Age-Dependent Changes in Heparan Sulfate in Human Bruch's Membrane: Implications for Age-Related Macular Degeneration

Keenan, Tiarnán D L; Pickford, Claire E.; Holley, Rebecca; Clark, Simon J.; Lin, Wen; Dowsey, Andrew W.; Merry, Catherine L.R.; Day, Anthony J.; Bishop, Paul N.

doi:10.1167/iovs.14-14126

Cited by 57 publications

(65 citation statements)

References 59 publications

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“…Because the main binding partner for CFH in human macular BrM is heparan sulfate (55, 56) and lipoproteins interact with heparan sulfate (54), we hypothesized that CFH competes with lipoproteins for binding to HSPGs. This hypothesis is further supported by the high concentrations of HSPGs found in BrM as well as studies implicating HSPGs in AMD (55, 56, 74–76). Here, we show that CFH plays a direct role in modulating the interaction between BrM and endogenous lipoprotein particles that accumulate with age in human BrM.…”

Section: Discussionmentioning

confidence: 58%

Regulation of age-related macular degeneration-like pathology by complement factor H

Toomey

Kelly

Saban

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

157

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SignificanceAge-related macular degeneration (AMD) affects approximately one-third of Americans over 70 and is characterized by lipoprotein-rich sub-retinal pigmented epithelium (sub-RPE) deposits. Substantial evidence has emerged that implicates complement factor H (CFH) in the pathogenesis of AMD. Here, we conduct an in vivo analysis to elucidate the role of CFH in AMD pathology. We show that (i) CFH and lipoproteins compete for binding in the sub-RPE extracellular matrix such that decreasing CFH leads to lipoprotein accumulation and sub-RPE deposit formation; and (ii) detrimental complement activation within sub-RPE deposits leads to RPE damage and vision loss. This new understanding of the complicated interactions of CFH in development of AMD-like pathology paves the way for identifying more targeted therapeutic strategies for AMD.

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Section: Discussionmentioning

confidence: 58%

Regulation of age-related macular degeneration-like pathology by complement factor H

Toomey

Kelly

Saban

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

157

View full text Add to dashboard Cite

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“…The primary cause of AMD is not known, but several lines of investigation have been directed at elucidating the connection between BM aging and cellular changes seen in the disease, such as RPE atrophy and photoreceptor degeneration. 10,11,14,18,20 Age-related changes within BM occur several decades before cellular ones, thus suggesting that BM dysfunction can precede and may induce changes in surrounding cells. 14,15,19,20 In our system, previously developed to isolate the effects of basement membrane aging from the effects of cellular aging, we have shown that BM aging affects proper attachment and proliferation of RPE cells and increases their rate of apoptosis while decreasing the rate of phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…10,11,14,18,20 Age-related changes within BM occur several decades before cellular ones, thus suggesting that BM dysfunction can precede and may induce changes in surrounding cells. 14,15,19,20 In our system, previously developed to isolate the effects of basement membrane aging from the effects of cellular aging, we have shown that BM aging affects proper attachment and proliferation of RPE cells and increases their rate of apoptosis while decreasing the rate of phagocytosis. 27,28 We have also shown that reengineering human BM can improve the attachment, survival, and proliferation of the RPE.…”

Section: Discussionmentioning

confidence: 99%

“…10 In addition, aging of BM may also affect other proteins (e.g., heparan sulfate) that may play an important role in the overall function of the RPE. 20 These results are not surprising, since the molecular changes that occur within BM with aging are protean in nature, and not completely understood. Nevertheless, the fact that there is an increase in proliferation, survival, and RPE function by providing fresh ECM protein may also be important in other systems designed to reproduce an artificial BM.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is known that the structural changes that are due to aging within BM precede cellular changes in the RPE by one or two decades, well before there are signs of early AMD on clinical examination and imaging. 11,14,19,20 In the human eye in vivo, the RPE and BM age together and therefore it is impossible to separate the effects of BM aging from the primary effects of cellular aging. Thus, we have developed a system in our laboratory to separate the effects of aging within BM from the effects of aging in the RPE.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

Moreira

Cai

Tezel

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: We have shown previously that Bruch's membrane (BM) aging decreases retinal pigment epithelium (RPE) phagocytosis. Herein, we determine the effects of BM reengineering on RPE phagocytosis.Methods: BM explants were dissected from young and old donor eyes. Some old BM explants were reengineered by cleaning with Triton X-100 and/or coating with extracellular matrix (ECM) ligands. ARPE-19 cell-derived ECM (ARPE-ECM) modified (''aged'') by sodium nitrite was subjected to similar treatments. ARPE-19 cells were then cultured to confluence onto the different surfaces. Fluorescently-labeled bovine rod outer segments (ROS) were fed to cells with or without aVb5 integrin antibody. Image acquisition and phagocytosis quantification was performed by fluorescence microscopy and ImageJ analysis.Results: Cleaning old donor-derived BM with detergent does not increase the uptake of ROS, but a combination of cleaning and coating with ECM ligands significantly increases RPE phagocytosis (54.9 6 6.2 vs. 83.5 6 6.5 arbitrary units; P , 0.05) to levels closer to young donor BM (123.6 6 9.9 arbitrary units). Similar effects were observed on nitrite-modified ARPE-ECM subjected to the same treatments. Incubation of aVb5 blocking antibody with ROS significantly decreased RPE phagocytosis. Conclusions:The detrimental effects of aging BM on RPE phagocytosis can be reversed by reengineering the BM surface with detergent cleaning and recoating with ECM ligands.Translation Relevance: These results demonstrate that the therapeutic success of transplanted RPE cells may require, at least in part, reengineering of diseased BM to make it a more suitable environment for attachment, survival and proper functioning of the RPE.

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An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure

et al. 2017

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Age‐related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease; however, these do not exist for the dry form. Complement factor H polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, RPE damage, and visual decline. We have derived and characterized induced pluripotent stem cell (iPSC) lines from two subjects without AMD and low‐risk genotype and two patients with advanced AMD and high‐risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H, factor I, and factor H‐like protein 1. The iPSC RPE cells derived from high‐risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy, and deposition of “drüsen”‐like deposits. The low‐ and high‐risk RPE cells respond differently to intermittent exposure to UV light, which leads to an improvement in cellular and functional phenotype only in the high‐risk AMD‐RPE cells. Taken together, our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing. Stem Cells 2017;35:2305–2320

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Age-Dependent Changes in Heparan Sulfate in Human Bruch's Membrane: Implications for Age-Related Macular Degeneration

Abstract: The quantity of HS decreases substantially with age in human BrM, resulting in fewer binding sites for CFH and especially affecting the ability of the 402H variant of CFH to bind BrM.

Cited by 57 publications

References 59 publications

Regulation of age-related macular degeneration-like pathology by complement factor H

Regulation of age-related macular degeneration-like pathology by complement factor H

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure

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