bims-mideyd 2026-09-20 papers

MedComm (2020). 2026 Oct;7(10): e71000

Mesenchymal Stem Cell-Derived Extracellular Vesicles Ameliorate NaIO3-Induced Dry AMD by Delivering miR-486-3p to Inhibit Lipocalin-2-Mediated Ferroptosis.

Zheng Li, Tujing Zhao, Lin Ye, Runze Li, Huaping Tian, Ruilin Liao, Lulin Huang.

Dry age-related macular degeneration (AMD), affecting over 196 million people globally, represents the leading cause of irreversible blindness with limited disease-modifying therapies. The disease is characterized by progressive retinal pigment epithelium (RPE) degeneration driven by ferroptosis, an iron-dependent form of regulated cell death. While mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) show therapeutic promise, their mechanisms in counteracting RPE ferroptosis remain unexplored. Here, we prove that human umbilical cord MSC-derived EVs (hucMSC-EVs) significantly attenuate NaIO3-induced retinal degeneration, preserving retinal structure and improving visual function in mice. Transcriptomic profiling identified Lipocalin-2 (Lcn2) as a key ferroptosis-related target. MSC-EVs administration markedly downregulated Lcn2 and upregulated Gpx4 in NaIO3-induced models, demonstrating potent ferroptosis suppression. Furthermore, AAV-mediated Lcn2 overexpression induced AMD-like retinal pathology, which was effectively attenuated by subsequent MSC-EVs treatment. Small RNA sequencing reveals miR-486-3p as the key factor in the MSC-EVs, and dual-luciferase reporter assays confirm its direct binding to the Lcn2 3'UTR. Functional validation demonstrates that miR-486-3p agomir recapitulates the effects of MSC-EVs, including preservation of retinal structure and improvement of electrophysiological responses. Our findings establish a novel strategy where hucMSC-EVs deliver miR-486-3p to suppress Lcn2-mediated ferroptosis, offering a potential treatment for dry AMD.

Keywords: Lipocalin‐2; dry age‐related macular degeneration; extracellular vesicles; ferroptosis; miR‐486‐3p; retinal pigment epithelium

DOI: https://doi.org/10.1002/mco2.71000

Annu Rev Vis Sci. 2026 Sep;12(1): 99-126

The Biology and Cell Engineering of Retinal Pigment Epithelium Cell Transplantation: Developing a Living Drug.

Sudipta Mahato, Elena Daniele, Colby F Lewallen, Ruchi Sharma, Kapil Bharti.

Age-related macular degeneration (AMD) is a multifactorial retinal disease that causes progressive vision loss, with retinal pigment epithelium (RPE) atrophy representing a key initiating event. The RPE monolayer plays a crucial role in maintaining photoreceptor and choriocapillaris health and function. In advanced AMD stages, degeneration extends to the photoreceptors and choriocapillaris, likely as a consequence of preceding RPE atrophy. Existing treatment modalities aim to slow disease progression rather than restore degenerated cells and improve visual function. Pluripotent stem cell-derived RPE cell replacement therapy has emerged as a promising approach for restoring native retinal structure and visual function. This review provides an overview of RPE biology and function, clinical-grade manufacturing of RPE transplants, quality control considerations, and the use of scaffolds to improve delivery and integration. We also summarize preclinical and clinical studies that assess the safety, efficacy, and translational potential of RPE transplantation for AMD and other retinal degenerative conditions.

Keywords: AMD; RPE differentiation; cell therapy; iPSC-RPE transplant; iPSCs; retinal pigment epithelium

DOI: https://doi.org/10.1146/annurev-vision-110725-100948

Exp Eye Res. 2026 Sep 12. pii: S0014-4835(26)00373-8. [Epub ahead of print] 111217

Using Patient iPSC-derived Retinal Pigment Epithelium to Evaluate Differential Susceptibility to MEK Inhibitor-Associated Retinopathy.

Lola P Lozano, Timothy M Boyce, Andrew P Groves, Henry L Keen, Culver Boldt, Robert F Mullins, Elaine M Binkley, Budd A Tucker.

PURPOSE: Compare the effect of MEK inhibition on iPSC-derived retinal pigment epithelial (RPE) cells generated from a patient who developed MEK inhibitor-Associated Retinopathy (MEKAR) versus a patient who did not develop retinopathy. This is an exploratory, hypothesis-generating comparison of one donor line per clinical phenotype.
DESIGN: Exploratory case-control comparison (one patient-derived line per phenotype) SUBJECTS: Two female patients with Neurofibromatosis Type 1 who were treated with MEK inhibitors. One patient developed MEKAR, the other did not.
METHODS: RPE were generated from human induced pluripotent stem cells (hiPSCs) from these two patients. These hiPSC-derived RPE were treated with selumetinib for 10 days.
MAIN OUTCOME MEASURES: Phagocytic activity and changes in gene expression RESULTS: As previously reported, there was a significant increase in internalized rhodopsin in phagocytosis assays, yet this was only found in hiPSC-derived RPE from the patient who developed MEKAR. Selumetinib decreased expression of genes related to fluid transport and cell volume, including aquaporins and solute transporters. At baseline, cells from the patients without MEKAR had higher expression of these genes. Interestingly, selumetinib-induced changes in gene expression only reached statistical significance in cells from the patient who did not develop MEKAR, suggesting these changes may be a compensatory protective mechanism. Patients susceptible to forming MEKAR may have increased phagocytosis without a compensatory change in expression of genes related to fluid flux, thereby inhibiting their ability to transport fluid out of the subretinal space. Because only one donor line was studied per clinical phenotype, and because the two donors also differ in age, NF1 variant class, and MEK inhibitor exposure, these associations are hypothesis-generating and cannot be attributed to MEKAR status independently of donor background.
CONCLUSIONS: These exploratory findings support a testable hypothesis: that MEK inhibitor-Associated Retinopathy preferentially affects susceptible patients whose retinal pigment epithelium cannot sufficiently regulate expression of genes related to fluid transport and cell volume, altering the ability of these cells to properly function. Confirmation will require additional donor lines from each clinical phenotype.

Keywords: MEK Inhibitor-Associated Retinopathy; Retinopathy; chemotherapy side effects; eye tumors; induced pluripotent stem cells; neurofibromas; ocular oncology; retinal pigment epithelium

DOI: https://doi.org/10.1016/j.exer.2026.111217

Dev Biol. 2026 Sep 16. pii: S0012-1606(26)00194-6. [Epub ahead of print]

The emergence of retinal pigment epithelial cell heterogeneity in the larval zebrafish retina.

C L Hehr, S Sanyal, S Storey, S Selje, S McFarlane.

Vision depends on the function of retinal circuits, supported by the retinal pigment epithelium (RPE) that lines the back of the eye. This single-cell layer thick epithelium provides growth factors and nutrients for the underlying photoreceptors, phagocytoses shed photoreceptor outer segment debris, and contributes to the blood-retinal barrier. Whether the cells of the RPE represent a single homogeneous population or represent distinct functional entities or states is poorly understood. Here, we use single cell RNA sequencing (scRNAseq) data from our mature 5-day post-fertilization zebrafish retina dataset and a publicly available adult zebrafish eye dataset, alongside in situ hybridization, to explore the transcriptomic diversity of RPE cells, its emergence over development, and its persistence into the adult. We identify 6 transcriptomically distinct RPE populations in the 5 day larval eye, representing either RPE subtypes or states, that exhibit different localization within the eye. Specifically, we find potential proliferative, iris-associated, dorso-ventral differentiating, and mature RPE subpopulations. These populations appear to emerge via separate developmental trajectories and may be distinct from the transcriptomic RPE subpopulations of the adult eye.

DOI: https://doi.org/10.1016/j.ydbio.2026.09.001

Elife. 2026 Sep 18. pii: RP104055. [Epub ahead of print]13

Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.

Grzegorz Walkiewicz, Siyu Chen, Chienhui Lo, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Benjamin Lawson, Yang Sun.

Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.

Keywords: Lowe syndrome; ROS; cell biology; cilia formation; human; mitochondria; mouse; neuronal differentiation; oxidative stress; zebrafish

DOI: https://doi.org/10.7554/eLife.104055