Research progress of retinal pigment epithelial cell transplantation in the treatment of retinitis pigmentosa_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Yunxi , Liu Boshi , Xing Dongjun ,  Li Xiaorong

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Centerfor Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin300384, China;

Corresponding author：

Li Xiaorong, Email: xiaorli@163.com

Keywords：

Retintis pigmentosa; Retinal pigment epithelium; Cell therapy; Review

DOI：

10.3760/cma.j.cn511434-20240619-00233

Video：

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Abstract Full text Figures/Tables Video References Cited by

Retinitis pigmentosa (RP) is a genetic disorder resulting in apoptosis of photoreceptors and atrophy of the retinal pigment epithelium due to genetic mutations. It is characterized by night blindness, peripheral visual field loss and progressive vision loss. The apoptosis of retinal pigment epithelium (RPE) cells plays an important role in the progression of RP, which has been confirmed in animal experiments and clinical trials through exogenous implantation of RPE cells as replacement therapy. With the diversification of cell sources, the update of surgical techniques and the continuous emergence of biological materials, more possibilities and hopes are provided for cell therapy. In the future, it is still necessary to strengthen the cooperation in many fields such as medicine and bioengineering, and jointly promote the innovation and development of treatment methods. It is believed that RPE transplantation therapy will show a brighter prospect in the future.

1.	Ameri H. Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation[J]. J Curr Ophthalmol, 2018, 30(1): 1-2. DOI: 10.1016/j.joco.2018.01.006.
2.	Fabre M, Mateo L, Lamaa D, et al. Recent advances in age-related macular degeneration therapies[J/OL]. Molecules, 2022, 27(16): 5089[2022-08-10]. https://pubmed.ncbi.nlm.nih.gov/36014339/. DOI: 10.3390/molecules27165089.
3.	Busskamp V. Stem cells for treating retinal degeneration[J]. J Perinat Med, 2022, 51(6): 759-762. DOI: 10.1515/jpm-2022-0510.
4.	Lakkaraju A, Umapathy A, Tan LX, et al. The cell biology of the retinal pigment epithelium[J/OL]. Prog Retin Eye Res, 2020, 24: 100846[2020-02-24]. https://pubmed.ncbi.nlm.nih.gov/32105772/. DOI: 10.1016/j.preteyeres.2020.100846.
5.	Yang YP, Hsiao YJ, Chang KJ, et al. Pluripotent stem cells in clinical cell transplantation: focusing on induced pluripotent stem cell-derived RPE cell therapy in age-related macular degeneration[J/OL]. Int J Mol Sci, 2022, 23(22): 13794[2022-11-09]. https://pubmed.ncbi.nlm.nih.gov/36430270/. DOI: 10.3390/ijms232213794.
6.	刘明, 夏晓丽, 方攀峰. 视网膜色素上皮细胞移植治疗年龄相关性黄斑变性的临床研究及相关药物开发[J]. 药学进展, 2019, 43(6): 430-436.Liu M, Xia XL, Fang PF. Clinical study of retinal pigment epithelial cell transplantation for age-related macular degeneration and development of related drugs[J]. Progress in Pharmaceutical Sciences, 2019, 43(6): 430-436.
7.	Aramant R, Seiler M, Turner JE. Donor age influences on the success of retinal grafts to adult rat retina[J]. Invest Ophthalmol Vis Sci, 1988, 29(3): 498-503.
8.	Kolomeyer AM, Sugino IK, Zarbin MA. Characterization of conditioned media collected from aged versus young human eye cups[J/OL]. Invest Ophthalmol Vis Sci, 2011, 52(8): 5963-5972[2011-07-29]. https://pubmed.ncbi.nlm.nih.gov/21398279/. DOI: 10.1167/iovs.10-6440.
9.	Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype[J]. Invest Ophthalmol Vis Sci, 1995, 36(2): 391-405.
10.	Zhou M, Geathers JS, Grillo SL, et al. Role of epithelial-mesenchymal transition in retinal pigment epithelium dysfunction[J/OL]. Front Cell Dev Biol, 2020, 8: 501[2020-06-25]. https://pubmed.ncbi.nlm.nih.gov/32671066/. DOI: 10.3389/fcell.2020.00501.
11.	Varzideh F, Gambardella J, Kansakar U, et al. Molecular mechanisms underlying pluripotency and self-renewal of embryonic stem cells[J/OL]. Int J Mol Sci, 2023, 24(9): 8386[2023-05-07]. https://pubmed.ncbi.nlm.nih.gov/37176093/. DOI: 10.3390/ijms24098386.
12.	Vugler A, Carr AJ, Lawrence J, et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation[J]. Exp Neurol, 2008, 214(2): 347-361. DOI: 10.1016/j.expneurol.2008.09.007.
13.	Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science, 2007, 318(5858): 1917-1920. DOI: 10.1126/science.1151526.
14.	Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors[J]. Cell, 2006, 126(4): 663-676. DOI: 10.1016/j.cell.2006.07.024.
15.	Gupta S, Lytvynchuk L, Ardan T, et al. Progress in stem cells-based replacement therapy for retinal pigment epithelium: In vitro differentiation to in vivo delivery[J]. Stem Cells Transl Med, 2023, 12(8): 536-552. DOI: 10.1093/stcltm/szad039.
16.	Nguyen HV, Li Y, Tsang SH. Patient-specific iPSC-derived RPE for modeling of retinal diseases[J]. J Clin Med, 2015, 4(4): 567-578. DOI: 10.3390/jcm4040567.
17.	Saini N, Roberts SA, Klimczak LJ, et al. The impact of environmental and endogenous damage on somatic mutation load in human skin fibroblasts[J/OL]. PLoS Genet, 2016, 12(10): e1006385[2016-10-27]. https://pubmed.ncbi.nlm.nih.gov/27788131/. DOI: 10.1371/journal.
18.	Liang Y, Sun X, Duan C, et al. Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases[J]. Stem Cell Res Ther, 2023, 14(1): 340. DOI: 10.1186/s13287-023-03564-5.
19.	Burnight ER, Gupta M, Wiley LA, et al. Using CRISPR-Cas9 to generate gene-corrected autologous iPSCs for the treatment of inherited retinal degeneration[J]. Mol Ther, 2017, 25(9): 1999-2013. DOI: 10.1016/j.ymthe.2017.05.015.
20.	Barnea-Cramer AO, Singh M, Fischer D, et al. Repair of retinal degeneration following ex vivo minicircle DNA gene therapy and transplantation of corrected photoreceptor progenitors[J. Mol Ther, 2020, 28(3): 830-844. DOI: 10.1016/j.ymthe.2020.01.023.
21.	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.
22.	Umekage M, Sato Y, Takasu N. Overview: an iPS cell stock at CiRA[J/OL]. Inflamm Regen, 2019, 39: 17[2019-09-02]. https://pubmed.ncbi.nlm.nih.gov/31497180/. DOI: 10.1186/s41232-019-0106-0.
23.	Salero E, Blenkinsop TA, Corneo B, et al. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives[J]. Cell Stem Cell, 2012, 10(1): 88-95. DOI: 10.1016/j.stem.2011.11.018.
24.	Davis RJ, Alam NM, Zhao C, et al. The developmental stage of adult human stem cell-derived retinal pigment epithelium cells influences transplant efficacy for vision rescue[J]. Stem Cell Reports, 2017, 9(1): 42-49. DOI: 10.1016/j.stemcr.2017.05.016.
25.	Diniz B, Thomas P, Thomas B, et al. Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer[J] Invest Ophthalmol Vis Sci, 2013, 54(7): 5087-5096. DOI: 10.1167/iovs.12-11239.
26.	Hsiung J, Zhu D, Hinton DR. Polarized human embryonic stem cell-derived retinal pigment epithelial cell monolayers have higher resistance to oxidative stress-induced cell death than nonpolarized cultures[J]. Stem Cells Transl Med, 2015, 4(1): 10-20. DOI: 10.5966/sctm.2014-0205.
27.	Mattern L, Otten K, Miskey C, et al. Molecular and functional characterization of BDNF-overexpressing human retinal pigment epithelial cells established by sleeping beauty transposon-mediated gene transfer[J/OL]. Int J Mol Sci, 2022, 23(21): 12982[2022-10-26]. https://pubmed.ncbi.nlm.nih.gov/36361771/. DOI: 10.3390/ijms232112982.
28.	Nishida M, Tanaka Y, Tanaka Y, et al. Human iPS cell derived RPE strips for secure delivery of graft cells at a target place with minimal surgical invasion[J/OL]. Sci Rep, 2021, 11(1): 21421[2021-11-02]. https://pubmed.ncbi.nlm.nih.gov/34728664/. DOI: 10.1038/s41598-021-00703-x.
29.	Ong JM, da Cruz L. A review and update on the current status of stem cell therapy and the retina[J]. Br Med Bull, 2012, 102: 133-146. DOI: 10.1093/bmb/lds013.
30.	Varela-Fernández R, Díaz-Tomé V, Luaces-Rodríguez A, et al. Drug delivery to the posterior segment of the eye: biopharmaceutic and pharmacokinetic considerations[J]. Pharmaceutics, 2020, 12(3): 269. DOI: 10.3390/pharmaceutics12030269.
31.	Gullapalli VK, Zarbin MA. New prospects for retinal pigment epithelium transplantation[J]. Asia Pac J Ophthalmol (Phila), 2022, 11(4): 302-313. DOI: 10.1097/APO.0000000000000521.
32.	de Smet MD, Lynch JL, Dejneka NS, et al. A subretinal cell delivery method via suprachoroidal access in minipigs: safety and surgical outcomes[J]. Invest Ophthalmol Vis Sci, 2018, 59(1): 311-320. DOI: 10.1167/iovs.17-22233.
33.	Thomas BB, Lin B, Martinez-Camarillo JC, et al. Co-grafts of human embryonic stem cell derived retina organoids and retinal pigment epithelium for retinal reconstruction in immunodeficient retinal degenerate royal college of surgeons rats[J/OL]. Front Neurosci, 2021, 15: 752958[2021-10-26]. https://pubmed.ncbi.nlm.nih.gov/34764853/. DOI: 10.3389/fnins.2021.752958.
34.	Salas A, Duarri A, Fontrodona L, et al. Cell therapy with hiPSC-derived RPE cells and RPCs prevents visual function loss in a rat model of retinal degeneration[J]. Mol Ther Methods Clin Dev, 2021, 20: 688-702. DOI: 10.1016/j.omtm.2021.02.006.
35.	West EL, Ribeiro J, Ali RR. Development of stem cell therapies for retinal degeneration[J/OL]. Cold Spring Harb Perspect Biol, 2020, 12(8): a035683[2020-08-03]. https://pubmed.ncbi.nlm.nih.gov/31818854/. DOI: 10.1101/cshperspect.a035683.
36.	Lytvynchuk L, Ebbert A, Studenovska H, et al. Subretinal implantation of human primary RPE cells cultured on nanofibrous membranes in minipigs[J/OL]. Biomedicines, 2022, 10(3): 669[2022-03-14]. https://pubmed.ncbi.nlm.nih.gov/35327471/. DOI: 10.3390/biomedicines10030669.
37.	Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration[J/OL]. Sci Transl Med, 2018, 10(435): eaao4097[2018-04-04]. https://pubmed.ncbi.nlm.nih.gov/29618560/. DOI: 10.1126/scitranslmed.aao4097.

1. Ameri H. Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation[J]. J Curr Ophthalmol, 2018, 30(1): 1-2. DOI: 10.1016/j.joco.2018.01.006.
2. Fabre M, Mateo L, Lamaa D, et al. Recent advances in age-related macular degeneration therapies[J/OL]. Molecules, 2022, 27(16): 5089[2022-08-10]. https://pubmed.ncbi.nlm.nih.gov/36014339/. DOI: 10.3390/molecules27165089.
3. Busskamp V. Stem cells for treating retinal degeneration[J]. J Perinat Med, 2022, 51(6): 759-762. DOI: 10.1515/jpm-2022-0510.
4. Lakkaraju A, Umapathy A, Tan LX, et al. The cell biology of the retinal pigment epithelium[J/OL]. Prog Retin Eye Res, 2020, 24: 100846[2020-02-24]. https://pubmed.ncbi.nlm.nih.gov/32105772/. DOI: 10.1016/j.preteyeres.2020.100846.
5. Yang YP, Hsiao YJ, Chang KJ, et al. Pluripotent stem cells in clinical cell transplantation: focusing on induced pluripotent stem cell-derived RPE cell therapy in age-related macular degeneration[J/OL]. Int J Mol Sci, 2022, 23(22): 13794[2022-11-09]. https://pubmed.ncbi.nlm.nih.gov/36430270/. DOI: 10.3390/ijms232213794.
6. 刘明, 夏晓丽, 方攀峰. 视网膜色素上皮细胞移植治疗年龄相关性黄斑变性的临床研究及相关药物开发[J]. 药学进展, 2019, 43(6): 430-436.Liu M, Xia XL, Fang PF. Clinical study of retinal pigment epithelial cell transplantation for age-related macular degeneration and development of related drugs[J]. Progress in Pharmaceutical Sciences, 2019, 43(6): 430-436.
7. Aramant R, Seiler M, Turner JE. Donor age influences on the success of retinal grafts to adult rat retina[J]. Invest Ophthalmol Vis Sci, 1988, 29(3): 498-503.
8. Kolomeyer AM, Sugino IK, Zarbin MA. Characterization of conditioned media collected from aged versus young human eye cups[J/OL]. Invest Ophthalmol Vis Sci, 2011, 52(8): 5963-5972[2011-07-29]. https://pubmed.ncbi.nlm.nih.gov/21398279/. DOI: 10.1167/iovs.10-6440.
9. Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype[J]. Invest Ophthalmol Vis Sci, 1995, 36(2): 391-405.
10. Zhou M, Geathers JS, Grillo SL, et al. Role of epithelial-mesenchymal transition in retinal pigment epithelium dysfunction[J/OL]. Front Cell Dev Biol, 2020, 8: 501[2020-06-25]. https://pubmed.ncbi.nlm.nih.gov/32671066/. DOI: 10.3389/fcell.2020.00501.
11. Varzideh F, Gambardella J, Kansakar U, et al. Molecular mechanisms underlying pluripotency and self-renewal of embryonic stem cells[J/OL]. Int J Mol Sci, 2023, 24(9): 8386[2023-05-07]. https://pubmed.ncbi.nlm.nih.gov/37176093/. DOI: 10.3390/ijms24098386.
12. Vugler A, Carr AJ, Lawrence J, et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation[J]. Exp Neurol, 2008, 214(2): 347-361. DOI: 10.1016/j.expneurol.2008.09.007.
13. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science, 2007, 318(5858): 1917-1920. DOI: 10.1126/science.1151526.
14. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors[J]. Cell, 2006, 126(4): 663-676. DOI: 10.1016/j.cell.2006.07.024.
15. Gupta S, Lytvynchuk L, Ardan T, et al. Progress in stem cells-based replacement therapy for retinal pigment epithelium: In vitro differentiation to in vivo delivery[J]. Stem Cells Transl Med, 2023, 12(8): 536-552. DOI: 10.1093/stcltm/szad039.
16. Nguyen HV, Li Y, Tsang SH. Patient-specific iPSC-derived RPE for modeling of retinal diseases[J]. J Clin Med, 2015, 4(4): 567-578. DOI: 10.3390/jcm4040567.
17. Saini N, Roberts SA, Klimczak LJ, et al. The impact of environmental and endogenous damage on somatic mutation load in human skin fibroblasts[J/OL]. PLoS Genet, 2016, 12(10): e1006385[2016-10-27]. https://pubmed.ncbi.nlm.nih.gov/27788131/. DOI: 10.1371/journal.
18. Liang Y, Sun X, Duan C, et al. Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases[J]. Stem Cell Res Ther, 2023, 14(1): 340. DOI: 10.1186/s13287-023-03564-5.
19. Burnight ER, Gupta M, Wiley LA, et al. Using CRISPR-Cas9 to generate gene-corrected autologous iPSCs for the treatment of inherited retinal degeneration[J]. Mol Ther, 2017, 25(9): 1999-2013. DOI: 10.1016/j.ymthe.2017.05.015.
20. Barnea-Cramer AO, Singh M, Fischer D, et al. Repair of retinal degeneration following ex vivo minicircle DNA gene therapy and transplantation of corrected photoreceptor progenitors[J. Mol Ther, 2020, 28(3): 830-844. DOI: 10.1016/j.ymthe.2020.01.023.
21. 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.
22. Umekage M, Sato Y, Takasu N. Overview: an iPS cell stock at CiRA[J/OL]. Inflamm Regen, 2019, 39: 17[2019-09-02]. https://pubmed.ncbi.nlm.nih.gov/31497180/. DOI: 10.1186/s41232-019-0106-0.
23. Salero E, Blenkinsop TA, Corneo B, et al. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives[J]. Cell Stem Cell, 2012, 10(1): 88-95. DOI: 10.1016/j.stem.2011.11.018.
24. Davis RJ, Alam NM, Zhao C, et al. The developmental stage of adult human stem cell-derived retinal pigment epithelium cells influences transplant efficacy for vision rescue[J]. Stem Cell Reports, 2017, 9(1): 42-49. DOI: 10.1016/j.stemcr.2017.05.016.
25. Diniz B, Thomas P, Thomas B, et al. Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer[J] Invest Ophthalmol Vis Sci, 2013, 54(7): 5087-5096. DOI: 10.1167/iovs.12-11239.
26. Hsiung J, Zhu D, Hinton DR. Polarized human embryonic stem cell-derived retinal pigment epithelial cell monolayers have higher resistance to oxidative stress-induced cell death than nonpolarized cultures[J]. Stem Cells Transl Med, 2015, 4(1): 10-20. DOI: 10.5966/sctm.2014-0205.
27. Mattern L, Otten K, Miskey C, et al. Molecular and functional characterization of BDNF-overexpressing human retinal pigment epithelial cells established by sleeping beauty transposon-mediated gene transfer[J/OL]. Int J Mol Sci, 2022, 23(21): 12982[2022-10-26]. https://pubmed.ncbi.nlm.nih.gov/36361771/. DOI: 10.3390/ijms232112982.
28. Nishida M, Tanaka Y, Tanaka Y, et al. Human iPS cell derived RPE strips for secure delivery of graft cells at a target place with minimal surgical invasion[J/OL]. Sci Rep, 2021, 11(1): 21421[2021-11-02]. https://pubmed.ncbi.nlm.nih.gov/34728664/. DOI: 10.1038/s41598-021-00703-x.
29. Ong JM, da Cruz L. A review and update on the current status of stem cell therapy and the retina[J]. Br Med Bull, 2012, 102: 133-146. DOI: 10.1093/bmb/lds013.
30. Varela-Fernández R, Díaz-Tomé V, Luaces-Rodríguez A, et al. Drug delivery to the posterior segment of the eye: biopharmaceutic and pharmacokinetic considerations[J]. Pharmaceutics, 2020, 12(3): 269. DOI: 10.3390/pharmaceutics12030269.
31. Gullapalli VK, Zarbin MA. New prospects for retinal pigment epithelium transplantation[J]. Asia Pac J Ophthalmol (Phila), 2022, 11(4): 302-313. DOI: 10.1097/APO.0000000000000521.
32. de Smet MD, Lynch JL, Dejneka NS, et al. A subretinal cell delivery method via suprachoroidal access in minipigs: safety and surgical outcomes[J]. Invest Ophthalmol Vis Sci, 2018, 59(1): 311-320. DOI: 10.1167/iovs.17-22233.
33. Thomas BB, Lin B, Martinez-Camarillo JC, et al. Co-grafts of human embryonic stem cell derived retina organoids and retinal pigment epithelium for retinal reconstruction in immunodeficient retinal degenerate royal college of surgeons rats[J/OL]. Front Neurosci, 2021, 15: 752958[2021-10-26]. https://pubmed.ncbi.nlm.nih.gov/34764853/. DOI: 10.3389/fnins.2021.752958.
34. Salas A, Duarri A, Fontrodona L, et al. Cell therapy with hiPSC-derived RPE cells and RPCs prevents visual function loss in a rat model of retinal degeneration[J]. Mol Ther Methods Clin Dev, 2021, 20: 688-702. DOI: 10.1016/j.omtm.2021.02.006.
35. West EL, Ribeiro J, Ali RR. Development of stem cell therapies for retinal degeneration[J/OL]. Cold Spring Harb Perspect Biol, 2020, 12(8): a035683[2020-08-03]. https://pubmed.ncbi.nlm.nih.gov/31818854/. DOI: 10.1101/cshperspect.a035683.
36. Lytvynchuk L, Ebbert A, Studenovska H, et al. Subretinal implantation of human primary RPE cells cultured on nanofibrous membranes in minipigs[J/OL]. Biomedicines, 2022, 10(3): 669[2022-03-14]. https://pubmed.ncbi.nlm.nih.gov/35327471/. DOI: 10.3390/biomedicines10030669.
37. Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration[J/OL]. Sci Transl Med, 2018, 10(435): eaao4097[2018-04-04]. https://pubmed.ncbi.nlm.nih.gov/29618560/. DOI: 10.1126/scitranslmed.aao4097.

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