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

Little, Karis; Jacey, H.; Yang, Nan; Chen, Mei; Xu, Heping

doi:10.1016/j.ebiom.2018.11.029

Cited by 73 publications

(67 citation statements)

References 90 publications

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“…In an experimental CNV model using irradiated mice engrafted with green fluorescent protein (GFP)-positive bone marrow cells, many of the α-SMA-positive cells were also GFP-positive suggesting a systemic source of mesenchymal cells in CNV lesions [201]. 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

183

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

183

138

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“…It has been suggested that anti-VEGF therapy significantly improved vision and quality of life for patients with nAMD [11,12]. Nevertheless, about one-third of patients do not get effects from anti-VEGF therapy owing to macular fibrosis or atrophy [13]. In addition, there is a heavy demand for repeated intravitreal injections to maintain efficacy [14,15], which leads to a heavy economic burden.…”

Section: Introductionmentioning

confidence: 99%

The Role of Inflammation in Age-Related Macular Degeneration

Tan¹,

Zou²,

Yoshida³

et al. 2020

Int. J. Biol. Sci.

165

103

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Age-related macular degeneration (AMD) is a blinding eye disease which incidence gradually increases with age. Inflammation participates in AMD pathogenesis, including choroidal neovascularization and geographic atrophy. It is also a kind of self-protective regulation from injury for the eyes. In this review, we described inflammation in AMD pathogenesis, summarized the roles played by inflammation-related cytokines, including pro-inflammatory and anti-inflammatory cytokines, as well as leukocytes (macrophages, dendritic cells, neutrophils, T lymphocytes and B lymphocytes) in the innate or adaptive immunity in AMD. Possible clinical applications such as potential diagnostic biomarkers and anti-inflammatory therapies were also discussed. This review overviews the inflammation as a target of novel effective therapies in treating AMD.

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“…Die CNV bei nAMD verändert sich unter der Anti-VEGF-Therapie zu einer fibrosierten Läsion [14]. Die funktionellen Auswirkungen dieser fibrovaskulären Umwandlung, wie auch morphologische Veränderungen, sind individuell sehr unterschiedlich [15 -17].…”

Section: Diskussionunclassified

Analysis of the Vascular Morphology of the Fibrotic Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Using Optical Coherence Tomography Angiography

Book

Ziegler

Rothaus

et al. 2020

Klin Monbl Augenheilkd

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Purpose Choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nAMD) undergoing anti-VEGF therapy transforms into a fibrotic lesion. This fibrovascular transformation is associated with a great variety of functional and morphological effects. The aim of this study was to investigate the vascular morphology of fibrotic CNV, to compare it with its surrounding tissue and to identify phenotypes using optical coherence tomography angiography (OCTA). Methods In 18 eyes with fibrotic CNV in nAMD spectral domain OCT (SD-OCT) and OCTA were performed. The automated segmentation lines were manually adjusted. A slab from 60 µm beneath Bruchʼs membrane to the inner edge of the subretinal hyperreflective material was applied. Quantitative analysis of the vascular morphology was performed using skeletonized OCTA images. Results Compared to the perilesional rim, the number of segments per area was significantly lower (234.75 ± 25.68 vs. 255.30 ± 20.34 1/mm2, p = 0.0003) within the fibrovascular lesion. Two phenotypes could be identified within the lesion. The phenotypic traits of cluster 1 were few, long and thick vascular segments; Cluster 2 was characterized by many, short and thin vascular segments (number of segments per area: 219.4 ± 18.8 vs. 258.8 ± 13.2 1/mm2, p = 0.00009, segment length: 49.6 ± 2.7 vs. 45.0 ± 1.3 µm, p = 0.0002, vascular caliber: 26.6 ± 1.2 vs. 23.5 ± 1.8 µm, p = 0.003). The clusters did not differ significantly regarding visual acuity (0.52 ± 0.44 vs. 0.54 ± 0.18 logMAR, p = 0.25), differentiability of subretinal (OR = 3.43, CI = [0.30, 39.64], p = 0.6) and intraretinal fluid (OR = 5.34, CI = [0.48, 89.85], p = 0.14). Less normalized ellipsoid zone (EZ) loss could be observed in cluster 1 (131.0 ± 161.3 vs. 892.4 ± 955.6 1/m, p = 0.006). Conclusion In this study the vascular morphology of fibrotic CNV was analyzed using OCTA. Differences between the lesion and a perilesional rim could be detected. Two phenotypes within the fibrovascular lesion were identified. These morphological clusters could indicate different patterns of fibrovascular transformation of the CNV under long-term anti-VEGF therapy and be useful identifying possible predictive biomarkers in future studies.

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

Cited by 73 publications

References 90 publications

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

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

The Role of Inflammation in Age-Related Macular Degeneration

Analysis of the Vascular Morphology of the Fibrotic Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Using Optical Coherence Tomography Angiography

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