bims-mideyd 2026-05-10 papers

Stem Cell Res Ther. 2026 May 02.

3D spheroids of umbilical cord-derived MSCs protect retinal pigment epithelium against oxidative and inflammatory injury by activating autophagy.

Qian Xu, Mengyao Li, Dong Li, Xiaoyu Dai, Yifei Zhang, Yi Qu.

BACKGROUND: Age-related macular degeneration (AMD) is characterized by progressive retinal pigment epithelium (RPE) dysfunction driven by oxidative stress and chronic inflammation, in which NLRP3 inflammasome activation plays a critical role. Mesenchymal stem cells (MSCs) exhibit therapeutic potential, but their efficacy is limited by poor survival and reduced paracrine activity in hostile microenvironments. Here, we investigated whether three-dimensional (3D) spheroid culture enhances the protective effects of umbilical cord-derived MSCs (UC-MSCs) on RPE cells by promoting autophagy and suppressing inflammasome activation.
METHODS: Human UC-MSCs were cultured as 3D spheroids or conventional 2D monolayers and applied in sodium iodate (NaIO3)-induced oxidative injury models both in vitro and in vivo. Retinal morphology and function were assessed via histology and electroretinography, while NLRP3/caspase-1 activation, LC3-II/I ratios, and autophagy flux were quantified using immunofluorescence and Western blot. GO/KEGG enrichment was performed to identify pathways associated with 3D MSCs efficacy. Mechanistic involvement of autophagy was validated using 3-methyladenine (3-MA) and rapamycin.
RESULTS: 3D MSCs formed compact spheroids exhibiting enhanced paracrine potential and significantly outperformed 2D MSCs in protecting RPE cells against NaIO3-induced injury. In vivo, 3D MSC treatment preserved retinal structure, reduced RPE cell loss, and improved retinal function. In vitro, co-culture with 3D MSCs markedly improved ARPE-19 viability, reduced apoptosis, and modulated autophagy-related marker expression, as evidenced by increased LC3-II/I ratios. 3D MSCs significantly inhibited NLRP3 inflammasome activation and pro-inflammatory cytokine release, effects reversed by 3-MA and further enhanced by rapamycin.
CONCLUSIONS: 3D spheroid culture substantially augments the therapeutic efficacy of UC-MSCs by boosting autophagy and suppressing NLRP3 inflammasome signaling, resulting in enhanced protection of RPE cells from oxidative and inflammatory injury. These findings provide preclinical evidence supporting 3D MSCs as a promising therapeutic strategy for AMD.

Keywords: Age-related macular degeneration; Autophagy; NLRP3 inflammasome; Retinal pigment epithelium; Umbilical cord-derived mesenchymal stem cells

DOI: https://doi.org/10.1186/s13287-026-05043-z

Int J Biol Macromol. 2026 May 02. pii: S0141-8130(26)02286-5. [Epub ahead of print]364 152359

Free-standing chondroitin sulfate/collagen multilayered films as preliminary Bruch's membrane-mimetic platform for retinal pigment epithelial cell culture.

Lan Duo, Pengfei Cheng, Wenpei Jiang, Quankui Lin.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness, primarily associated with retinal pigment epithelial (RPE) cell degeneration. Although RPE cell therapy has emerged as a promising strategy for AMD, maintaining RPE cell attachment, organization, and functional characteristics remains a major challenge. In this study, free-standing chondroitin sulfate (CS)/collagen (Col) multilayered films were fabricated via spin-coating-assisted layer-by-layer (LbL) assembly and evaluated in vitro as preliminary Bruch's membrane (BM)-mimetic platform for supporting RPE growth and preserving cellular functionality. Genipin cross-linking improved the mechanical stability of the films and reduced their swelling behavior. ARPE-19 cells cultured on the 2 h cross-linked films showed improved attachment and proliferation compared with uncross-linked films, together with detectable RPE65 expression and several RPE-related functional features, including apical-basal differences in pigment epithelium-derived factor (PEDF) secretion, phagocytosis of labeled photoreceptor outer segments (POS), and formation of microvilli-like structures. Collectively, these findings suggest that CS/Col free-standing films can support ARPE-19 cell growth and maintain several RPE-related phenotypic and functional features in vitro, providing a preliminary BM-mimetic platform for future RPE culture studies.

Keywords: Biomimetic scaffold; Free-standing film; Layer-by-layer

DOI: https://doi.org/10.1016/j.ijbiomac.2026.152359

Front Ophthalmol (Lausanne). 2026 ;6 1804578

Shengyu Zhu, Taoshuo Yang, Limei Sheng, Lei Shi.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. Advanced AMD comprises an atrophic ("dry") form characterized by retinal pigment epithelium (RPE) and photoreceptor degeneration and a neovascular ("wet") form driven by choroidal neovascularization (CNV). Beyond genetic predisposition and environmental stressors, chronic dysregulation of innate immunity is increasingly recognized as a convergent mechanism linking drusen/Bruch's membrane alterations to outer retinal cell death and pathological angiogenesis. Retinal myeloid cells-including resident microglia and, in specific disease contexts, recruited monocyte-derived macrophages-can support homeostasis by clearing lipids and cellular debris, yet may also exacerbate inflammation, matrix remodeling, and neovascularization. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia and other myeloid cells that regulates phagocytosis, lipid handling, migration, survival, immunometabolism, and inflammatory tone. Recent retinal studies suggest that TREM2-associated programs can restrain lesion expansion in outer retinal degeneration models and modulate CNV severity in experimental neovascularization; however, interpretation remains limited by disease stage, anatomical niche, and the difficulty of cleanly separating microglia from infiltrating macrophages in vivo. Here, we synthesize current evidence on retinal myeloid contributions to dry and neovascular AMD, provide an updated mechanistic framework for TREM2 signaling, and discuss therapeutic strategies and translational challenges for targeting TREM2 in AMD.

Keywords: TREM2; age-related macular degeneration; aging; inflammation; microglia

DOI: https://doi.org/10.3389/fopht.2026.1804578

J Neural Transm (Vienna). 2026 May 04.

Spontaneous whole retinal degeneration in aged Beclin1 heterozygous mice.

Francesca Biagioni, Maurizio Forte, Flavio di Nonno, Carla Letizia Busceti, Roberto Pinelli, Violet Vakunseh Bumah, Michela Ferrucci, Gloria Lazzeri, Sebastiano Sciarretta, Giacomo Frati, Francesco Fornai.

Retinal degenerative diseases range from rare inherited forms to common multifactorial disorders such as age-related macular degeneration, which is the leading cause of blindness in developed countries. Recent evidence identifies impaired autophagy as a key pathogenetic mechanism. In the disease process alterations of the outer retina start from the retinal pigment epithelium (RPE), to progress downstream in the inner retina leading to widespread whole retinal degeneration. Recent studies indicate that among autophagy-related proteins Beclin1 plays a relevant effect in sustaining retinal integrity, since it is induced by light exposure and it is placed at the intersection between mitophagy, lipophagy, and glycophagy, which are involved during retinal degeneration. The present study was carried out by profiting of BECN1 heterozygous aged mice (BECN+/-), where RT-PCR and western blotting analysis confirmed the loss of both the primary transcript (BECN1) and protein (Beclin1) in the whole retina. Multiple converging techniques indicate a marked degeneration of RPE and photoreceptor layer, where a dismantling of proteins forming tight junction was documented. Inner retinal degeneration was extended within outer and inner nuclear layer. In the inner retina the expression of the detrimental protein alpha synuclein was increased concomitantly with a defect of autophagy markers. The study indicates a seminal role of Beclin1 in maintaining retinal integrity and it defines the vulnerability of various retinal layers in the spreading of Beclin1-dependent retinal degeneration. The potential of increasing the expression of Beclin1 through photobiomodulation is discussed, since it supports retinal integrity when amber/red light-induced stimulation occurs.

Keywords: AMD; Beclin1; Photobiomodulation; RPE65; Retinal degenerative disorders; ZO1

DOI: https://doi.org/10.1007/s00702-026-03166-4

Antioxid Redox Signal. 2026 May 09. 15230864261442217

Physalin A Restores Redox and Mitochondrial Homeostasis to Protect against Diabetic Retinopathy.

Yan-Ru Xiao, Yow-Wen Hsieh, Wei-Yong Lin, Yu-Sheng Hsieh, Wei-Cheng Jiang, Pei-Ying Pai, Yueh-Hsiung Kuo, Dah-Yuu Lu, Yu-Jung Lin, Wen-Tsong Hsieh.

AIMS: To determine whether physalin A (PA) safeguards the outer blood-retinal barrier under diabetic stress by engaging nuclear factor erythroid 2-related factor 2 (Nrf2) to restore redox balance and restrain ferroptosis in human retinal pigment epithelial (hRPE) cells and C57BLKS/J Iar -+Leprdb/+Leprdb mice.
RESULTS: In high-glucose challenged hRPE cells, PA dose-dependently preserved viability, maintained claudin-1/occludin/zonula occludens-1 abundance and membrane localization, and reversed ferroptosis hallmarks (restored solute carrier family 7 member 11 [SLC7A11], SLC3A2, and glutathione peroxidase 4; reduced ferrous iron [Fe2+] overload and lipid peroxidation). PA restored glutathione levels, reduced malondialdehyde (MDA), and enhanced the antioxidant defense pathway mediated by Nrf2, including upregulation of heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 2. Silencing Nrf2 abolished the effects of PA on barrier integrity and ferroptosis suppression, with rebounds in reactive oxygen species, MDA, Fe2+, and tight junction loss. In db/db mice treated systemically for 20 weeks, PA reduced Evans Blue leakage, increased retinal thickness, restored RPE tight junction proteins, and normalized mitochondrial architecture by transmission electron microscopy. PA rebalanced mitochondrial dynamics (dynamin 1-like, optic atrophy 1, fission 1, mitofusin 1, FUN14 domain containing 1), increased retinal mitochondrial DNA copy number, and partially stabilized glycemia and weight.
CONCLUSION: PA restores redox tone, restrains ferroptosis, and preserves junctional integrity to protect the diabetic retina, with Nrf2 being indispensable for these benefits. These findings position PA as a promising adjunctive candidate for early diabetic retinopathy and support Nrf2-centered strategies to reinforce the outer blood-retinal barrier. Antioxid. Redox Signal. 00, 000-000.

Keywords: antioxidant; diabetic retinopathy; ferroptosis; nuclear factor erythroid 2-related factor 2; physalin A; tight junction

DOI: https://doi.org/10.1177/15230864261442217