Choroidal pericytes promote subretinal fibrosis after experimental photocoagulation

Luo, Xueting; Yang, Sheng; Liang, Jian; Zhai, Yadi; Shen, Mengxi; Sun, Junran; Feng, Yueqiao; Lu, Xinmin; Zhu, Hong; Wang, Fenghua; Sun, Xiaodong

doi:10.1242/dmm.032060

Cited by 24 publications

(27 citation statements)

References 32 publications

(51 reference statements)

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“…Macrophages may also give rise to myofibroblasts via macrophage-myofibroblast transition (MMT) in subretinal fibrosis secondary to nAMD [202]. Choroidal pericytes may represent another potential source of myofibroblast precursors where they have been found to infiltrate CNV and transdifferentiate into collagen I-expressing cells in a photocoagulation CNV mouse model [203].…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

175

138

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Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

175

138

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“…Various choroidal stromal cells have been detected in the experimental model CNV and fibrosis [28]. A recent study in a mouse model of CNV/fibrosis has shown that choroidal pericytes can infiltrate the CNV and differentiate into collagen 1-expressing cells [46]. The choroidal stromal cells may be a potential source of myofibroblast precursors.…”

Section: Molecular Mechanism Of Macular Fibrosis In Namdmentioning

confidence: 99%

Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation

et al. 2018

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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Neovascular AMD (nAMD) accounts for 90% of AMD-related vision loss. Although intravitreal injection of VEGF inhibitors can improve vision in nAMD, approximately 1/3 of patients do not benefit from the therapy due to macular fibrosis. The molecular mechanism underlying the transition of the neovascular lesion to a fibrovascular phenotype remains unknown. Here we discussed the clinical features and risk factors of macular fibrosis secondary to nAMD. Myofibroblasts are key cells in fibrosis development. However, fibroblasts do not exist in the macula. Potential sources of myofibroblast precursors, the molecular cues in the macular microenvironment that recruit them and the pathways that control their differentiation and activation in macular fibrosis were also discussed. Furthermore, we highlighted the challenges in macular fibrosis research and the urgent need for better animal models for mechanistic and therapeutic studies.

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“…The specimens were mounted in mounting medium, including DAPI (1:500, Vector Laboratories, Burlingame, CA, USA), and examined under a fluorescence microscope (BIOREVO, Keyence, Tokyo, Japan). The number of nucleus surrounded by NG-2 positive signals, corresponding to pericytes, are counted unbiasedly in five consecutive tissue sections, as previously described [ 17 , 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…Since PDGFR-β signaling is involved in pericyte activation, proliferation, and migration, blockade of pericyte activation with PDGFR inhibitor attenuated interstitial kidney fibrosis in mice [ 14 ]. Additionally, it has been reported that pericytes expressing PDGFR-β infiltrate into the subretinal space after CNV induction and subsequently contribute to subretinal fibrosis formation in mice [ 18 ]. Interestingly, levels of PDGFs were reported to positively correlate with fibrosis in patients with proliferative diabetic retinopathy (PDR) [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice

Liu

Noda

Murata

et al. 2020

JCM

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Neovascular age related macular degeneration (nAMD) leads to severe vision loss worldwide and is characterized by the formation of choroidal neovascularization (CNV) and fibrosis. In the current study, we aimed to investigate the effect of blockade for platelet derived growth factor receptor-β (PDGFR-β) on the formation of choroidal neovascularization and fibrosis in the laser-induced CNV model in mice. Firstly, the presence of PDGFR-β in CNV lesions were confirmed. Intravitreal injection of PDGFR-β neutralizing antibody significantly reduced the size of CNV and subretinal fibrosis. Additionally, subretinal hyperreflective material (SHRM), a landmark feature on OCT as a risk factor for subretinal fibrosis formation in nAMD patients was also suppressed by PDGFR-β blockade. Furthermore, pericytes were abundantly recruited to the CNV lesions during CNV formation, however, blockade of PDGFR-β significantly reduced pericyte recruitment. In addition, PDGF-BB stimulation increased the migration of the rat retinal pericyte cell line, R-rPCT1, which was abrogated by the neutralization of PDGFR-β. These results indicate that blockade of PDGFR-β attenuates laser-induced CNV and fibrosis through the inhibition of pericyte migration.

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Choroidal pericytes promote subretinal fibrosis after experimental photocoagulation

Cited by 24 publications

References 32 publications

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation

Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice

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