Biology subjects

Wilson, C. W.

Publications and source records attributed to Wilson, C. W..

5 recordsLinked to original sources

bioRxiv2026

Angiopoietin-like protein 7 (ANGPTL7)-mediated effects on resident immune cells contribute to neurodegeneration in glaucomatous optic nerve head

Glaucoma is an optic neuropathy characterized by progressive retinal degeneration. Population genetic analyses describe an association of variants in angiopoietin-like protein 7 (ANGPTL7) with lower intraocular pressure (IOP) and decreased glaucoma susceptibility. In addition to its reported role in the trabecular meshwork (TM), we demonstrate that ANGPTL7 is also expressed within disease-relevant cell types of the human posterior eye, specifically prelaminar optic nerve head astrocytes (ONHA). Contrasting with previously published findings, we observe no difference in IOP between Angptl7-/- mice and wild-type littermates. Despite absence of an IOP phenotype, loss of ANGPTL7 protects from IOPinduced retinal ganglion cell (RGC) damage in a rodent glaucoma neurodegeneration model. ANGPTL7 may signal through LAIR1-positive immune cells, potentially contributing to pro-inflammatory signaling and phenotypic modulation of resident immune cells, with evidence suggesting that oligomerization of ANGPTL7 is necessary for its activity. Comprehensively, our data highlight an unappreciated role of ANGPTL7 in modulating neuroinflammation in the posterior eye, contributing to glaucoma progression.

neuroscience↗

bioRxiv2025

Identification of cellular and molecular risk signatures for progression to late-stage age-related macular degeneration using the 9-step Minnesota Grading System

Age-related macular degeneration (AMD) is a complex multifactorial disease, and the molecular mechanisms underpinning the progression of intermediate AMD to geographic atrophy are not fully understood. To better understand mechanisms driving progression, we performed bulk RNA sequencing on dissected macular and peripheral RPE/choroid and neural retina tissue from postmortem human eyes graded using the 9-step Minnesota Grading System (MGS). Binning of intermediate AMD cases into three distinct groups (AMD3L, AMD3M, AMD3H) based on the 5-year risk of progression enabled identification of distinct gene and pathway changes associated with progression to late-stage disease. Identified changes in gene expression were validated using ELISA or histological methods. RPE-specific genes and lipid metabolic pathways showed a transient increase in AMD3L followed by a pronounced decrease in AMD3H. In AMD3H, immune response genes such as C3, TREM2, and OLR1 were upregulated when compared to AMD3L samples, as well as genes specific to Muller glia/astrocytes (NGFR, SPP1, GPX3). Our findings support complement inhibition as a promising therapeutic option for slowing conversion to advanced AMD and identify macrophage and Muller/astrocyte genes as potential cell types to target in AMD. Further, we demonstrate the value of combining emerging, outcomes-based, clinically relevant grading systems with profiling technologies to generate new insights into ocular diseases. HighlightsO_LIIntermediate AMD (AMD3) can be further divided into 3 stages - AMD3L (low risk), AMD3M (intermediate risk), AMD3H (high risk) - using the MGS9 grading system based on the risk of disease progression to late AMD. C_LIO_LIRNA sequencing of the macular RPE/choroid shows opposing changes in gene expression of multiple biological pathways for both RPE and immune cells between AMD3L and AMD3H stages. C_LIO_LIIn the macular neural retina, most biological pathways were downregulated in AMD2 (early AMD) but upregulated in AMD4 (late AMD) compared to AMD1 (non-AMD control). C_LIO_LIMolecular and cellular signatures associated with a high risk of progression to AMD4 include activation of complement C3, two subtypes of macrophages expressing either TREM2 or OLR1, and Muller glia/astrocytes as evidenced by the upregulation of GFAP and NGFR. C_LIO_LIUnderstanding the roles of these high-risk associated genes in AMD progression will facilitate the development of new treatments that prevent or delay the irreversible central vision loss in AMD patients. C_LI

neuroscience↗

bioRxiv2024

APOE Impacts Lipid Trafficking in Retinal Pigment Epithelium Cells

Age-related macular degeneration (AMD) is typified by the formation of lipid-rich drusen under the retinal pigment epithelium (RPE) layer. Apolipoprotein E (APOE) is a known genetic risk factor for AMD and a substantial component of drusen, however, the mechanism by which APOE variants contribute to AMD pathology remains unclear. APOE is the primary cholesterol and lipid transport protein of the central nervous system, as well as a component circulating lipoproteins. To better understand how APOE-dependent lipid transport may impact AMD risk, we generated isogenic APOE iPS-RPE cells expressing each of the common human APOE isoforms, as well as an APOE knockout line. APOE knockout cells showed significant morphological and barrier function deficits, suggesting that APOE is essential for RPE health. Furthermore, we observed that APOE abundance is isoform-dependent in RPE cells and that lipid transport is deficient in APOE knockout RPE cells, as well as in RPE cells expressing APOE2, a variant associated with higher risk of AMD. Contrastingly, cells expressing APOE4 seem to respond strongly to lipid challenges by upregulating APOE to support efficient lipid transport. Our results suggest that disease associated APOE variants may impact lipid transport in RPE, contributing to the formation of drusen and impairing cellular function.

cell biology↗

bioRxiv2024

Multiparametric grading of glaucoma severity by histopathology can enable post-mortem substratification of disease state

Neurodegeneration in glaucoma patients is clinically identified through longitudinal assessment of structure-function changes, including intraocular pressure, cup-to-disc ratios from fundus images, and optical coherence tomography imaging of the retinal nerve fiber layer. Use of human post-mortem ocular tissue for basic research is rising in the glaucoma field, yet there are challenges in assessing disease stage and severity, since tissue donations with informed consent are often unaccompanied by detailed pre-mortem clinical information. Further, the interpretation of disease severity based solely on anatomical and morphological assessments by histology can be affected by differences in death-to-preservation time and tissue processing. These are difficult confounders that cannot be easily controlled. As pathogenesis and molecular mechanisms can vary depending on the stage and severity of glaucoma, there is a need for the field to maximize use of donated tissue to better understand the molecular mechanisms of glaucoma and develop new therapeutic hypotheses. Further, there is a lack of consensus around the molecular RNA and protein markers that can be used to classify glaucoma severity. Here, we describe a multiparametric grading system that combines structural measurements of the retinal nerve fiber layer with linear regression and principal component analyses of molecular markers of retinal ganglion cells and glia (RBPMS, NEFL, IBA1 and GFAP) to stratify post-mortem glaucoma eyes by the severity of disease. Our findings show that a quantitative grading approach can stratify post-mortem glaucoma samples with minimal clinical histories into at least three severity groups and suggest that this type of approach may be useful for researchers aiming to maximize insights derived from eye bank donor tissue.

pathology↗

bioRxiv2020

Control of dynamic cell behaviors during angiogenesis and anastomosis by Rasip 1

Organ morphogenesis is driven by a wealth of tightly orchestrated cellular behaviors, which ensure proper organ assembly and function. Many of these cell activities involve cell-cell interactions and remodeling of the F-actin cytoskeleton. Here, we analyze the requirement for Rasip1 (Ras-interacting protein 1), an endothelial-specific regulator of junctional dynamics, during blood vessel formation. Phenotype analysis of rasip1 mutants in zebrafish embryos reveal distinct requirements for Rasip1 during sprouting angiogenesis, vascular anastomosis and lumen formation. During angiogenic sprouting, Rasip1 is required for efficient cell pairing, which is essential for multicellular tube formation. High-resolution time-lapse analyses show that these cell pairing defects are caused by a destabilization of tricellular junctions suggesting that tri-cellular junctions may serve as a counterfort to tether sprouting endothelial cells during morphogenetic cell rearrangements. During anastomosis, Rasip1 is required to establish a stable apical membrane compartment; rasip1 mutants display ectopic, reticulated junctions and the apical compartment is frequently collapsed. Loss of Ccm1 and Heg1 function leads to junctional defects similar to those seen in rasip1 mutants. Analysis of radil-b single and rasip1/radil-b double mutants reveal distinct and overlapping functions of both proteins. While Rasip1 and Radil-b have similar functions during angiogenic sprouting, the junction formation during anastomosis may primarily depend on Rasip1.

developmental biology↗