PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids

Microglia are the resident immune cells of the central nervous system (CNS). They govern the immunogenicity of the retina, which is considered to be part of the CNS; however, it is not known how microglia develop in the eye. Here, we studied human-induced pluripotent stem cells (hiPSCs) that had been expanded into a self-formed ectodermal autonomous multi-zone (SEAM) of cells that partially mimics human eye development. Our results indicated that microglia-like cells, which have characteristics of yolk-sac-like linage cells, naturally develop in 2D eye-like SEAM organoids, which lack any vascular components. These cells are unique in that they are paired box protein 6 (PAX6)-positive, yet they possess some characteristics of mesoderm. Collectively, the data support the notion of the existence of an isolated, locally developing immune system in the eye, which is independent of the body’s vasculature and general immune system

Deletion of the gene encoding Nupr1/p8, a regulator of autophagy, attenuates osteoclastogenesis but increases trabecular bone mass by enhancing osteoblast differentiation

Annual Meeting of the American-Society-for-Bone-and-Mineral-Research, Montreal, CANADA, SEP 28-OCT 01, 201

Deletion of the gene encoding Nupr1/p8, a regulator of autophagy, attenuates osteoclastogenesis but increases trabecular bone mass by enhancing osteoblast differentiation

Annual Meeting of the American-Society-for-Bone-and-Mineral-Research, Montreal, CANADA, SEP 28-OCT 01, 201

Supplemental Materials: Associations of homocysteine metabolism with the risk of spinal osteoarthritis progression in postmenopausal women

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Deficiency of stress‐associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts

International audienceNuclear protein 1 (NUPR1) is a multifunctional stress-induced protein involved in regulating tumorigenesis, apoptosis, and autophagy. Bone homeostasis is maintained by bone-resorbing osteoclasts and bone-forming osteoblasts and osteocytes. We aimed to determine the role of NUPR1 in bone metabolism. Using microcomputed tomography, we found that mice lacking Nupr1 exhibited increased bone volume. Histologic analysis showed that Nupr1 deficiency decreased osteoclast numbers but increased osteoblast numbers and osteoid formation. In vitro culture of bone marrow macrophages showed that receptor activator of NF-κB ligand-induced osteoclastogenesis was down-regulated in Nupr1-deficient mice. In contrast, primary osteoblasts from Nupr1-deficient mice revealed that proliferation of osteoblasts and expression of bone matrix proteins were markedly enhanced. In addition, expression of autophagy-related genes, formation of autophagosomes, and cell survival were up-regulated in Nupr1-deficient osteoblasts. In contract, deletion of Nupr1 reduced the formation of osteocyte cellular projection, which is an indicator of mature osteocytes. Importantly, we found that the expression of sclerostin (Sost), an inhibitor of bone formation, was down-regulated in the osteoblasts and osteocytes of Nupr1-deficient mice. Conversely, Nupr1 overexpression enhanced Sost expression in primary osteoblasts. Collectively, these results indicate that Nupr1 deficiency increases bone volume by attenuating production of Sost and osteoclastogenesis and enhancing differentiation of osteoblasts.-Shiraki, M., Xu, X., Iovanna, J. L., Kukita, T., Hirata, H., Kamohara, A., Kubota, Y., Miyamoto, H., Mawatari, M., Kukita, A. Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts

Telomere Length and Arterial Stiffness Reflected by Brachial–Ankle Pulse Wave Velocity: A Population-Based Cross-Sectional Study

Telomere (TL) is a biomarker of biological aging, and its shortening is associated with major risk factors for cardiovascular diseases (CVD). This study aimed to identify whether TL is associated with arterial stiffness as reflected by brachial–ankle pulse wave velocity (baPWV). This population-based cross-sectional study involved 1065 individuals in the Iwaki area, Japan. Total TL length and TL G-tail length were measured by hybridization protection assay. The baPWV was measured on the right and left sides using a non-invasive vascular screening device. The associations between TL and baPWV were assessed by multivariate linear regression. Compared with the shortest total TL tertile, the longest total TL group showed a significant decrease in baPWV (lowest vs. highest tertile: adjusted beta: −41.24, 95% confidence interval (CI): −76.81, −5.68). The mean baPWV decreased with a longer TL (TL G-tail length: p trend p trend < 0.001). TL G-tail and total TL lengths were inversely associated with baPWV, implicating TL shortening in the development of CVD. This study provides evidence of the factors influencing CVD risks at a very early stage when individuals can still take necessary precautions before CVD gives rise to a symptomatic health outcome

脂肪肝における肝由来低エントロピー小胞による動脈硬化発症のメカニズムの解明

脂肪肝（NAFLD）患者では疫学的に動脈硬化を有する例が多いことが示されているが、脂肪化肝細胞が動脈硬化形成にどのような役割を果たすかは明らかになっていない。今回の研究では脂肪化肝細胞より分泌された細胞外小胞（EV）が血管平滑筋細胞の炎症、アポトーシス、遊走関連遺伝子の発現を増強させることと平滑筋細胞の遊走能を増強させることを示した。これにより脂肪化肝細胞がEVを介して動脈硬化を発症させる機序が示された。Several epidemiologic studies have shown NAFLD has close relation to atherosclerosis, however, whether steatotic liver cells can directly induce atherosclerosis is not clear yet. In this study, we showed extracellular vesicles (EV) derived from steatotic liver cells enhanced the gene expressions related inflammation, apoptosis and cell motility of arterial smooth muscle cells, and also enhanced cell migration of these cells. These data indicate steatotic liver cells play an important role in the generation of atherosclerosis by releasing EV.2016年度～2019年度科学研究費補助金(基盤研究(C))研究成果報告書16K0935

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model

Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC