Role of stem cells in ocular diseases: Progress and challenges

Abstract

Ocular diseases, including corneal disease, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity, can significantly impair vision and reduce quality of life. Because degenerated cells in these diseases are unable to regenerate, treatments for these conditions have limited efficacy. Stem cell therapies are revolutionizing the treatment of degenerative eye conditions, enabling structural and functional restoration through mechanisms such as cell replacement and paracrine signaling. This review examines advances in stem cell therapy for ocular diseases, from preclinical studies to early clinical trials, focusing on various types of stem cells, including embryonic stem cells, induced pluripotent stem cells (iPSCs), and mesenchymal stem cells. Significant progress has been made with iPSC-derived retinal pigment epithelial cell transplantation in AMD treatment, showing cell survival in trials, and with mesenchymal stem cells for corneal repair through anti-inflammatory effects. Challenges remain, such as controlling differentiation to prevent tumorigenesis, managing immune rejection, and ensuring manufacturing processes that comply with Good Manufacturing Practice standards. By integrating mechanistic insights with translational strategies, this review outlines pathways to optimize stem cell therapies for previously intractable ocular diseases.

Keywords

stem cells / cell therapies / ocular diseases / progress / challenges

Funding

This work was generously supported by grants from the National Natural Science Foundation of China (Grant No. 82271101 to Q.J.) and the Medical Science and Technology Development Project Fund of Nanjing (Grant No. YKK22263 to X.L.).

Acknowledgments

We would like to acknowledge our colleagues for their helpful comments on this paper.

References

[1] Ma S, Xie Y, Wang Q, et al. Application of eye organoids in the study of eye diseases[J]. Exp Eye Res, 2024, 247: 110068. doi: 10.1016/j.exer.2024.110068

[2] Baudouin C, Kolko M, Melik-Parsadaniantz S, et al. Inflammation in glaucoma: From the back to the front of the eye, and beyond[J]. Prog Retin Eye Res, 2021, 83: 100916. doi: 10.1016/j.preteyeres.2020.100916

[3] Boya P, Esteban-Martínez L, Serrano-Puebla A, et al. Autophagy in the eye: Development, degeneration, and aging[J]. Prog Retin Eye Res, 2016, 55: 206-245. doi: 10.1016/j.preteyeres.2016.08.001

[4] Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges[J]. Cell Stem Cell, 2020, 27(4): 523-531. doi: 10.1016/j.stem.2020.09.014

[5] Tian Z, Yu T, Liu J, et al. Introduction to stem cells[J]. Prog Mol Biol Transl Sci, 2023, 199: 3-32. doi: 10.1016/bs.pmbts.2023.02.012

[6] Maeda T, Mandai M, Sugita S, et al. Strategies of pluripotent stem cell-based therapy for retinal degeneration: Update and challenges[J]. Trends Mol Med, 2022, 28(5): 388-404. doi: 10.1016/j.molmed.2022.03.001

[7] Lee V, Rompolas P. Corneal regeneration: Insights in epithelial stem cell heterogeneity and dynamics[J]. Curr Opin Genet Dev, 2022, 77: 101981. doi: 10.1016/j.gde.2022.101981

[8] Jin Z, Gao M, Deng W, et al. Stemming retinal regeneration with pluripotent stem cells[J]. Prog Retin Eye Res, 2019, 69: 38-56. doi: 10.1016/j.preteyeres.2018.11.003

[9] Ljubimov AV, Saghizadeh M. Progress in corneal wound healing[J]. Prog Retin Eye Res, 2015, 49: 17-45. doi: 10.1016/j.preteyeres.2015.07.002

[10] Ruan Y, Jiang S, Musayeva A, et al. Corneal epithelial stem cells-physiology, pathophysiology and therapeutic options[J]. Cells, 2021, 10(9): 2302. doi: 10.3390/cells10092302

[11] Pacini S. Deterministic and stochastic approaches in the clinical application of mesenchymal stromal cells (MSCs)[J]. Front Cell Dev Biol, 2014, 2: 50. doi: 10.3389/fcell.2014.00050

[12] Trounson A, McDonald C. Stem cell therapies in clinical trials: Progress and challenges[J]. Cell Stem Cell, 2015, 17(1): 11-22. doi: 10.1016/j.stem.2015.06.007

[13] Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: Follow-up of two open-label phase 1/2 studies[J]. Lancet, 2015, 385(9967): 509-516. doi: 10.1016/S0140-6736(14)61376-3

[14] Sharma R, Khristov V, Rising A, et al. Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs[J]. Sci Transl Med, 2019, 11(475): eaat5580. doi: 10.1126/scitranslmed.aat5580

[15] da Cruz L, Fynes K, Georgiadis O, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration[J]. Nat Biotechnol, 2018, 36(4): 328-337. doi: 10.1038/nbt.4114

[16] Mandai M, Watanabe A, Kurimoto Y, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration[J]. N Engl J Med, 2017, 376(11): 1038-1046. doi: 10.1056/NEJMoa1608368

[17] Robinson PG, Murray IR, West CC, et al. Reporting of mesenchymal stem cell preparation protocols and composition: A systematic review of the clinical orthopaedic literature[J]. Am J Sports Med, 2019, 47(4): 991-1000. doi: 10.1177/0363546518758667

[18] Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD[J]. N Engl J Med, 2017, 376(11): 1047-1053. doi: 10.1056/NEJMoa1609583

[19] Stern JH, Tian Y, Funderburgh J, et al. Regenerating eye tissues to preserve and restore vision[J]. Cell Stem Cell, 2018, 22(6): 834-849. doi: 10.1016/j.stem.2018.05.013

[20] Santa Cruz-Pavlovich FJ, Bolaños-Chang AJ, Del Rio-Murillo XI, et al. Beyond vision: An overview of regenerative medicine and its current applications in ophthalmological care[J]. Cells, 2024, 13(2): 179. doi: 10.3390/cells13020179

[21] Kimbrel EA, Lanza R. Next-generation stem cells—ushering in a new era of cell-based therapies[J]. Nat Rev Drug Discov, 2020, 19(7): 463-479. doi: 10.1038/s41573-020-0064-x

[22] Puri MC, Nagy A. Concise review: Embryonic stem cells versus induced pluripotent stem cells: The game is on[J]. Stem Cells, 2012, 30(1): 10-14. doi: 10.1002/stem.788

[23] Ng AP, Alexander WS. Haematopoietic stem cells: Past, present and future[J]. Cell Death Discov, 2017, 3: 17002. doi: 10.1038/cddiscovery.2017.2

[24] Naji A, Eitoku M, Favier B, et al. Biological functions of mesenchymal stem cells and clinical implications[J]. Cell Mol Life Sci, 2019, 76(17): 3323-3348. doi: 10.1007/s00018-019-03125-1

[25] Tang Y, Yu P, Cheng L. Current progress in the derivation and therapeutic application of neural stem cells[J]. Cell Death Dis, 2017, 8(10): e3108. doi: 10.1038/cddis.2017.504

[26] Chambers SEJ, Pathak V, Pedrini E, et al. Current concepts on endothelial stem cells definition, location, and markers[J]. Stem Cells Transl Med, 2021, 10 Suppl 2(Suppl 2): S54-S61. doi: 10.1002/sctm.21-0022

[27] Zakrzewski W, Dobrzyński M, Szymonowicz M, et al. Stem cells: Past, present, and future[J]. Stem Cell Res Ther, 2019, 10(1): 68. doi: 10.1186/s13287-019-1165-5

[28] Zhang J, Bolli R, Garry DJ, et al. Basic and translational research in cardiac repair and regeneration: JACC state-of-the-art review[J]. J Am Coll Cardiol, 2021, 78(21): 2092-2105. doi: 10.1016/j.jacc.2021.09.019

[29] Wang R, Yao Q, Chen W, et al. Stem cell therapy for Crohn's disease: Systematic review and meta-analysis of preclinical and clinical studies[J]. Stem Cell Res Ther, 2021, 12(1): 463. doi: 10.1186/s13287-021-02533-0

[30] Liu Y, Dong Y, Wu X, et al. The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: A systematic review and meta-analysis of randomized controlled clinical trials[J]. Stem Cell Res Ther, 2022, 13(1): 204. doi: 10.1186/s13287-022-02882-4

[31] Hmadcha A, Martin-Montalvo A, Gauthier BR, et al. Therapeutic potential of mesenchymal stem cells for cancer therapy[J]. Front Bioeng Biotechnol, 2020, 8: 43. doi: 10.3389/fbioe.2020.00043

[32] Graw J. Eye development[J]. Curr Top Dev Biol, 2010, 90: 343-386. doi: 10.1016/S0070-2153(10)90010-0

[33] GBD 2019 Blindness and Vision Impairment Collaborators, Vision Loss Expert Group of the Global Burden of Disease Study. Trends in prevalence of blindness and distance and near vision impairment over 30 years: An analysis for the Global Burden of Disease Study[J]. Lancet Glob Health, 2021, 9( 2): e130-e143. doi: 10.1016/S2214-109X(20)30425-3

[34] Flaxman SR, Bourne RRA, Resnikoff S, et al. Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis[J]. Lancet Glob Health, 2017, 5(12): e1221-e1234. doi: 10.1016/S2214-109X(17)30393-5

[35] Ong ES, Jeng BH. Current and future therapies for persistent corneal epithelial defects and neurotrophic keratopathy[J]. Curr Opin Ophthalmol, 2021, 32(3): 262-267. doi: 10.1097/ICU.0000000000000749

[36] Zhu J, Inomata T, Di Zazzo A, et al. Role of immune cell diversity and heterogeneity in corneal graft survival: A systematic review and meta-analysis[J]. J Clin Med, 2021, 10(20): 4667. doi: 10.3390/jcm10204667

[37] 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[J]. Cell, 1989, 57(2): 201-209. doi: 10.1016/0092-8674(89)90958-6

[38] Genna VG, Maurizi E, Rama P, et al. Biology and medicine on ocular surface restoration: Advancements and limits of limbal stem cell deficiency treatments[J]. Ocul Surf, 2025, 35: 57-67. doi: 10.1016/j.jtos.2024.11.005

[39] Deng SX, Borderie V, Chan CC, et al. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency[J]. Cornea, 2019, 38(3): 364-375. doi: 10.1097/ICO.0000000000001820

[40] Sangwan VS. Limbal stem cells in health and disease[J]. Biosci Rep, 2001, 21(4): 385-405. doi: 10.1023/A:1017935624867

[41] Di Zazzo A, Gaudenzi D, Yin J, et al. Corneal angiogenic privilege and its failure[J]. Exp Eye Res, 2021, 204: 108457. doi: 10.1016/j.exer.2021.108457

[42] Pellegrini G, Rama P, Mavilio F, et al. Epithelial stem cells in corneal regeneration and epidermal gene therapy[J]. J Pathol, 2009, 217(2): 217-228. doi: 10.1002/path.2441

[43] Wei ZG, Cotsarelis G, Sun TT, et al. Label-retaining cells are preferentially located in fornical epithelium: Implications on conjunctival epithelial homeostasis[J]. Invest Ophthalmol Vis Sci, 1995, 36(1): 236-246. https://pubmed.ncbi.nlm.nih.gov/7822151/

[44] Qi H, Zheng X, Yuan X, et al. Potential localization of putative stem/progenitor cells in human bulbar conjunctival epithelium[J]. J Cell Physiol, 2010, 225(1): 180-185. doi: 10.1002/jcp.22215

[45] Stewart RMK, Sheridan CM, Hiscott PS, et al. Human conjunctival stem cells are predominantly located in the medial canthal and inferior forniceal areas[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 2021-2030. doi: 10.1167/iovs.14-16266

[46] Alfonso EC. Treatment of severe ocular-surface disorders with corneal epithelial stem cell transplantation[J]. Arch Ophthalmol, 2000, 118(1): 123-124. doi: 10.1001/archopht.118.1.123

[47] Ilari L, Daya SM. Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders[J]. Ophthalmology, 2002, 109(7): 1278-1284. doi: 10.1016/S0161-6420(02)01081-3

[48] Oie Y, Sugita S, Yokokura S, et al. Clinical trial of autologous cultivated limbal epithelial cell sheet transplantation for patients with limbal stem cell deficiency[J]. Ophthalmology, 2023, 130(6): 608-614. doi: 10.1016/j.ophtha.2023.01.016

[49] O'Callaghan AR, Dziasko MA, Sheth-Shah R, et al. Oral mucosa tissue equivalents for the treatment of limbal stem cell deficiency[J]. Adv Biosyst, 2020, 4(7): 1900265. doi: 10.1002/adbi.201900265

[50] Al-Aqaba MA, Dhillon VK, Mohammed I, et al. Corneal nerves in health and disease[J]. Prog Retin Eye Res, 2019, 73: 100762. doi: 10.1016/j.preteyeres.2019.05.003

[51] Oh JY, Lee RH. Mesenchymal stromal cells for the treatment of ocular autoimmune diseases[J]. Prog Retin Eye Res, 2021, 85: 100967. doi: 10.1016/j.preteyeres.2021.100967

[52] Shichinohe H, Kawabori M, Iijima H, et al. Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): A study protocol for a phase Ⅰ open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke[J]. BMC Neurol, 2017, 17(1): 179. doi: 10.1186/s12883-017-0955-6

[53] Yao L, Li Z, Su W, et al. Role of mesenchymal stem cells on cornea wound healing induced by acute alkali burn[J]. PLoS One, 2012, 7(2): e30842. doi: 10.1371/journal.pone.0030842

[54] Hayashi R, Ishikawa Y, Sasamoto Y, et al. Co-ordinated ocular development from human iPS cells and recovery of corneal function[J]. Nature, 2016, 531(7594): 376-380. doi: 10.1038/nature17000

[55] Sahu A, Foulsham W, Amouzegar A, et al. The therapeutic application of mesenchymal stem cells at the ocular surface[J]. Ocul Surf, 2019, 17(2): 198-207. doi: 10.1016/j.jtos.2019.01.006

[56] Lu X, Li N, Zhao L, et al. Human umbilical cord mesenchymal stem cells alleviate ongoing autoimmune dacryoadenitis in rabbits via polarizing macrophages into an anti-inflammatory phenotype[J]. Exp Eye Res, 2020, 191: 107905. doi: 10.1016/j.exer.2019.107905

[57] Møller-Hansen M, Larsen AC, Toft PB, et al. Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease[J]. Ocul Surf, 2021, 19: 43-52. doi: 10.1016/j.jtos.2020.11.013

[58] Meek KM, Knupp C. Corneal structure and transparency[J]. Prog Retin Eye Res, 2015, 49: 1-16. doi: 10.1016/j.preteyeres.2015.07.001

[59] Thompson RW Jr, Price MO, Bowers PJ, et al. Long-term graft survival after penetrating keratoplasty[J]. Ophthalmology, 2003, 110(7): 1396-1402. doi: 10.1016/S0161-6420(03)00463-9

[60] Basu S, Hertsenberg AJ, Funderburgh ML, et al. Human limbal biopsy-derived stromal stem cells prevent corneal scarring[J]. Sci Transl Med, 2014, 6(266): 266ra172. doi: 10.1126/scitranslmed.3009644

[61] Hertsenberg AJ, Shojaati G, Funderburgh ML, et al. Corneal stromal stem cells reduce corneal scarring by mediating neutrophil infiltration after wounding[J]. PLoS One, 2017, 12(3): e0171712. doi: 10.1371/journal.pone.0171712

[62] Du Y, Funderburgh ML, Mann MM, et al. Multipotent stem cells in human corneal stroma[J]. Stem Cells, 2005, 23(9): 1266-1275. doi: 10.1634/stemcells.2004-0256

[63] Funderburgh JL, Funderburgh ML, Du Y. Stem cells in the limbal stroma[J]. Ocul Surf, 2016, 14(2): 113-120. doi: 10.1016/j.jtos.2015.12.006

[64] Kumar A, Yun H, Funderburgh ML, et al. Regenerative therapy for the cornea[J]. Prog Retin Eye Res, 2022, 87: 101011. doi: 10.1016/j.preteyeres.2021.101011

[65] Kumar A, Kumar V, Rattan V, et al. Secretome proteins regulate comparative osteogenic and adipogenic potential in bone marrow and dental stem cells[J]. Biochimie, 2018, 155: 129-139. doi: 10.1016/j.biochi.2018.10.014

[66] Ghoubay D, Borderie M, Grieve K, et al. Corneal stromal stem cells restore transparency after N₂ injury in mice[J]. Stem Cells Transl Med, 2020, 9(8): 917-935. doi: 10.1002/sctm.19-0306

[67] Yam GHF, Yang T, Geary ML, et al. Human corneal stromal stem cells express anti-fibrotic microRNA-29a and 381-5p-a robust cell selection tool for stem cell therapy of corneal scarring[J]. J Adv Res, 2023, 45: 141-155. doi: 10.1016/j.jare.2022.05.008

[68] Bourne WM. Clinical estimation of corneal endothelial pump function[J]. Trans Am Ophthalmol Soc, 1998, 96: 229-239. https://pubmed.ncbi.nlm.nih.gov/10360291/

[69] Shao C, Fu Y, Lu W, et al. Bone marrow-derived endothelial progenitor cells: A promising therapeutic alternative for corneal endothelial dysfunction[J]. Cells Tissues Organs, 2011, 193(4): 253-263. doi: 10.1159/000319797

[70] Zhang K, Pang K, Wu X. Isolation and transplantation of corneal endothelial cell-like cells derived from in-vitro-differentiated human embryonic stem cells[J]. Stem Cells Dev, 2014, 23(12): 1340-1354. doi: 10.1089/scd.2013.0510

[71] Li Z, Duan H, Jia Y, et al. Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide[J]. J Clin Invest, 2022, 132(1): e146658. doi: 10.1172/JCI146658

[72] Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. doi: 10.1016/j.preteyeres.2018.03.005

[73] Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis[J]. Lancet Glob Health, 2014, 2(2): e106-e116. doi: 10.1016/S2214-109X(13)70145-1

[74] Van Gelder RN, Chiang MF, Dyer MA, et al. Regenerative and restorative medicine for eye disease[J]. Nat Med, 2022, 28(6): 1149-1156. doi: 10.1038/s41591-022-01862-8

[75] Pan CK, Heilweil G, Lanza R, et al. Embryonic stem cells as a treatment for macular degeneration[J]. Expert Opin Biol Ther, 2013, 13(8): 1125-1133. doi: 10.1517/14712598.2013.793304

[76] Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis[J]. Ophthalmology, 2014, 121(11): 2081-2090. doi: 10.1016/j.ophtha.2014.05.013

[77] Jayaram H, Kolko M, Friedman DS, et al. Glaucoma: Now and beyond[J]. Lancet, 2023, 402(10414): 1788-1801. doi: 10.1016/S0140-6736(23)01289-8

[78] Coulon SJ, Schuman JS, Du Y, et al. A novel glaucoma approach: Stem cell regeneration of the trabecular meshwork[J]. Prog Retin Eye Res, 2022, 90: 101063. doi: 10.1016/j.preteyeres.2022.101063

[79] Mallick S, Sharma M, Kumar A, et al. Cell-based therapies for trabecular meshwork regeneration to treat glaucoma[J]. Biomolecules, 2021, 11(9): 1258. doi: 10.3390/biom11091258

[80] Yun H, Wang Y, Zhou Y, et al. Human stem cells home to and repair laser-damaged trabecular meshwork in a mouse model[J]. Commun Biol, 2018, 1: 216. doi: 10.1038/s42003-018-0227-z

[81] Samples JR, Bradley JMB, Bacon DR, et al. Trabecular repopulation by anterior trabecular meshwork cells after laser trabeculoplasty[J]. Am J Ophthalmol, 1989, 107(1): 1-6. doi: 10.1016/0002-9394(89)90805-2

[82] Du Y, Yun H, Yang E, et al. Stem cells from trabecular meshwork home to TM tissue in vivo[J]. Invest Ophthalmol Vis Sci, 2013, 54(2): 1450-1459. doi: 10.1167/iovs.12-11056

[83] Xiong S, Kumar A, Tian S, et al. Stem cell transplantation rescued a primary open-angle glaucoma mouse model[J]. Elife, 2021, 10: e63677. doi: 10.7554/eLife.63677

[84] Manuguerra-Gagné R, Boulos PR, Ammar A, et al. Transplantation of mesenchymal stem cells promotes tissue regeneration in a glaucoma model through laser-induced paracrine factor secretion and progenitor cell recruitment[J]. Stem Cells, 2013, 31(6): 1136-1148. doi: 10.1002/stem.1364

[85] Roubeix C, Godefroy D, Mias C, et al. Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma[J]. Stem Cell Res Ther, 2015, 6(1): 177. doi: 10.1186/s13287-015-0168-0

[86] Zhu W, Jain A, Gramlich OW, et al. Restoration of aqueous humor outflow following transplantation of iPSC-derived trabecular meshwork cells in a transgenic mouse model of glaucoma[J]. Invest Ophthalmol Vis Sci, 2017, 58(4): 2054-2062. doi: 10.1167/iovs.16-20672

[87] Zhu W, Godwin CR, Cheng L, et al. Transplantation of iPSC-TM stimulates division of trabecular meshwork cells in human eyes[J]. Sci Rep, 2020, 10(1): 2905. doi: 10.1038/s41598-020-59941-0

[88] Venugopalan P, Wang Y, Nguyen T, et al. Transplanted neurons integrate into adult retinas and respond to light[J]. Nat Commun, 2016, 7: 10472. doi: 10.1038/ncomms10472

[89] Klassen H. Stem cells in clinical trials for treatment of retinal degeneration[J]. Expert Opin Biol Ther, 2016, 16(1): 7-14. doi: 10.1517/14712598.2016.1093110

[90] Wang Z, Gao F, Zhang M, et al. Intravitreal injection of human retinal progenitor cells for treatment of retinal degeneration[J]. Med Sci Monit, 2020, 26: e921184. doi: 10.12659/MSM.921184

[91] Luo Z, Chang KC, Wu S, et al. Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo[J]. Stem Cell Reports, 2022, 17(12): 2690-2703. doi: 10.1016/j.stemcr.2022.10.011

[92] Zhao T, Li Y, Tang L, et al. Protective effects of human umbilical cord blood stem cell intravitreal transplantation against optic nerve injury in rats[J]. Graefes Arch Clin Exp Ophthalmol, 2011, 249(7): 1021-1028. doi: 10.1007/s00417-011-1635-7

[93] Labrador-Velandia S, Alonso-Alonso ML, Di Lauro S, et al. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures[J]. Exp Eye Res, 2019, 185: 107671. doi: 10.1016/j.exer.2019.05.011

[94] Weiss JN, Levy S. Stem Cell Ophthalmology Treatment Study (SCOTS): Bone marrow derived stem cells in the treatment of dominant optic atrophy[J]. Stem Cell Investig, 2019, 6: 41. doi: 10.21037/sci.2019.11.01

[95] Fine SL, Berger JW, Maguire MG, et al. Age-related macular degeneration[J]. N Engl J Med, 2000, 342(7): 483-492. doi: 10.1056/NEJM200002173420707

[96] Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: Consensus on neovascular age-related macular degeneration nomenclature study group[J]. Ophthalmology, 2020, 127(5): 616-636. doi: 10.1016/j.ophtha.2019.11.004

[97] Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration[J]. Ophthalmology, 2018, 125(11): 1765-1775. doi: 10.1016/j.ophtha.2018.04.037

[98] Humayun MS, Clegg DO, Dayan MS, et al. Long-term follow-up of a phase 1/2a clinical trial of a stem cell-derived bioengineered retinal pigment epithelium implant for geographic atrophy[J]. Ophthalmology, 2024, 131(6): 682-691. doi: 10.1016/j.ophtha.2023.12.028

[99] Saini JS, Corneo B, Miller JD, et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration[J]. Cell Stem Cell, 2017, 20(5): 635-647.e7. doi: 10.1016/j.stem.2016.12.015

[100] Li G, Liu S, Chen W, et al. Acellularized uvea hydrogel as novel injectable platform for cell-based delivering treatment of retinal degeneration and optimizing retinal organoids inducible system[J]. Adv Healthc Mater, 2022, 11(23): 2202114. doi: 10.1002/adhm.202202114

[101] Wang S, Ma W, Yan R, et al. Generating retinal neurons by reprogramming retinal pigment epithelial cells[J]. Expert Opin Biol Ther, 2010, 10(8): 1227-1239. doi: 10.1517/14712598.2010.495218

[102] Burns ME, Baylor DA. Activation, deactivation, and adaptation in vertebrate photoreceptor cells[J]. Annu Rev Neurosci, 2001, 24: 779-805. doi: 10.1146/annurev.neuro.24.1.779

[103] Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives[J]. Prog Retin Eye Res, 2018, 63: 107-131. doi: 10.1016/j.preteyeres.2017.10.004

[104] Wert KJ, Lin JH, Tsang SH. General pathophysiology in retinal degeneration[M]// Casaroli-Marano RP, Zarbin MA. Cell-Based Therapy for Retinal Degenerative Disease. Basel: Karger, 2014: 33-43.

[105] Sears AE, Bernstein PS, Cideciyan AV, et al. Towards treatment of Stargardt disease: Workshop organized and sponsored by the foundation fighting blindness[J]. Transl Vis Sci Technol, 2017, 6(5): 6. doi: 10.1167/tvst.6.5.6

[106] Huang S, Zeng Y, Guo Q, et al. Small extracellular vesicles of organoid-derived human retinal stem cells remodel Müller cell fate via miRNA: A novel remedy for retinal degeneration[J]. J Control Release, 2024, 370: 405-420. doi: 10.1016/j.jconrel.2024.04.036

[107] Hirami Y, Mandai M, Sugita S, et al. Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa[J]. Cell Stem Cell, 2023, 30(12): 1585-1596.e6. doi: 10.1016/j.stem.2023.11.004

[108] Saha A, Capowski E, Fernandez Zepeda MA, et al. Cone photoreceptors in human stem cell-derived retinal organoids demonstrate intrinsic light responses that mimic those of primate fovea[J]. Cell Stem Cell, 2022, 29(3): 460-471.e3. doi: 10.1016/j.stem.2022.01.002

[109] Gasparini SJ, Tessmer K, Reh M, et al. Transplanted human cones incorporate into the retina and function in a murine cone degeneration model[J]. J Clin Invest, 2022, 132(12): e154619. doi: 10.1172/JCI154619

[110] Le HG, Shakoor A. Diabetic and retinal vascular eye disease[J]. Med Clin North Am, 2021, 105(3): 455-472. doi: 10.1016/j.mcna.2021.02.004

[111] Park SS. Cell therapy applications for retinal vascular diseases: Diabetic retinopathy and retinal vein occlusion[J]. Invest Ophthalmol Vis Sci, 2016, 57(5): ORSFj1-ORSFj10. doi: 10.1167/iovs15

[112] Kim H, Kim JJ, Yoon YS. Emerging therapy for diabetic neuropathy: Cell therapy targeting vessels and nerves[J]. Endocr Metab Immune Disord Drug Targets, 2012, 12(2): 168-178. doi: 10.2174/187153012800493486

[113] Pushparani DS, Varalakshmi J, Roobini K, et al. Diabetic retinopathy-a review[J]. Curr Diabetes Rev, 2025, 21(7): e310524230559. doi: 10.2174/0115733998296228240521151050

[114] Stitt AW, Curtis TM, Chen M, et al. The progress in understanding and treatment of diabetic retinopathy[J]. Prog Retin Eye Res, 2016, 51: 156-186. doi: 10.1016/j.preteyeres.2015.08.001

[115] Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications[J]. Redox Biol, 2020, 37: 101799. doi: 10.1016/j.redox.2020.101799

[116] Lee CY, Yang CH. The role of fractalkine in diabetic retinopathy: Pathophysiology and clinical implications[J]. Int J Mol Sci, 2025, 26(1): 378. doi: 10.3390/ijms26010378

[117] Safwat A, Sabry D, Ragiae A, et al. Adipose mesenchymal stem cells-derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits[J]. J Circ Biomark, 2018, 7: 1849454418807827. doi: 10.1177/1849454418807827

[118] Park SS, Bauer G, Abedi M, et al. Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: Preliminary phase 1 clinical trial findings[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 81-89. doi: 10.1167/iovs.14-15415

[119] Song Y, Yin C, Kong N. Stem cell-derived exosomes: Natural intercellular messengers with versatile mechanisms for the treatment of diabetic retinopathy[J]. Int J Nanomedicine, 2024, 19: 10767-10784. doi: 10.2147/IJN.S475234

[120] Rong L, Wei W, Fang Y, et al. Clinical-grade human embryonic stem cell-derived mesenchymal stromal cells ameliorate diabetic retinopathy in db/db mice[J]. Cytotherapy, 2024, 26(6): 606-615. doi: 10.1016/j.jcyt.2024.02.020

[121] Sun F, Sun Y, Wang X, et al. Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway[J]. Bioact Mater, 2023, 33: 444-459. doi: 10.1016/j.bioactmat.2023.11.008

[122] Lu Y, Tian H, Peng H, et al. Novel lipid mediator 7S, 14R-docosahexaenoic acid: Biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss[J]. Front Cell Dev Biol, 2024, 12: 1380059. doi: 10.3389/fcell.2024.1380059

[123] Dammann O, Stansfield BK. Neonatal sepsis as a cause of retinopathy of prematurity: An etiological explanation[J]. Prog Retin Eye Res, 2024, 98: 101230. doi: 10.1016/j.preteyeres.2023.101230

[124] Grant MB, May WS, Caballero S, et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization[J]. Nat Med, 2002, 8(6): 607-612. doi: 10.1038/nm0602-607

[125] Otani A, Kinder K, Ewalt K, et al. Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis[J]. Nat Med, 2002, 8(9): 1004-1010. doi: 10.1038/nm744

[126] Bressler NM, Kaiser PK, Do DV, et al. Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review[J]. Surv Ophthalmol, 2024, 69(4): 521-538. doi: 10.1016/j.survophthal.2024.03.009

[127] Spaide RF. Choroidal neovascularization[J]. Retina, 2017, 37(4): 609-610. doi: 10.1097/IAE.0000000000001575

[128] Miyamoto N, Mandai M, Kojima H, et al. Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning[J]. Clin Ophthalmol, 2017, 11: 809-816. doi: 10.2147/OPTH.S133332

[129] Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group Writing Committee, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results[J]. Ophthalmology, 2020, 127(4S): S135-S145. doi: 10.1016/j.ophtha.2019.11.025

[130] Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration[J]. Ophthalmology, 2012, 119(12): 2537-2548. doi: 10.1016/j.ophtha.2012.09.006

[131] Ying GS, Kim BJ, Maguire MG, et al. Sustained visual acuity loss in the comparison of age-related macular degeneration treatments trials[J]. JAMA Ophthalmol, 2014, 132(8): 915-921. doi: 10.1001/jamaophthalmol.2014.1019

[132] Sengupta N, Caballero S, Mames RN, et al. The role of adult bone marrow-derived stem cells in choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2003, 44(11): 4908-4913. doi: 10.1167/iovs.03-0342

[133] Li F, Zeng Y, Xu H, et al. Subretinal transplantation of retinal pigment epithelium overexpressing fibulin-5 inhibits laser-induced choroidal neovascularization in rats[J]. Exp Eye Res, 2015, 136: 78-85. doi: 10.1016/j.exer.2015.05.004

[134] Takagi S, Mandai M, Gocho K, et al. Evaluation of transplanted autologous induced pluripotent stem cell-derived retinal pigment epithelium in exudative age-related macular degeneration[J]. Ophthalmol Retina, 2019, 3(10): 850-859. doi: 10.1016/j.oret.2019.04.021

[135] Zhang L, Qiang W, Li M, et al. A drug delivery system of HIF-1α siRNA nanoparticles loaded by mesenchymal stem cells on choroidal neovascularization[J]. Nanomedicine (Lond), 2024, 19(26): 2171-2185. doi: 10.1080/17435889.2024.2393075

[136] Barbosa-Sabanero K, Hoffmann A, Judge C, et al. Lens and retina regeneration: New perspectives from model organisms[J]. Biochem J, 2012, 447(3): 321-334. doi: 10.1042/BJ20120813

[137] Yeo BSY, Ong RYX, Ganasekar P, et al. Cataract surgery and cognitive benefits in the older person: A systematic review and meta-analysis[J]. Ophthalmology, 2024, 131(8): 975-984. doi: 10.1016/j.ophtha.2024.02.003

[138] Lin H, Ouyang H, Zhu J, et al. Lens regeneration using endogenous stem cells with gain of visual function[J]. Nature, 2016, 531(7594): 323-328. doi: 10.1038/nature17181

[139] Wu X, Long E, Lin H, et al. Prevalence and epidemiological characteristics of congenital cataract: A systematic review and meta-analysis[J]. Sci Rep, 2016, 6(1): 28564. doi: 10.1038/srep28564

[140] Liu Y, Granet D, Lin H, et al. Liu et al. reply[J]. Nature, 2018, 556(7699): E3-E4. doi: 10.1038/nature26150

[141] Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist[J]. BMJ, 2021, 372: m4979. doi: 10.1136/bmj.m4979

[142] Sugita S, Mandai M, Kamao H, et al. Immunological aspects of RPE cell transplantation[J]. Prog Retin Eye Res, 2021, 84: 100950. doi: 10.1016/j.preteyeres.2021.100950

[143] Sugita S, Futatsugi Y, Ishida M, et al. Retinal pigment epithelial cells derived from induced pluripotent stem (iPS) cells suppress or activate T cells via costimulatory signals[J]. Int J Mol Sci, 2020, 21(18): 6507. doi: 10.3390/ijms21186507

[144] Diedrichs-Möhring M, Kaufmann U, Wildner G. The immunopathogenesis of chronic and relapsing autoimmune uveitis—Lessons from experimental rat models[J]. Prog Retin Eye Res, 2018, 65: 107-126. doi: 10.1016/j.preteyeres.2018.02.003

[145] Zhang X, Ren X, Li G, et al. Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3143-3152. doi: 10.1167/iovs.10-6334

[146] Zhao P, Zhang L, Shao H, et al. Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis[J]. Int J Ophthalmol, 2016, 9(10): 1381-1389. doi: 10.18240/ijo.2016.10.03

[147] Caras IW, Collins LR, Creasey AA. A stem cell journey in ophthalmology: From the bench to the clinic[J]. Stem Cells Transl Med, 2021, 10(12): 1581-1587. doi: 10.1002/sctm.21-0239

[148] Miotti G, Parodi PC, Zeppieri M. Stem cell therapy in ocular pathologies in the past 20 years[J]. World J Stem Cells, 2021, 13(5): 366-385. doi: 10.4252/wjsc.v13.i5.366

[149] Tomczak W, Winkler-Lach W, Tomczyk-Socha M, et al. Advancements in ocular regenerative therapies[J]. Biology (Basel), 2023, 12(5): 737. doi: 10.3390/biology12050737