bims-mideyd 2026-11-08 papers

Cell Death Dis. 2026 Aug 07. pii: 937. [Epub ahead of print]17(1):

Lipidomic and transcriptomic remodeling underlies early retinal pathogenesis in dry age-related macular degeneration.

Neeta Roy, Jen-Zen Chuang, Ting-Huan Chen, Ye Sun, Danielle E Allen, Marie-Audrey I Kautzmann, Surjyadipta Bhattacharjee, Maxwell Ping Lee, Laura Beth J McIntire, Nicolas G Bazan, Ching-Hwa Sung.

Dry age-related macular degeneration (AMD) is initiated by retinal pigment epithelium (RPE) dysfunction, yet early metabolic mechanisms linking RPE injury to photoreceptor dysfunction remain unclear. Using a physiologically relevant mouse model, we performed cell-type-resolved lipidomic and transcriptomic profiling with ultrastructural analyses. RPE-specific loss of Chloride Intracellular Channel 4 (CLIC4) induced coordinated lipid remodeling and transcriptional rewiring compromising RPE-photoreceptor lipid homeostasis. Both RPE and neural retina exhibited shifts toward very-long-chain unsaturated phospholipids and ceramides, while mutant RPE also accumulated saturated very-long-chain ceramides and cholesterol, particularly in females, favoring drusen deposition. Strikingly, RPE and rods mounted divergent responses: RPE activated compensatory mechanisms, whereas rods exhibited transcriptomic and ultrastructural evidence of bioenergetic suppression, mitochondrial structural abnormalities, and mitochondria-derived oxidative damage, establishing a feed-forward stress cycle extending beyond canonical rod-RPE carbon-energy coupling. These findings underscore rod mitochondrial structural integrity as a potential early biomarker, positioning disrupted lipid recycling as a targetable axis in dry AMD pathogenesis.

DOI: https://doi.org/10.1038/s41419-026-09147-5

Exp Eye Res. 2026 Nov 02. pii: S0014-4835(26)00465-3. [Epub ahead of print]274 111309

Cell-cycle regulatory responses in retinal degeneration: From post-mitotic homeostasis to cell-state transitions and fate decisions.

Wenyu Du, Ruyu Ma, Yiwen Hong, Yongjiang Chen, Ling Huang, Lirong Xiao, Li Tang, Danian Chen.

Cell-cycle regulatory perturbations are increasingly implicated in retinal degeneration, yet their biological significance varies fundamentally across retinal cell types because proliferative competence differs between terminally differentiated neurons and proliferation-capable retinal populations. While retinal neurons normally maintain permanent cell-cycle exit, Müller glia, microglia, retinal pigment epithelial (RPE) cells, endothelial cells, and pericytes retain varying capacities for quiescence, proliferation, and injury-induced reactivation. Consequently, alterations in cyclins, cyclin-dependent kinases (CDKs), RB-E2F signaling, DNA replication machinery, or checkpoint regulators may represent distinct biological states depending on cellular context. In this review, we examine cell-cycle perturbations across inherited retinal diseases (IRDs), age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal gliosis and inflammation, and retinal organoid models. We critically assess current evidence for neuronal cell-cycle re-entry and propose a practical evidence hierarchy that distinguishes pathway activation, neuronal localization, progression through cell-cycle phases, cell-type-specific causality, and longitudinal cellular fate. We argue that many reported findings reflect incomplete or ambiguous evidence and should not be equated with bona fide neuronal cell-cycle re-entry. We further propose a fate-bifurcation model in which cellular outcomes are determined by the depth and duration of cell-cycle engagement together with cell identity, checkpoint integrity, CDK inhibitor activity, DNA damage burden, metabolic state, and microenvironment cues. Under this framework, limited or checkpoint-restrained engagement may support transient neuronal adaptation or survival, whereas sustained activation may promote senescence-like states, and deeper progression under inadequate checkpoint control may contribute to neuronal dysfunction and death. In proliferation-competent retinal compartments, related pathways may instead drive gliosis, immune expansion, epithelial remodeling, angiogenesis, or senescence. By integrating evidence across retinal diseases and cell types, this state-based framework provides a unified interpretation of apparently conflicting observations and offers a conceptual foundation for developing cell-type- and state-specific therapeutic strategies for retinal degeneration.

Keywords: CDK; Cell-cycle regulation; Cell-state transition; Cellular senescence; Müller glia; Neuronal cell-cycle re-entry; Neuroprotection; RB–E2F; Retinal degeneration; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.exer.2026.111309

iScience. 2026 Nov 20. 29(11): 117998

iPSC-derived RPE and retinal organoids from two phenotypically different Stargardt disease patients show differences in ABCA4 function.

Arnau Navinés-Ferrer, Pilar Méndez-Vendrell, Laura Siles, Rafael Navarro, Anniken Burés-Jelstrup, Esther Pomares.

Stargardt disease is a phenotypically heterogeneous disease caused by bi-allelic mutations in the ABCA4 gene. We generated retinal pigment epithelium (RPE) cells, photoreceptor precursors (PhRPs), and retinal organoids (ROs) from two induced pluripotent stem (iPS) cell lines derived from two phenotypically different Stargardt disease patients. We observed that RPE cells from the patient with peripheral affectation showed reduced ABCA4 expression, reduced phagocytosis and digestion of photoreceptor outer segments (POSs), and accumulation of lipid byproducts. ROs from both patients show stunted segments, more rods, caspase-3 activation, and lipofuscin accumulation at week 45 of maturation. Phenotypical differences seen in Stargardt disease patients are caused by their specific ABCA4 variants, but cellular and molecular mechanisms underlying the process of photoreceptor degeneration are still poorly understood. Here, we suggest that peripheral phenotypes associated with these macular dystrophies can be linked to poor clearance of POSs by RPE cells, giving these cells a higher role in the pathogenesis of the disease.

Keywords: ABCA4; Stargardt disease; cone-rod dystrophy; fundus flavimaculatus; iPSC; inherited retinal dystrophies; organoid; photoreceptor; retina; retinal pigment epithelium

DOI: https://doi.org/10.1016/j.isci.2026.117998

Front Immunol. 2026 ;17 1898554

Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration.

Adarsha Koirala, Ann Marshak-Rothstein, Bruce R Ksander, Meredith Gregory-Ksander.

Introduction: Age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggest that Fas Ligand (FasL) on retinal pigment epithelial cells inhibits CNV by inducing apoptosis of infiltrating Fas+ vascular endothelial cells. However, membrane-bound FasL (mFasL) can be cleaved by metalloproteinases to release a soluble fragment (sFasL) and the two isoforms have distinct functions. mFasL induces apoptosis and inflammation while sFasL has been shown to promote cell activation, cell survival, cell proliferation, and cell migration. In this current study, we use a genetic approach to prevent cleavage of mFasL in order to determine the extent to which sFasL and/or mFasL contribute to vascular leakage in a mouse model of laser-induced CNV.
Methods: To distinguish the role of mFasL from sFasL in regulating CNV and vascular leakage, we used a 532 nm laser to induce CNV in three types of mice: (i) wild-type (WT) FasLWT/WT mice that express low levels of mFasL and high levels of sFasL, (ii) homozygous FasLΔCS/ΔCS mice that express greater than normal levels of mFasL and no sFasL, and (iii) heterozygous FasLΔCS/WT mice that express greater than normal levels of mFasL and less than normal levels of sFasL.
Results: Unexpectedly, CNV size and the area of vascular leakage were comparable in homozygous FasLΔCS/ΔCS and WT mice. However, heterozygous FasLΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation that depended on the expression of the Fas receptor in LysM-positive myeloid cells. Moreover, the protective phenotype observed in heterozygous FasLΔCS/WT mice correlated with increased retinal expression of PDGFRb and TGFβ1, reduced retinal expression of VEGFA, and increased expression of PEDF, which is known to inhibit VEGF-induced vascular permeability and promote vessel normalization.
Discussion: Overall, these data indicate that FasL-mediated protection from CNV depends on expression of both sFasL and mFasL. Moreover, the accelerated neovessel maturation observed in heterozygous FasLΔCS/WT mice depends on Fas signaling in LysM-positive myeloid cells and is highly dependent on the extent of FasL cleavage, identifying Fas ligand cleavage as a potential therapeutic strategy to promote neovessel maturation and prevent vascular leakage in wet AMD.

Keywords: Fas Ligand; age-related macular degeneration; choroidal neovascularization; macrophage; myeloid cells; vascular leakage; vessel normalization

DOI: https://doi.org/10.3389/fimmu.2026.1898554

Front Biosci (Landmark Ed). 2026 Oct 20. 31(10): 55037

Differential Modulation of Oxidative Stress and VEGF-A Secretion by Saffron Repron® Pretreatment in ARPE-19 Cells Exposed to High Glucose.

Alessandra Puddu, Matilde Balbi, Alessia Galante, Ilaria Piano, Davide Carlo Maggi, Silvia Ravera.

BACKGROUND: Hyperglycemia contributes to diabetic retinopathy by promoting oxidative stress, inflammatory signaling, retinal pigment epithelial (RPE) dysfunction, and vascular endothelial growth factor A (VEGF-A) secretion. Saffron Repron® (sR), selected (and patented) according to its chemical composition, has been shown to activate neuroprotective responses. This study investigated whether sR pretreatment modulates high glucose-induced oxidative damage, antioxidant and inflammatory signaling, VEGF-A secretion, and paracrine endothelial activation in ARPE-19 cells.
METHODS: ARPE-19 cells were pretreated with sR (40 μg/mL for 24 h), washed, and exposed to high-glucose (HG) (25 mM) for 24 or 96 h. Cell viability and cytotoxicity were assessed using colorimetric assays, reactive oxygen species (ROS) using a luminescence assay, superoxide dismutase 2 (SOD2), nuclear factor erythroid 2-related factor 2 (NRF2), KEAP1, nuclear factor kappa B (NF-κB), and IκBα expression by western blotting, catalase activity by spectrophotometry, and VEGF-A secretion by bioluminescent immunoassay. Human microvascular endothelial cells (HMEC-1) were exposed to ARPE-19 conditioned media for 24 h, after which viability and ROS levels were evaluated. Data were analyzed using one-way analysis of variance followed by Tukey's post-hoc test.
RESULTS: sR alone did not substantially affect basal ARPE-19 viability or VEGF-A secretion. HG increased cytotoxicity and ROS levels at 24 h and reduced viability, while increasing the cytotoxicity/viability ratio and ROS levels at 96 h. sR reduced HG-induced cytotoxicity, restored viability at 96 h, and normalized ROS levels. However, SOD2 expression and catalase activity were reduced by HG and/or sR, indicating that sR-mediated ROS reduction was not associated with induction of these antioxidant defenses. Total NRF2 expression and the NRF2/KEAP1 ratio remained unchanged, although sR prevented HG-induced KEAP1 upregulation at 24 h. HG altered the NF-κB/IκBα balance and increased VEGF-A secretion at both time points; sR did not prevent increase in VEGF-A at 24 h but significantly reduced the HG-induced increase at 96 h. Conditioned media from HG-treated ARPE-19 cells increased HMEC-1 viability and ROS levels, whereas media from sR-pretreated HG cells attenuated these effects.
CONCLUSIONS: Pretreatment with sR protects ARPE-19 cells from HG-induced cytotoxicity and oxidative stress primarily by reducing ROS levels rather than by inducing NRF2/SOD2-associated antioxidant responses. sR pretreatment also attenuated the pro-oxidative paracrine effects of HG-exposed ARPE-19 RPE model on endothelial cells, supporting further investigation of its potential protective effects in models of hyperglycemic retinal stress.

Keywords: ARPE-19 cells; NADPH oxidases; Saffron Repron®; diabetic retinopathy; oxidative stress; vascular endothelial growth factor A

DOI: https://doi.org/10.31083/FBL55037