Research progress on the role of mesenchymal transformation in subretinal fibrosis secondary to age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

 Zhang Pengfei , Sun Xiaodong

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China;

Corresponding?author：

Zhang Pengfei, Email: zhangpengfei1023@126.com

Keywords：

Age-related macular degeneration; Subretinal fibrosis; Mesenchymal transformation; Review

DOI：

10.3760/cma.j.cn511434-20251016-00450

Video：

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Abstract Full text Figures/Tables Video References Cited by

Age-related macular degeneration is the leading cause of irreversible blindness in the elderly.Subretinal fibrosis secondary to neovascular age-related macular degeneration is an important factor in irreversible vision loss. Due to the lack of fibroblasts in retinal tissue, mesenchymal transformation becomes the main cellular source of subretinal fibrosis. During this process, multiple cell types, including retinal pigment epithelial cells, vascular endothelial cells, macrophages, and perivascular cells are driven by key cytokines such as transforming growth factor-beta (TGF-β) and a chronic inflammatory microenvironment to transdifferentiate into myofibroblasts through epithelial–mesenchymal transition and endothelial–mesenchymal transition. Together, these cells constitute the cellular basis of fibrosis. In addition, Müller cells and fibroblasts derived from the peripheral circulation also contribute to this process. Future preventive and therapeutic strategies should therefore simultaneously target both fibrotic and inflammatory pathways. At present, experimental studies have demonstrated the potential of interventions targeting TGF-β, platelet-derived growth factor, and Yes-associated protein signaling, as well as combined anti-inflammatory strategies involving interleukin-6 and complement component 3a. Further elucidation of the underlying molecular mechanisms will facilitate the development of precision therapies and offer new hope for improving visual outcomes in affected patients.

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14.	Tenbrock L, Wolf J, Boneva S, et al. Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives[J]. Cell Tissue Res, 2021, 387(3): 361-375. DOI: 10.1007/s00441-021-03514-8.
15.	Xiao H, Zhao X, Li S, et al. Risk factors for subretinal fibrosis after anti-VEGF treatment of myopic choroidal neovascularisation[J]. Br J Ophthalmol, 2021, 105(1): 103-108. DOI: 10.1136/bjophthalmol-2019-315763.
16.	Saika S. TGFbeta pathobiology in the eye[J]. Lab Invest, 2006, 86(2): 106-115. DOI: 10.1038/labinvest.3700375.
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18.	Gamulescu MA, Chen Y, He S, et al. Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells: regulation by extracellular matrix proteins and hepatocyte growth factor[J]. Exp Eye Res, 2006, 83(1): 212-22. DOI: 10.1016/j.exer.2005.12.007.
19.	Miyazawa K, Itoh Y, Fu H, et al. Receptor-activated transcription factors and beyond: multiple modes of Smad2/3-dependent transmission of TGF-β signaling[J/OL]. J Biol Chem, 2024, 300(5): 107256[2024-04-02]. https://pubmed.ncbi.nlm.nih.gov/38569937/. DOI: 10.1016/j.jbc.2024.107256.
20.	Hirasawa M, Noda K, Noda S, et al. Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization[J]. Mol Vis, 2011, 17: 1222-1230.
21.	Luo K. Signaling cross talk between TGF-β/smad and other signaling pathways[J/OL]. Cold Spring Harb Perspect Biol, 2017, 9(1): a022137[2017-01-03]. https://pubmed.ncbi.nlm.nih.gov/27836834/. DOI: 10.1101/cshperspect.a022137.
22.	Klaassen I, van Geest RJ, Kuiper EJ, et al. The role of CTGF in diabetic retinopathy[J]. Exp Eye Res, 2015, 133: 37-48. DOI: 10.1016/j.exer.2014.10.016.
23.	Hu B, Zhang Y, Zeng Q, et al. Intravitreal injection of ranibizumab and CTGF shRNA improves retinal gene expression and microvessel ultrastructure in a rodent model of diabetes[J]. Int J Mol Sci, 2014, 15(1): 1606-1624. DOI: 10.3390/ijms15011606.
24.	Rossato FA, Su Y, Mackey A, et al. Fibrotic changes and endothelial-to-mesenchymal transition promoted by VEGFR2 antagonism alter the therapeutic effects of VEGFA pathway blockage in a mouse model of choroidal neovascularization[J/OL]. Cells, 2020, 9(9): 2057[2020-09-09]. https://pubmed.ncbi.nlm.nih.gov/32917003/. DOI: 10.3390/cells9092057.
25.	Saika S, Kono-Saika S, Tanaka T, et al. Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice[J]. Lab Invest, 2004, 84(10): 1245-1258. DOI: 10.1038/labinvest.3700156.
26.	Yang X, Zou R, Dai X, et al. YAP is critical to inflammation, endothelial-mesenchymal transition and subretinal fibrosis in experimental choroidal neovascularization[J/OL]. Exp Cell Res, 2022, 417(2): 113221[2022-08-15]. https://pubmed.ncbi.nlm.nih.gov/35623419/. DOI: 10.1016/j.yexcr.2022.113221.
27.	Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways[J]. Science, 2004, 303(5663): 1483-1487. DOI: 10.1126/science.1094291.
28.	Wang H, Ramshekar A, Kunz E, et al. 7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment[J]. Angiogenesis, 2021, 24(3): 583-595. DOI: 10.1007/s10456-021-09770-0.
29.	Pérez L, Mu?oz-Durango N, Riedel CA, et al. Endothelial-to-mesenchymal transition: cytokine-mediated pathways that determine endothelial fibrosis under inflammatory conditions[J]. Cytokine Growth Factor Rev, 2017, 33: 41-54. DOI: 10.1016/j.cytogfr.2016.09.002.
30.	Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 6425-6440. DOI: 10.1002/jcp.26429.
31.	Deng W, Yi C, Pan W, et al. Vascular cell adhesion molecule-1 (VCAM-1) contributes to macular fibrosis in neovascular age-related macular degeneration through modulating macrophage functions[J/OL]. Immun Ageing, 2023, 20(1): 65[2023-11-20]. https://pubmed.ncbi.nlm.nih.gov/37985993/. DOI: 10.1186/s12979-023-00389-x.
32.	Chen M, Luo C, Zhao J, et al. Immune regulation in the aging retina[J]. Prog Retin Eye Res, 2019, 69: 159-172. DOI: 10.1016/j.preteyeres.2018.10.003.
33.	Sato K, Takeda A, Hasegawa E, et al. Interleukin-6 plays a crucial role in the development of subretinal fibrosis in a mouse model[J]. Immunol Med, 2018, 41(1): 23-29. DOI: 10.1080/09114300.2018.1451609.
34.	Szczepan M, Llorián-Salvador M, Yi C, et al. Differential roles of macrophages and microglia in subretinal fibrosis secondary to neovascular age-related macular degeneration[J/OL]. Invest Ophthalmol Vis Sci, 2025, 66(3): 41[2025-03-03]. https://pubmed.ncbi.nlm.nih.gov/40111356/. DOI: 10.1167/iovs.66.3.41.
35.	Lechner J, Chen M, Hogg RE, et al. Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration: complement activation in AMD[J/OL]. Immun Ageing, 2016, 13: 4[2016-02-16]. https://pubmed.ncbi.nlm.nih.gov/26884800/. DOI: 10.1186/s12979-016-0060-5.
36.	Park DY, Lee J, Kim J, et al. Plastic roles of pericytes in the blood-retinal barrier[J/OL]. Nat Commun, 2017, 8: 15296[2017-05-16]. https://pubmed.ncbi.nlm.nih.gov/28508859/. DOI: 10.1038/ncomms15296.
37.	Zhao Z, Zhang Y, Zhang C, et al. TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways[J]. Exp Mol Med, 2022, 54(5): 673-684. DOI: 10.1038/s12276-022-00778-0.
38.	Xu YH, Feng YF, Zou R, et al. Silencing of YAP attenuates pericyte-myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization[J]. Cell Biol Int, 2022, 46(8): 1249-1263. DOI: 10.1002/cbin.11809.
39.	Zhang J, Sheng X, Ding Q, et al. Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets[J]. Neural Regen Res, 2025, 20(2): 378-393. DOI: 10.4103/NRR.NRR-D-23-01642.
40.	Jo YJ, Sonoda KH, Oshima Y, et al. Establishment of a new animal model of focal subretinal fibrosis that resembles disciform lesion in advanced age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6089-6095. DOI: 10.1167/iovs.10-5189.
41.	Adler M, Mayo A, Zhou X, et al. Principles of cell circuits for tissue repair and fibrosis[J/OL]. iScience, 2020, 23(2): 100841[2020-02-21]. https://pubmed.ncbi.nlm.nih.gov/32058955/. DOI: 10.1016/j.isci.2020.100841.

1. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern?[J]. Ophthalmology, 2020, 127(1): 1-65. DOI: 10.1016/j.ophtha.2019.09.024.
2. Grossniklaus HE, Green WR. Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group[J]. Arch Ophthalmol, 1998, 116(6): 745-749. DOI: 10.1001/archopht.116.6.745.
3. Little K, Ma JH, Yang N, et al. Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration-the potential sources and molecular cues for their recruitment and activation[J]. EBioMedicine, 2018, 38: 283-291. DOI: 10.1016/j.ebiom.2018.11.029.
4. Shu DY, Butcher E, Saint-Geniez M. EMT and EndMT: emerging roles in age-related macular degeneration[J/OL]. Int J Mol Sci, 2020, 21(12): 4271[2020-06-16]. https://pubmed.ncbi.nlm.nih.gov/32560057/. DOI: 10.3390/ijms21124271.
5. Ishikawa K, Kannan R, Hinton DR. Molecular mechanisms of subretinal fibrosis in age-related macular degeneration[J]. Exp Eye Res, 2016, 142: 19-25. DOI: 10.1016/j.exer.2015.03.009.
6. Luo X, Yang S, Liang J, et al. Choroidal pericytes promote subretinal fibrosis after experimental photocoagulation[J/OL]. Dis Model Mech, 2018, 11(4): dmm032060[2018-04-23]. https://pubmed.ncbi.nlm.nih.gov/29622551/. DOI: 10.1242/dmm.032060.
7. Little K, Llorián-Salvador M, Tang M, et al. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration[J/OL]. J Neuroinflammation, 2020, 17(1): 355[2020-11-25]. https://pubmed.ncbi.nlm.nih.gov/33239022/. DOI: 10.1186/s12974-020-02033-7.
8. Algvere PV, Libert C, Lindg?rde G, et al. Transpupillary thermotherapy of predominantly occult choroidal neovascularization in age-related macular degeneration with 12 months follow-up[J]. Acta Ophthalmol Scand, 2003, 81(2): 110-107. DOI: 10.1034/j.1600-0420.2003.00041.x.
9. de Juan E Jr, Machemer R. Vitreous surgery for hemorrhagic and fibrous complications of age-related macular degeneration[J]. Am J Ophthalmol, 1988, 105(1): 25-29. DOI: 10.1016/0002-9394(88)90116-X.
10. Daniel E, Pan W, Ying GS, et al. Development and course of scars in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2018, 125(7): 1037-1046. DOI: 10.1016/j.ophtha.2018.01.004.
11. Wolff B, Macioce V, Vasseur V, et al. Ten-year outcomes of anti-vascular endothelial growth factor treatment for neovascular age-related macular disease: a single-centre French study[J]. Clin Exp Ophthalmol, 2020, 48(5): 636-643. DOI: 10.1111/ceo.13742.
12. Bachmeier I, Armendariz BG, Yu S, et al. Fibrosis in neovascular age-related macular degeneration: a review of definitions based on clinical imaging[J]. Surv Ophthalmol, 2023, 68(5): 835-848. DOI: 10.1016/j.survophthal.2023.03.004.
13. Cheong KX, Cheung CMG, Teo KYC. Review of fibrosis in neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2023, 246: 192-222. DOI: 10.1016/j.ajo.2022.09.008.
14. Tenbrock L, Wolf J, Boneva S, et al. Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives[J]. Cell Tissue Res, 2021, 387(3): 361-375. DOI: 10.1007/s00441-021-03514-8.
15. Xiao H, Zhao X, Li S, et al. Risk factors for subretinal fibrosis after anti-VEGF treatment of myopic choroidal neovascularisation[J]. Br J Ophthalmol, 2021, 105(1): 103-108. DOI: 10.1136/bjophthalmol-2019-315763.
16. Saika S. TGFbeta pathobiology in the eye[J]. Lab Invest, 2006, 86(2): 106-115. DOI: 10.1038/labinvest.3700375.
17. Robertson IB, Rifkin DB. Regulation of the bioavailability of TGF-β and TGF-β-related proteins[J/OL]. Cold Spring Harb Perspect Biol, 2016, 8(6): a021907[2016-06-01]. https://pubmed.ncbi.nlm.nih.gov/27252363/. DOI: 10.1101/cshperspect.a021907.
18. Gamulescu MA, Chen Y, He S, et al. Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells: regulation by extracellular matrix proteins and hepatocyte growth factor[J]. Exp Eye Res, 2006, 83(1): 212-22. DOI: 10.1016/j.exer.2005.12.007.
19. Miyazawa K, Itoh Y, Fu H, et al. Receptor-activated transcription factors and beyond: multiple modes of Smad2/3-dependent transmission of TGF-β signaling[J/OL]. J Biol Chem, 2024, 300(5): 107256[2024-04-02]. https://pubmed.ncbi.nlm.nih.gov/38569937/. DOI: 10.1016/j.jbc.2024.107256.
20. Hirasawa M, Noda K, Noda S, et al. Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization[J]. Mol Vis, 2011, 17: 1222-1230.
21. Luo K. Signaling cross talk between TGF-β/smad and other signaling pathways[J/OL]. Cold Spring Harb Perspect Biol, 2017, 9(1): a022137[2017-01-03]. https://pubmed.ncbi.nlm.nih.gov/27836834/. DOI: 10.1101/cshperspect.a022137.
22. Klaassen I, van Geest RJ, Kuiper EJ, et al. The role of CTGF in diabetic retinopathy[J]. Exp Eye Res, 2015, 133: 37-48. DOI: 10.1016/j.exer.2014.10.016.
23. Hu B, Zhang Y, Zeng Q, et al. Intravitreal injection of ranibizumab and CTGF shRNA improves retinal gene expression and microvessel ultrastructure in a rodent model of diabetes[J]. Int J Mol Sci, 2014, 15(1): 1606-1624. DOI: 10.3390/ijms15011606.
24. Rossato FA, Su Y, Mackey A, et al. Fibrotic changes and endothelial-to-mesenchymal transition promoted by VEGFR2 antagonism alter the therapeutic effects of VEGFA pathway blockage in a mouse model of choroidal neovascularization[J/OL]. Cells, 2020, 9(9): 2057[2020-09-09]. https://pubmed.ncbi.nlm.nih.gov/32917003/. DOI: 10.3390/cells9092057.
25. Saika S, Kono-Saika S, Tanaka T, et al. Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice[J]. Lab Invest, 2004, 84(10): 1245-1258. DOI: 10.1038/labinvest.3700156.
26. Yang X, Zou R, Dai X, et al. YAP is critical to inflammation, endothelial-mesenchymal transition and subretinal fibrosis in experimental choroidal neovascularization[J/OL]. Exp Cell Res, 2022, 417(2): 113221[2022-08-15]. https://pubmed.ncbi.nlm.nih.gov/35623419/. DOI: 10.1016/j.yexcr.2022.113221.
27. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways[J]. Science, 2004, 303(5663): 1483-1487. DOI: 10.1126/science.1094291.
28. Wang H, Ramshekar A, Kunz E, et al. 7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment[J]. Angiogenesis, 2021, 24(3): 583-595. DOI: 10.1007/s10456-021-09770-0.
29. Pérez L, Mu?oz-Durango N, Riedel CA, et al. Endothelial-to-mesenchymal transition: cytokine-mediated pathways that determine endothelial fibrosis under inflammatory conditions[J]. Cytokine Growth Factor Rev, 2017, 33: 41-54. DOI: 10.1016/j.cytogfr.2016.09.002.
30. Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 6425-6440. DOI: 10.1002/jcp.26429.
31. Deng W, Yi C, Pan W, et al. Vascular cell adhesion molecule-1 (VCAM-1) contributes to macular fibrosis in neovascular age-related macular degeneration through modulating macrophage functions[J/OL]. Immun Ageing, 2023, 20(1): 65[2023-11-20]. https://pubmed.ncbi.nlm.nih.gov/37985993/. DOI: 10.1186/s12979-023-00389-x.
32. Chen M, Luo C, Zhao J, et al. Immune regulation in the aging retina[J]. Prog Retin Eye Res, 2019, 69: 159-172. DOI: 10.1016/j.preteyeres.2018.10.003.
33. Sato K, Takeda A, Hasegawa E, et al. Interleukin-6 plays a crucial role in the development of subretinal fibrosis in a mouse model[J]. Immunol Med, 2018, 41(1): 23-29. DOI: 10.1080/09114300.2018.1451609.
34. Szczepan M, Llorián-Salvador M, Yi C, et al. Differential roles of macrophages and microglia in subretinal fibrosis secondary to neovascular age-related macular degeneration[J/OL]. Invest Ophthalmol Vis Sci, 2025, 66(3): 41[2025-03-03]. https://pubmed.ncbi.nlm.nih.gov/40111356/. DOI: 10.1167/iovs.66.3.41.
35. Lechner J, Chen M, Hogg RE, et al. Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration: complement activation in AMD[J/OL]. Immun Ageing, 2016, 13: 4[2016-02-16]. https://pubmed.ncbi.nlm.nih.gov/26884800/. DOI: 10.1186/s12979-016-0060-5.
36. Park DY, Lee J, Kim J, et al. Plastic roles of pericytes in the blood-retinal barrier[J/OL]. Nat Commun, 2017, 8: 15296[2017-05-16]. https://pubmed.ncbi.nlm.nih.gov/28508859/. DOI: 10.1038/ncomms15296.
37. Zhao Z, Zhang Y, Zhang C, et al. TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways[J]. Exp Mol Med, 2022, 54(5): 673-684. DOI: 10.1038/s12276-022-00778-0.
38. Xu YH, Feng YF, Zou R, et al. Silencing of YAP attenuates pericyte-myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization[J]. Cell Biol Int, 2022, 46(8): 1249-1263. DOI: 10.1002/cbin.11809.
39. Zhang J, Sheng X, Ding Q, et al. Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets[J]. Neural Regen Res, 2025, 20(2): 378-393. DOI: 10.4103/NRR.NRR-D-23-01642.
40. Jo YJ, Sonoda KH, Oshima Y, et al. Establishment of a new animal model of focal subretinal fibrosis that resembles disciform lesion in advanced age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6089-6095. DOI: 10.1167/iovs.10-5189.
41. Adler M, Mayo A, Zhou X, et al. Principles of cell circuits for tissue repair and fibrosis[J/OL]. iScience, 2020, 23(2): 100841[2020-02-21]. https://pubmed.ncbi.nlm.nih.gov/32058955/. DOI: 10.1016/j.isci.2020.100841.

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Latest ArticlesResearch progress on the role of mesenchymal transformation in subretinal fibrosis secondary to age-related macular degeneration

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