β-catenin regulates the transcription of genes involved in diverse biological processes, including embryogenesis, tissue homeostasis and regeneration. Endothelial cell (EC)-specific gene-targeting analyses in mice have revealed that β-catenin is required for vascular development. However, the precise function of β-cateninmediated gene regulation in vascular development is not well understood, since β-catenin regulates not only gene expression but also the formation of cell-cell junctions. To address this question, we have developed a novel transgenic zebrafish line that allows the visualization of β-catenin transcriptional activity specifically in ECs and discovered that β-catenin-dependent transcription is central to the bone morphogenetic protein (Bmp)-mediated formation of venous vessels. During caudal vein (CV) formation, Bmp induces the expression of aggf1, a putative causative gene for KlippelTrenaunay syndrome, which is characterized by venous malformation and hypertrophy of bones and soft tissues. Subsequently, Aggf1 potentiates β-catenin transcriptional activity by acting as a transcriptional co-factor, suggesting that Bmp evokes β-catenin-mediated gene expression through Aggf1 expression. Bmp-mediated activation of β-catenin induces the expression of Nr2f2 (also known as Coup-TFII), a member of the nuclear receptor superfamily, to promote the differentiation of venous ECs, thereby contributing to CV formation. Furthermore, β-catenin stimulated by Bmp promotes the survival of venous ECs, but not that of arterial ECs. Collectively, these results indicate that Bmp-induced activation of β-catenin through Aggf1 regulates CV development by promoting the Nr2f2-dependent differentiation of venous ECs and their survival. This study demonstrates, for the first time, a crucial role of β-catenin-mediated gene expression in the development of venous vessels.
Background Interstitial lung disease (ILD) induced by immune checkpoint inhibitors (ICIs) is a potentially life‐threatening adverse event. The purpose of this study was to evaluate whether the development of immune‐related adverse events (irAEs), especially ILD, was associated with treatment efficacy and to research the features and risk factors of ILD in advanced non‐small cell lung cancer (NSCLC). Methods Between December 2015 and November 2018, 130 advanced NSCLC patients were treated with nivolumab, pembrolizumab or atezolizumab. The patients were categorized into two groups (irAEs group or non‐irAEs group). Subsequently, we divided the irAEs group into two groups based on the incidence of ILD (ILD group and irAEs‐non‐ILD group). Treatment efficacy and the characteristics of ILD were evaluated. Results A total of 39 (30%) patients developed irAEs. ILD was observed in 16 (12%) patients. Patients with ILD had a higher objective response rate (ORR) compared with irAEs‐non‐ILD patients and non‐irAEs patients (63%, 43% and 22%, respectively). Median progression‐free survival (mPFS) was 15.9 months in ILD patients, 5.4 months in irAEs‐non‐ILD patients and 3.3 months in non‐irAEs patients (log‐rank test, P = 0.033). Pre‐existing interstitial pneumonia (IP) was an independent risk factor for ILD‐induced ICIs (odds ratio [OR] 14.7; 95% confidence interval [CI]: 2.16–99.6, P = 0.006). Conclusions ORR and PFS were significantly better in ILD patients than in irAEs‐non‐ILD and non‐irAEs patients. Pre‐existing history of IP was an independent risk factor for ILD‐induced ICIs.
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
BackgroundAlthough aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and their relevance to fibroblast-to-myofibroblast differentiation have not been fully elucidated. In this study, we aimed to identify exosome-derived miRNAs relevant to fibrosis development. MethodsWe profiled exosome-derived miRNAs expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis by miRNA array analysis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblastto-myofibroblast differentiation was investigated using human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in-vivo pulmonary fibrosis model. ResultsMiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via the 3 inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. ConclusionsExosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present study warrants further investigations to shed light on miR-22 as a novel therapeutic target for patients with IPF.
Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in motoneurons resulted in enhanced axon growth of motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary motoneurons.
To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.
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