Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration

Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. However, studies often focus on astrocytes as single-cell units. Astrocytes are densely interconnected by gap junctions that are composed primarily of the protein connexin-43 (Cx43) and can function as a broader network of cells. Such networks contribute to a number of important processes, including metabolite distribution and extracellular ionic buffering, and are likely to play an important role in the progression of neurodegenerative disease. This review will focus on the pro-degenerative and pro-survival influence of astrocyte Cx43 in disease progression, with a focus on the roles of gap junctions and hemichannels in the spread of degenerative stress. Finally, we will highlight the specific evidence for targeting these networks in the treatment of glaucomatous neurodegeneration and other optic neuropathies.

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Faculty Opinions recommendation of Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735170781.793574482 ◽

2020 ◽

Author(s):

Vijay Tiwari ◽

Mohammed Inayatullah

Keyword(s):

Single Cell ◽

Disease Progression ◽

Rna Seq

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Insights into therapeutic targets and biomarkers using integrated multi-‘omics’ approaches for dilated and ischemic cardiomyopathies

Integrative Biology ◽

10.1093/intbio/zyab007 ◽

2021 ◽

Author(s):

Austė Kanapeckaitė ◽

Neringa Burokienė

Keyword(s):

Machine Learning ◽

Single Cell ◽

Learning Algorithm ◽

Expression Profiles ◽

Therapeutic Targets ◽

Development Stage ◽

Biological Data ◽

Specific Gene ◽

Tissue Remodelling ◽

Pharmacological Management

Abstract At present, heart failure (HF) treatment only targets the symptoms based on the left ventricle dysfunction severity; however, the lack of systemic ‘omics’ studies and available biological data to uncover the heterogeneous underlying mechanisms signifies the need to shift the analytical paradigm towards network-centric and data mining approaches. This study, for the first time, aimed to investigate how bulk and single cell RNA-sequencing as well as the proteomics analysis of the human heart tissue can be integrated to uncover HF-specific networks and potential therapeutic targets or biomarkers. We also aimed to address the issue of dealing with a limited number of samples and to show how appropriate statistical models, enrichment with other datasets as well as machine learning-guided analysis can aid in such cases. Furthermore, we elucidated specific gene expression profiles using transcriptomic and mined data from public databases. This was achieved using the two-step machine learning algorithm to predict the likelihood of the therapeutic target or biomarker tractability based on a novel scoring system, which has also been introduced in this study. The described methodology could be very useful for the target or biomarker selection and evaluation during the pre-clinical therapeutics development stage as well as disease progression monitoring. In addition, the present study sheds new light into the complex aetiology of HF, differentiating between subtle changes in dilated cardiomyopathies (DCs) and ischemic cardiomyopathies (ICs) on the single cell, proteome and whole transcriptome level, demonstrating that HF might be dependent on the involvement of not only the cardiomyocytes but also on other cell populations. Identified tissue remodelling and inflammatory processes can be beneficial when selecting targeted pharmacological management for DCs or ICs, respectively.

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PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43

Laboratory Investigation ◽

10.1038/s41374-021-00533-5 ◽

2021 ◽

Author(s):

Ting Guo ◽

Chao Gu ◽

Bin Li ◽

Congjian Xu

Keyword(s):

Ovarian Cancer ◽

Gap Junctions ◽

Connexin 43

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Role of FSH and triiodothyronine in Sertoli cell development expressed by formation of connexin 43-based gap junctions

Journal of Experimental Zoology Part A Ecological Genetics and Physiology ◽

10.1002/jez.679 ◽

2011 ◽

Vol 315A (6) ◽

pp. 329-336 ◽

Cited By ~ 10

Author(s):

Katarzyna Marchlewska ◽

Krzysztof Kula ◽

Renata Walczak-Jedrzejowska ◽

Elzbieta Oszukowska ◽

Eliza Filipiak ◽

...

Keyword(s):

Gap Junctions ◽

Sertoli Cell ◽

Connexin 43 ◽

Cell Development

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Cardiac macrophages prevent sudden death during heart stress

Nature Communications ◽

10.1038/s41467-021-22178-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Junichi Sugita ◽

Katsuhito Fujiu ◽

Yukiteru Nakayama ◽

Takumi Matsubara ◽

Jun Matsuda ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Sudden Death ◽

Gap Junctions ◽

Adrenergic Receptor ◽

Cardiac Death ◽

Connexin 43 ◽

Pressure Overload ◽

Impulse Conduction ◽

Cardiac Impulse ◽

Medical Need

AbstractCardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death.

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MO262THE SINGLE-CELL TRANSCRIPTOMICS OF HUMAN IGA NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0020 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Yong Zhong ◽

Xiangcheng Xiao

Keyword(s):

Gene Expression ◽

Single Cell ◽

Signaling Pathways ◽

Iga Nephropathy ◽

Molecular Mechanisms ◽

Mesangial Cells ◽

Therapeutic Targets ◽

Cell Types ◽

Receptor Crosstalk ◽

Overt Proteinuria

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

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TAMI-36. TAMEP ARE BRAIN TUMOR PARENCHYMAL CELLS CONTROLLING NEOPLASTIC ANGIOGENESIS AND PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noab196.820 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi205-vi206

Author(s):

Roland Kälin ◽

Linzhi Cai ◽

Yuping Li ◽

Ines Hellmann ◽

Rainer Glass

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Single Cell ◽

Disease Progression ◽

Progenitor Cell ◽

Local Environment ◽

Lineage Tracing ◽

Immunofluorescence Analysis ◽

Progenitor Cell Population ◽

Parenchymal Cells

Abstract Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor-parenchymal cells may promote specific phases of disease-progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Strikingly, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell-population, by conditional Sox2-knockout, drastically reduced glioblastoma-vascularization and -size. TAMEP manipulation profoundly altered vessel function and strongly attenuated the blood-tumor barrier. Hence, our data indicate TAMEP and their progenitors as new targets for glioblastoma therapy.

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