Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2–SLC7A11–HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.

Adipose-derived mesenchymal stem cells (ADSCs) are promising candidate for regenerative medicine to repair non-healing bone defects due to their high and easy availability. However, the limited osteogenic differentiation potential greatly hinders the clinical application of ADSCs in bone repair. Accumulating evidences demonstrate that circular RNAs (circRNAs) are involved in stem/progenitor cell fate determination, but their specific role in stem/progenitor cell osteogenesis, remains mostly undescribed. Here, we show that circRNA-vgll3 originating from the vgll3 locus markedly enhances osteogenic differentiation of ADSCs; nevertheless, silencing of circRNA-vgll3 dramatically attenuates ADSC osteogenesis. Furthermore, we validate that circRNA-vgll3 functions in ADSC osteogenesis through a circRNA-vgll3/miR-326-5p/ integrin α5 (Itga5) pathway. Itga5 promotes ADSC osteogenic differentiation and miR-326-5p suppresses Itga5 translation. CircRNA-vgll3 directly sequesters miR-326-5p in the cytoplasm and inhibits its activity to promote osteogenic differentiation. Moreover, the therapeutic potential of circRNA-vgll3-modified ADSCs with calcium phosphate cement (CPC) scaffolds was systematically evaluated in a critical-sized defect model in rats. Our results demonstrate that circRNA-vgll3 markedly enhances new bone formation with upregulated bone mineral density, bone volume/tissue volume, trabeculae number, and increased new bone generation. This study reveals the important role of circRNA-vgll3 during new bone biogenesis. Thus, circRNA-vgll3 engineered ADSCs may be effective potential therapeutic targets for bone regenerative medicine.

Large-sized orbital bone defects have serious consequences that destroy orbital integrity and result in maxillofacial deformities and vision loss. The treatment of orbital bone defects is currently palliative and not reparative, suggesting an urgent demand for biomaterials that regenerate orbital bones. In this study, via alloying, extrusion and surface modification, we developed mechanobiologically optimized magnesium (Mg) scaffolds (Ca–P-coated Mg–Zn–Gd scaffolds, referred to as Ca–P–Mg) for the orthotopic reconstruction of large-sized orbital bone defects. At 6 months after transplanting the scaffolds to a clinically relevant canine large animal model, large-sized defects were successfully bridged by an abundance of new bone with normal mechanical properties that corresponded to gradual degradation of the implants. The osteogenic and ancillary cells, including vascular endothelial cells and trigeminal neurons, played important roles in this process. The scaffolds robustly enhanced bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation. In addition, the increased angiogenesis including increased ratio of the specific endothelial subtype CD31hi endomucinhi (CD31hiEmcnhi) endothelial cells can facilitate osteogenesis. Furthermore, the scaffolds trigger trigeminal neurons via transient receptor potential vanilloid subtype 1 (Trpv1) to produce the neuropeptide calcitonin gene-related peptide (CGRP), which promotes angiogenesis and osteogenesis. Overall, our investigations revealed the efficacy of Ca–P–Mg scaffolds in healing orbital bone defects and warrant further exploration of these scaffolds for clinical applications.

Fabrication of self-healing injectable CS-Odex hydrogels via a dynamic Schiff-base linkage for RPC delivery.

Retinal degeneration is a main class of ocular diseases. So far, retinal progenitor cell (RPC) transplantation has been the most potential therapy for it, in which promoting RPCs neuronal differentiation remains an unmet challenge. To address this issue, innovatively designed L/ d - phenylalanine based chiral nanofibers (LPG and DPG) are employed and it finds that chirality of fibers can efficiently regulate RPCs differentiation. qPCR, western blot, and immunofluorescence analysis show that right-handed helical DPG nanofibers significantly promote RPCs neuronal differentiation, whereas left-handed LPG nanofibers decrease this effect. These effects are mainly ascribed to the stereoselective interaction between chiral helical nanofibers and retinol-binding protein 4 (RBP4, a key protein in the retinoic acid (RA) metabolic pathway). The findings of chirality-dependent neuronal differentiation provide new strategies for treatment of neurodegenerative diseases via optimizing differentiation of transplanted stem cells on chiral nanofibers.

Background and Purpose Retinal photodamage is a high‐risk factor for age‐related macular degeneration (AMD), the leading cause of irreversible blindness worldwide. However, both the pathogenesis and effective therapies for retinal photodamage are still unclear and debated. Experimental Approach The anti‐inflammatory effects of thrombospondin‐1 on blue light‐induced inflammation in ARPE‐19 cells and in retinal inflammation were evaluated. Furthermore, the anti‐angiogenic effects of thrombospondin‐1 on human microvascular endothelial cells (hMEC‐1 cells) and a laser‐induced choroidal neovascularisation (CNV) mouse model were evaluated. in vitro experiments, including western blotting, immunocytochemistry, migration assays and tube formation assays, as well as in vivo experiments, including immunofluorescence, visual electrophysiology, spectral‐domain optical coherence tomography, and fluorescein angiography, were employed to evaluate the anti‐inflammatory and anti‐angiogenic effects of thrombospondin‐1. Key Results Specific effects of blue light‐induced retinal inflammation and pathological angiogenesis were reflected by up‐regulation of pro‐inflammatory factors and activation of angiogenic responses, predominantly regulated by the NF‐κB and VEGFR2 pathways respectively. During the blue light‐induced pathological progress, THBS‐1 derived from retinal pigment epithelium down‐regulated proteomics and biological assays. Thrombospondin‐1 treatment also suppressed inflammatory infiltration and neovascular leakage. The protective effect of Thrombospondin‐1 was additionally demonstrated by a substantial rescue of visual function. Mechanistically, thrombospondin‐1 reversed blue light‐induced retinal inflammation and angiogenesis by blocking the activated NF‐κB and VEGFR2 pathways, respectively. Conclusion and Implications Thrombospondin‐1, with dual anti‐inflammatory and anti‐neovascularisation properties, is a promising agent for protection against blue light‐induced retinal damage and retinal degenerative disorders which are pathologically associated with inflammatory and angiogenic progress. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

various biological roles, including transepithelial transporting fluids and nutrients, constituting the outer blood-retinal barrier, phagocytosing photoreceptor outer segment tips, and recycling bleached visual pigments. [1] Therefore, RPE dysfunction could contribute to various ocular disorders accompanied by visual impairment and even blindness, most notably age-related macular degeneration (AMD). [2] Currently, the global prevalence of AMD in individuals aged 45 years and older is ≈8.7%. [3] Regarding AMD therapeutic options, the current anti-vascular therapeutic is limited for patients with neovascular AMD, whereas nearly no satisfactory strategies were available for non-neovascular AMD, which drives an urgent requirement to improve treatments among AMD patients. [4] The explicit etiology during the progression of AMD is not thoroughly understood. However, it has been generally accepted that detrimental oxidative stress in metabolically active RPE exerts a causative, primary impact on increased RPE vulnerability and subsequent photoreceptor cell degeneration, ultimately causing impairment of central vision or blindness. [5] Ferrous ions, as a typical source of oxidative stress, have been widely implicated in the progression of AMD. [6] In contrast to the age-matched healthy macula, higher levels of total iron in RPE cells in addition to in Bruch's membrane have been measured in the AMD-affected maculae, [7] and a more than twofold increase in iron concentration was detected in the aqueous humor of dry AMD. [8] Additionally, the excessive iron released from intraocular hemorrhage induces retinal inflammation and peroxidation of unsaturated phospholipids. [9] These studies have shown that iron toxicity and oxidative stress are closely associated with RPE death during AMD progression, suggesting that highly effective ferrous reduction provides a better platform to manage these diseases. Deferoxamine (DFO) is a typical type of iron chelator, yet it can be readily eliminated, with a plasma t 1/2 of ≈5-10 min, after intravenous injection in human subjects. [10] In addition, DFO mainly accumulates in lysosomes, [11] and protects against cells merely by chelating lysosomal iron. [12] However, iron accumulation in the RPE also involves a disruption of mitochondrial iron homeostasis, [13] implicating the limited effects of DFO on alleviating iron overload and oxidative stress-induced RPE damage. Inspiringly, it has been demonstrated that the potent Ca 2+ -substituted iron-binding Prussian blue analogue KCa[Fe III (CN) 6 ] (CaPB) can enter bacterial cells and selectively deplete intracellular iron by a simplistic Lethal oxidative stress and ferrous ion accumulation-mediated degeneration/ death in retinal pigment epithelium (RPE) exert an indispensable impact on retinal degenerative diseases with irreversible visual impairment, especially in age-related macular degeneration (AMD), but corresponding pathogenesisoriented medical intervention remains controversial. In this study, the potent iron-binding nanoscale Prussia...

Age‐related macular degeneration (AMD) is a major cause of visual impairment and severe vision loss worldwide, while the currently available treatments are often unsatisfactory. Previous studies have demonstrated both inflammation and oxidative‐stress‐induced damage to the retinal pigment epithelium are involved in the pathogenesis of aberrant development of blood vessels in wet AMD (wet‐AMD). Although antivascular endothelial growth factor (VEGF) therapy (e.g., Ranibizumab) can impair the growth of new blood vessels, side effects are still found with repeated monthly intravitreal injections. Here, an injectable antibody‐loaded supramolecular nanofiber hydrogel is fabricated by simply mixing betamethasone phosphate (BetP), a clinic anti‐inflammatory drug, anti‐VEGF, the gold‐standard anti‐VEGF drug for AMD treatment, with CaCl2. Upon intravitreal injection, such BetP‐based hydrogel (BetP‐Gel), while enabling long‐term sustained release of anti‐VEGF to inhibit vascular proliferation in the retina and attenuate choroidal neovascularization, can also scavenge reactive oxygen species to reduce local inflammation. Remarkably, such BetP‐Gel can dramatically prolong the effective treatment time of conventional anti‐VEGF therapy. Notably, anti‐VEGF‐loaded supramolecular hydrogel based on all clinically approved agents may be readily translated into clinical use for AMD treatment, with the potential to replace the current anti‐VEGF therapy.