conjunctival limbal autograft donor eyes. Cornea 2017; 36(9): 1031-5.
[http://dx.doi.org/10.1097/ICO.0000000000001260] [PMID: 28644241]
[28]
Eslani M, Cheung AY, Kurji K, Pierson K, Sarnicola E, Holland EJ. Long-term outcomes of conjunctival limbal autograft in patients with unilateral total limbal stem cell deficiency. Ocul Surf 2019; 17(4): 670-4.
[http://dx.doi.org/10.1016/j.jtos.2019.09.003] [PMID: 31499235]
[29]
Rama P, Ferrari G, Pellegrini G. Cultivated limbal epithelial transplantation. Curr Opin Ophthalmol 2017; 28(4): 387-9.
[http://dx.doi.org/10.1097/ICU.0000000000000382] [PMID: 28399065]
[30]
Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 1997; 349(9057): 990-3.
[http://dx.doi.org/10.1016/S0140-6736(96)11188-0] [PMID: 9100626]
[31]
Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 2010; 363(2): 147-55.
[http://dx.doi.org/10.1056/NEJMoa0905955] [PMID: 20573916]
[32]
Bardag-Gorce F, Hoft R, Meepe I, et al. Proteasomes in corneal epithelial cells and cultured autologous oral mucosal epithelial cell sheet (CAOMECS) graft used for the ocular surface regeneration. Ocul Surf 2017; 15(4): 749-58.
[http://dx.doi.org/10.1016/j.jtos.2017.05.010] [PMID: 28528957]
[33]
Inatomi T, Nakamura T, Koizumi N, Sotozono C, Yokoi N, Kinoshita S. Midterm results on ocular surface reconstruction using cultivated autologous oral mucosal epithelial transplantation. Am J Ophthalmol 2006; 141(2): 267-275.e1.
[http://dx.doi.org/10.1016/j.ajo.2005.09.003] [PMID: 16458679]
[34]
Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med 2004; 351(12): 1187-96.
[http://dx.doi.org/10.1056/NEJMoa040455] [PMID: 15371576]
[35]
Shore JW, Foster CS, Westfall CT, Rubin PAD. Results of buccal mucosal grafting for patients with medically controlled ocular cicatricial pemphigoid. Ophthalmology 1992; 99(3): 383-95.
[http://dx.doi.org/10.1016/S0161-6420(92)31962-1] [PMID: 1565450]
[36]
Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial transplantation (SLET): A novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol 2012; 96(7): 931-4.
[http://dx.doi.org/10.1136/bjophthalmol-2011-301164] [PMID: 22328817]
[37]
Amescua G, Atallah M, Nikpoor N, Galor A, Perez VL. Modified simple limbal epithelial transplantation using cryopreserved amniotic membrane for unilateral limbal stem cell deficiency. Am J Ophthalmol 2014; 158(3): 469-475.e2.
[http://dx.doi.org/10.1016/j.ajo.2014.06.002] [PMID: 24932987]
[38]
Basu S, Sureka SP, Shanbhag SS, Kethiri AR, Singh V, Sangwan VS. Simple limbal epithelial transplantation. Ophthalmology 2016; 123(5): 1000-10.
[http://dx.doi.org/10.1016/j.ophtha.2015.12.042] [PMID: 26896125]
[39]
Vazirani J, Ali MH, Sharma N, et al. Autologous simple limbal epithelial transplantation for unilateral limbal stem cell deficiency: multicentre results. Br J Ophthalmol 2016; 100(10): 1416-20.
[http://dx.doi.org/10.1136/bjophthalmol-2015-307348] [PMID: 26817481]
[40]
Le Q, Deng SX. The application of human amniotic membrane in the surgical management of limbal stem cell deficiency. Ocul Surf 2019; 17(2): 221-9.
[http://dx.doi.org/10.1016/j.jtos.2019.01.003] [PMID: 30633967]
[41]
Li Y, Yang Y, Yang L, Zeng Y, Gao X, Xu H. Poly(ethylene glycol)-modified silk fibroin membrane as a carrier for limbal epithelial stem cell transplantation in a rabbit LSCD model. Stem Cell Res Ther 2017; 8(1): 256.
[http://dx.doi.org/10.1186/s13287-017-0707-y] [PMID: 29116027]
[42]
Haagdorens M. In vitro cultivation of limbal epithelial stem cells on surface-modified crosslinked collagen scaffolds. Stem Cells International 2019; 2019
[http://dx.doi.org/10.1155/2019/7867613]
[43]
Xu W, Liu K, Li T, et al. An in situ hydrogel based on carboxymethyl chitosan and sodium alginate dialdehyde for corneal wound healing after alkali burn. J Biomed Mater Res A 2019; 107(4): 742-54.
[http://dx.doi.org/10.1002/jbm.a.36589] [PMID: 30548137]
[44]
Brown KD, Low S, Mariappan I, et al. Plasma polymer-coated contact lenses for the culture and transfer of corneal epithelial cells in the treatment of limbal stem cell deficiency. Tissue Eng Part A 2014; 20(3-4)
[http://dx.doi.org/10.1089/ten.tea.2013.0089] [PMID: 24328453]
[45]
Ramachandran C, Deshpande P, Ortega I, et al. Proof-of-concept study of electrospun PLGA membrane in the treatment of limbal stem cell deficiency. BMJ Open Ophthalmol 2021; 6(1): e000762.
[http://dx.doi.org/10.1136/bmjophth-2021-000762] [PMID: 34395914]
[46]
Zhao Y, Ma L. Systematic review and meta-analysis on transplantation of ex vivo cultivated limbal epithelial stem cell on amniotic membrane in limbal stem cell deficiency. Cornea 2015; 34(5): 592-600.
[http://dx.doi.org/10.1097/ICO.0000000000000398] [PMID: 25789694]
[47]
Zhou Z, Long D, Hsu CC, et al. Nanofiber-reinforced decellularized amniotic membrane improves limbal stem cell transplantation in a rabbit model of corneal epithelial defect. Acta Biomater 2019; 97: 310-20.
[http://dx.doi.org/10.1016/j.actbio.2019.08.027] [PMID: 31437637]
[48]
Higa K, Takeshima N, Moro F, et al. Porous silk fibroin film as a transparent carrier for cultivated corneal epithelial sheets. J Biomater Sci Polym Ed 2011; 22(17): 2261-76.
[http://dx.doi.org/10.1163/092050610X538218] [PMID: 21092419]
[49]
Gavrilova NA, Borzenok SA, Revishchin AV, et al. The effect of biodegradable silk fibroin-based scaffolds containing glial cell line-derived neurotrophic factor (GDNF) on the corneal regeneration process. Int J Biol Macromol 2021; 185: 264-76.
[http://dx.doi.org/10.1016/j.ijbiomac.2021.06.040] [PMID: 34119551]
[50]
Chae JJ, McIntosh Ambrose W, Espinoza FA, et al. Regeneration of corneal epithelium utilizing a collagen vitrigel membrane in rabbit models for corneal stromal wound and limbal stem cell deficiency. Acta Ophthalmol 2015; 93(1): e57-66.
[http://dx.doi.org/10.1111/aos.12503] [PMID: 25495158]
[51]
Grolik M. Szczubiałka K, Wowra B, et al. Hydrogel membranes based on genipin-cross-linked chitosan blends for corneal epithelium tissue engineering. J Mater Sci Mater Med 2012; 23(8): 1991-2000.
[http://dx.doi.org/10.1007/s10856-012-4666-7] [PMID: 22569736]
[52]
de la Mata A, Nieto-Miguel T, López-Paniagua M, et al. Chitosan–gelatin biopolymers as carrier substrata for limbal epithelial stem cells. J Mater Sci Mater Med 2013; 24(12): 2819-29.
[http://dx.doi.org/10.1007/s10856-013-5013-3] [PMID: 23892486]
[53]
Di Girolamo N, Bosch M, Zamora K, Coroneo MT, Wakefield D, Watson SL. A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction. Transplantation 2009; 87(10): 1571-8.
[http://dx.doi.org/10.1097/TP.0b013e3181a4bbf2] [PMID: 19461496]
[54]
de la Mata A, Mateos-Timoneda MA, Nieto-Miguel T, et al. Poly-l/dl-lactic acid films functionalized with collagen IV as carrier substrata for corneal epithelial stem cells. Colloids Surf B Biointerfaces 2019; 177: 121-9.
[http://dx.doi.org/10.1016/j.colsurfb.2019.01.054] [PMID: 30716697]
[55]
Sanie-Jahromi F, Eghtedari M, Mirzaei E, et al. Propagation of limbal stem cells on polycaprolactone and polycaprolactone/gelatin fibrous scaffolds and transplantation in animal model. Bioimpacts 2019; 10(1): 45-54.
[http://dx.doi.org/10.15171/bi.2020.06] [PMID: 31988856]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy