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Our eyes are increasingly exposed to light from the emitting diode (LED) light of video display terminals (VDT) which contain much blue light. VDTs are equipped with televisions, personal computers and smart phones. The present study aims to clarify the mechanism underlying blue LED light-induced photoreceptor cell damage. Murine cone photoreceptor-derived cells (661 W) were exposed to blue, white, or green LED light (0.38 mW/cm 2 ). In the present study, blue LED light increased reactive oxygen species (ROS) production, altered the protein expression level, induced the aggregation of short-wavelength opsins (S-opsin), resulting in severe cell damage. While, blue LED light damaged the primary retinal cells and the damage was photoreceptor specific. N -Acetylcysteine (NAC), an antioxidant, protected against the cellular damage induced by blue LED light. Overall, the LED light induced cell damage was wavelength-, but not energy-dependent and may cause more severe retinal photoreceptor cell damage than the other LED light.

Organ failure manifests severe symptoms affecting the whole body that may cause death. However, the number of organ donors is not enough for patients requiring transplantation worldwide. Illegal transplantation is also sometimes conducted. To help address this concern, primary hepatocytes are clinically transplanted in the liver. However, donor shortage and host rejection via instant blood-mediated inflammatory reactions are worrisome. Induced pluripotent stem cell-derived hepatocyte-like cells have been developed as an alternative treatment. Recently, organoid technology has been developed to investigate the pathology and mechanism of organoids in cultures. Organoids can be transplanted with vascularization and connected to host blood vessels, and functionally mature better in vivo than in vitro. Hepatic organoids improve pathology in liver disease models. In this review, we introduce induced pluripotent stem cell- and organoid-based therapies against liver diseases considering present and future perspectives.

In fetal development, tissue interaction such as the interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here we recapitulate the spatial arrangement between liver epithelial tissue and the portal vein to observe the formation of intrahepatic bile ducts (BDs) from human induced pluripotent stem cells (hiPSC). We co-culture hiPSC-liver progenitors on the artificial BV consisting of immature smooth muscle cells and endothelial cells, both derived from hiPSCs. After 3 weeks, liver progenitors within hiPSC-BV-incorporated liver organoids (BVLO) differentiate to cholangiocytes and acquire epithelial characteristics, including intercellular junctions, microvilli on the apical membrane, and secretory functions. Furthermore, liver surface transplanted-BVLO temporarily attenuates cholestatic injury symptoms. Single cell RNA sequence analysis suggests that BD interact with the BV in BVLO through TGFβ and Notch pathways. Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease. Overall, we develop a novel 3D co-culture method that successfully establishes functional human BDs by emulating liver epithelial-BV interaction. The interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here, the authors co-culture hiPSC-derived liver progenitors on artificial BV to establish functional human bile ducts for modeling congenital biliary disease.

Organoids derived from human induced pluripotent stem cells (hiPSC) are potentially applicable for regenerative medicine. However, the applications have been hampered by limited organoid size and function as a consequence of a lack of progenitor expansion. Here, we report the recapitulation of progenitor expansion in hiPSC-liver organoids based on the analysis of mouse development. Visualization of blood perfusion and oxygen levels in mouse embryos reveals a transient hypoxic environment during hepatoblast expansion, despite active blood flow. During this specific stage, the placenta expresses various growth factors. Human and mouse placenta-liver interaction analysis identifies various placenta-derived factors. Among them, IL1α efficiently induces the growth in hiPSC-liver organoids as well as mouse fetal livers following progenitor expansion under hypoxia. Furthermore, subsequent oxygenation demonstrates that progenitors expanded by IL1α contribute to hiPSC-liver organoid size and function. Taken together, we demonstrate that treatment with the placenta-derived factor under hypoxia is a crucial human organoid culture technique that efficiently induces progenitor expansion. Applications of hPSC-derived organoids have been hampered by limited organoid size and function. Here, authors report that treatment with IL1α, a placenta-derived factor, under hypoxia induces progenitor expansion in the hPSC-derived liver organoids.

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone’s therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.

Progranulin is a secreted growth factor associated with multiple physiological functions in ischemic pathophysiology. However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after myocardial infarction (MI). In this study, we investigated the effects of progranulin on myocardial ischemia and reperfusion injury. We investigated progranulin expression using Western blotting and immunostaining after permanent left coronary artery (LCA) occlusion in mice. Infarct size and the number of infiltrating neutrophils were measured 24 h after permanent LCA occlusion. Recombinant mouse progranulin was administered before LCA occlusion. In addition, we evaluated cardiac function using cardiac catheterization and echocardiography, and fibrosis size by Masson’s trichrome staining after myocardial ischemia/reperfusion in rabbits. Recombinant human progranulin was administered immediately after induction of reperfusion. Progranulin expression increased in the myocardial ischemic area 1, 3, and 5 days after permanent LCA occlusion in mice. The administration of recombinant mouse progranulin significantly attenuated infarct size and infiltrating neutrophils 24 h after permanent LCA occlusion in mice. We also found that administration of recombinant human progranulin ameliorated the deterioration of cardiac dysfunction and fibrosis after myocardial ischemia/reperfusion in rabbits. These findings suggest that progranulin may protect myocardial ischemia/reperfusion injury.

Astrocytes are glial cells that support and protect neurons in the central nervous systems including the retina. Retinal ganglion cells (RGCs) are in contact with the astrocytes and our earlier findings showed the reduction of the number of cells in the ganglion cell layer in adult progranulin deficient mice. In the present study, we focused on the time of activation of the astrocytes and the alterations in the number of RGCs in the retina and optic nerve in progranulin deficient mice. Our findings showed that the number of Brn3a-positive cells was reduced and the expression of glial fibrillary acidic protein (GFAP) was increased in progranulin deficient mice. The progranulin deficient mice had a high expression of GFAP on postnatal day 9 (P9) but not on postnatal day 1. These mice also had a decrease in the number of the Brn3a-positive cells on P9. Taken together, these findings indicate that the absence of progranulin can affect the survival of RGCs subsequent the activation of astrocytes during retinal development.

VGF nerve growth factor inducible (VGF) is a polypeptide that is induced by neurotrophic factors and is involved in neurite growth and neuroprotection. The mRNA of the Vgf gene has been detected in the adult rat retina, however the roles played by VGF in the retina are still undetermined. Thus, the purpose of this study was to determine the effects of VGF on the retinal ganglion cells (RGCs) of mice in the optic nerve crush (ONC) model, rat-derived primary cultured RGCs and human induced pluripotent stem cells (iPSCs)-derived RGCs. The mRNA and protein of Vgf were upregulated after the ONC. Immunostaining showed that the VGF was located in glial cells including Müller glia and astrocytes but not in the retinal neurons and their axons. AQEE-30, a VGF peptide, suppressed the loss of RGCs induced by the ONC, and it increased survival rat-derived RGCs and promoted the outgrowth of neurites of rat and human iPSCs derived RGCs in vitro . These findings indicate that VGF plays important roles in neuronal degeneration and has protective effects against the ONC on RGCs. Thus, VGF should be considered as a treatment of RGCs degeneration.

VGF nerve growth factor inducible (VGF) is a neuropeptide precursor induced by brain-derived neurotrophic factor and nerve growth factor. VGF is increased in the prefrontal cortex and cerebrospinal fluid in schizophrenia patients. In our previous study, VGF-overexpressing mice exhibited schizophrenia-like behaviors and smaller brain weights. Brain developmental abnormality is one cause of mental illness. Research on brain development is important for discovery of pathogenesis of mental disorders. In the present study, we investigated the role of VGF on cerebellar development. We performed a histological analysis with cerebellar sections of adult and postnatal day 3 mice by Nissl staining. To investigate cerebellar development, we performed immunostaining with antibodies of immature and mature granule cell markers. To understand the mechanism underlying these histological changes, we examined MAPK, Wnt, and sonic hedgehog signaling by Western blot. Finally, we performed rotarod and footprint tests using adult mice to investigate motor function. VGF-overexpressing adult mice exhibited smaller cerebellar sagittal section area. In postnatal day 3 mice, a cerebellar sagittal section area reduction of the whole cerebellum and external granule layer and a decrease in the number of mature granule cells were found in VGF-overexpressing mice. Additionally, the number of proliferative granule cell precursors was lower in VGF-overexpressing mice. Phosphorylation of Trk and Erk1 were increased in the cerebellum of postnatal day 3 VGF-overexpressing mice. Adult VGF-overexpressing mice exhibited motor disability. All together, these findings implicate VGF in the development of cerebellar granule cells via promoting MAPK signaling and motor function in the adult stage.

Myocardial infarction (MI) is a lethal disease that causes irreversible cardiomyocyte death and subsequent cardiovascular remodeling. We have previously shown that the administration of recombinant progranulin (PGRN) protects against myocardial ischemia and reperfusion injury. However, the post‐MI role of PGRN remains unclear. In the present study, we investigated the effects of PGRN deficiency on cardiac remodeling after MI. Wild‐type and PGRN‐knockout mice were subjected to MI by ligation of the left coronary artery for histological, electrophysiological, and protein expression analysis. Cardiac macrophage subpopulations were analyzed by flow cytometry. Bone marrow‐derived macrophages (BMDMs) were acquired and treated with LPS + IFN‐γ and IL‐4 to evaluate mRNA levels and phagocytic ability. PGRN expression was gradually increased in the whole heart at 1, 3, and 7 days after MI. Macrophages abundantly expressed PGRN at the border areas at 3 days post‐MI. PGRN‐knockout mice showed higher mortality, increased LV fibrosis, and severe arrhythmia following MI. PGRN deficiency increased the levels of CD206 and MerTK expression and macrophage infiltration in the infarcted myocardium, which was attributed to a larger subpopulation of cardiac CCR2 + Ly6C low CD11b + macrophages. PGRN‐deficient BMDMs exhibited higher TGF‐β, IL‐4R, and lower IL‐1β, IL‐10 and increased acute phagocytosis following stimulation of LPS and IFN‐γ. PGRN deficiency reduced survival and increased cardiac fibrosis following MI with the induction of abnormal subpopulation of cardiac macrophages early after MI, thereby providing insight into the relationship between properly initiating cardiac repair and macrophage polarization after MI.