Advances in Cell Transplantation Therapy for Limbal Stem Cell Deficiency


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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.

About the authors

Yujia Gui

Department of Ophthalmology, the Second Hospital of Jilin University

Email: info@benthamscience.net

Yuxi He

Department of Ophthalmology, the Second Hospital of Jilin University

Email: info@benthamscience.net

Di Wang

Department of Ophthalmology, the Second Hospital of Jilin University

Email: info@benthamscience.net

Shurong Wang

Department of Ophthalmology, the Second Hospital of Jilin University

Email: info@benthamscience.net

Yan Zhang

Department of Ophthalmology, the Second Hospital of Jilin University

Author for correspondence.
Email: info@benthamscience.net

References

  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. doi: 10.1002/sctm.20-0408 PMID: 33951336
  2. Bonnet C, Roberts JS, Deng SX. Limbal stem cell diseases. Exp Eye Res 2021; 205: 108437. doi: 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. doi: 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. doi: 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. doi: 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) doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1002/cbin.10007 PMID: 23339091
  26. Keivyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96(5): 709-23. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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 doi: 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. doi: 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) doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.15171/bi.2020.06 PMID: 31988856

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