Systems Biology and Kidney Disease

The kidney is a complex organ responsible for maintaining multiple aspects of homeostasis in the human body. The combination of distinct, yet interrelated, molecular functions across different cell types make the delineation of factors associated with loss or decline in kidney function challenging. Consequently, there has been a paucity of new diagnostic markers and treatment options becoming available to clinicians and patients in managing kidney diseases. A systems biology approach to understanding the kidney leverages recent advances in computational technology and methods to integrate diverse sets of data. It has the potential to unravel the interplay of multiple genes, proteins, and molecular mechanisms that drive key functions in kidney health and disease. The emergence of large, detailed, multilevel biologic and clinical data from national databases, cohort studies, and trials now provide the critical pieces needed for meaningful application of systems biology approaches in nephrology. The purpose of this review is to provide an overview of the current state in the evolution of the field. Recent successes of systems biology to identify targeted therapies linked to mechanistic biomarkers in the kidney are described to emphasize the relevance to clinical care and the outlook for improving outcomes for patients with kidney diseases.

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MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽

10.3390/biom11081074 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1074

Author(s):

Giuseppina Divisato ◽

Silvia Piscitelli ◽

Mariantonietta Elia ◽

Emanuela Cascone ◽

Silvia Parisi

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Development ◽

Special Focus ◽

Self Renewal ◽

Mesenchymal Transition ◽

Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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Filopodyan: An open-source pipeline for the analysis of filopodia

The Journal of Cell Biology ◽

10.1083/jcb.201705113 ◽

2017 ◽

Vol 216 (10) ◽

pp. 3405-3422 ◽

Cited By ~ 14

Author(s):

Vasja Urbančič ◽

Richard Butler ◽

Benjamin Richier ◽

Manuel Peter ◽

Julia Mason ◽

...

Keyword(s):

Molecular Mechanisms ◽

Dynamic Properties ◽

Cell Types ◽

Molecular Heterogeneity ◽

Interactive Editing ◽

Motile Cells ◽

Different Cell Types ◽

Neuronal Growth Cones

Filopodia have important sensory and mechanical roles in motile cells. The recruitment of actin regulators, such as ENA/VASP proteins, to sites of protrusion underlies diverse molecular mechanisms of filopodia formation and extension. We developed Filopodyan (filopodia dynamics analysis) in Fiji and R to measure fluorescence in filopodia and at their tips and bases concurrently with their morphological and dynamic properties. Filopodyan supports high-throughput phenotype characterization as well as detailed interactive editing of filopodia reconstructions through an intuitive graphical user interface. Our highly customizable pipeline is widely applicable, capable of detecting filopodia in four different cell types in vitro and in vivo. We use Filopodyan to quantify the recruitment of ENA and VASP preceding filopodia formation in neuronal growth cones, and uncover a molecular heterogeneity whereby different filopodia display markedly different responses to changes in the accumulation of ENA and VASP fluorescence in their tips over time.

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The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

Cells ◽

10.3390/cells9071711 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1711 ◽

Cited By ~ 1

Author(s):

Conor P. Duffy ◽

Claire E. McCoy

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Disorder ◽

Cell Types ◽

Repair Process ◽

Rna Molecules ◽

Current State ◽

Non Coding Rna ◽

Repair Mechanisms ◽

Different Cell Types

Multiple sclerosis (MS) is an autoimmune disorder characterised by demyelination of central nervous system neurons with subsequent damage, cell death and disability. While mechanisms exist in the CNS to repair this damage, they are disrupted in MS and currently there are no treatments to address this deficit. In recent years, increasing attention has been paid to the influence of the small, non-coding RNA molecules, microRNAs (miRNAs), in autoimmune disorders, including MS. In this review, we examine the role of miRNAs in remyelination in the different cell types that contribute to MS. We focus on key miRNAs that have a central role in mediating the repair process, along with several more that play either secondary or inhibitory roles in one or more aspects. Finally, we consider the current state of miRNAs as therapeutic targets in MS, acknowledging current challenges and potential strategies to overcome them in developing effective novel therapeutics to enhance repair mechanisms in MS.

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ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

ERJ Open Research ◽

10.1183/23120541.00350-2019 ◽

2020 ◽

Vol 6 (1) ◽

pp. 00350-2019

Author(s):

Niki D. Ubags ◽

Jonathan Baker ◽

Agnes Boots ◽

Rita Costa ◽

Natalia El-Merhie ◽

...

Keyword(s):

Lung Disease ◽

Molecular Mechanisms ◽

Respiratory Infections ◽

Function Analysis ◽

Treatment Options ◽

Cell Types ◽

International Congress ◽

European Respiratory Society ◽

Lung Health

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.

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Mapping multicellular programs from single-cell profiles

10.1101/2020.08.11.245472 ◽

2020 ◽

Author(s):

Livnat Jerby-Arnon ◽

Aviv Regev

Keyword(s):

Single Cell ◽

Spatial Data ◽

Spatial Information ◽

Single Cells ◽

Cell Types ◽

Risk Genes ◽

Health And Disease ◽

Different Cell Types ◽

Cellular Components ◽

Acting In Concert

ABSTRACTTissue homeostasis relies on orchestrated multicellular circuits, where interactions between different cell types dynamically balance tissue function. While single-cell genomics identifies tissues’ cellular components, deciphering their coordinated action remains a major challenge. Here, we tackle this problem through a new framework of multicellular programs: combinations of distinct cellular programs in different cell types that are coordinated together in the tissue, thus forming a higher order functional unit at the tissue, rather than only cell, level. We develop the open-access DIALOGUE algorithm to systematically uncover such multi-cellular programs not only from spatial data, but even from tissue dissociated and profiled as single cells, e.g., by single-cell RNA-Seq. Tested on spatial transcriptomes from the mouse hypothalamus, DIALOGUE recovered spatial information, predicted the properties of a cell’s environment only based on its transcriptome, and identified multicellular programs that mark animal behavior. Applied to brain samples and colon biopsies profiled by scRNA-Seq, DIALOGUE identified multicellular configurations that mark Alzheimer’s disease and ulcerative colitis (UC), including a program spanning five cell types that is predictive of response to anti-TNF therapy in UC patients and enriched for UC risk genes from GWAS, each acting in different cell types, but all cells acting in concert. Taken together, our study provides a novel conceptual and methodological framework to unravel multicellular regulation in health and disease.

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Single-cell RNA-Seq Reveals Transcriptional Landscape and Intra-tumor Heterogenicity in Gallbladder Cancer Liver Metastasis Microenvironment

10.21203/rs.3.rs-117830/v1 ◽

2020 ◽

Author(s):

Wenhua You ◽

Xiangyu Li ◽

Peng Wang ◽

Bowen Sha ◽

Yuan Liang ◽

...

Keyword(s):

T Cells ◽

Liver Metastasis ◽

Gallbladder Cancer ◽

Single Cell ◽

Molecular Mechanisms ◽

Cell Types ◽

Malignant Cells ◽

Different Cell Types ◽

High Degree

Abstract Background: Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. Tumor invasion and metastasis contributed to the high mortality of GBC patients. However, molecular mechanisms involved in GBC metastases are still little known. Methods: We performed single-cell RNA sequencing on GBC liver metastasis tissue and analyzed the data based on different cell types.Results: In this study, 8 cell types, including T cells, B cells, malignant cells, fibroblasts, endothelial cells, macrophages, dendritic cells, and mast cells were identified. Malignant cells displayed a high degree of intra-tumor heterogenicity and neutrophils could promote GBC progression in vitro. Besides, cytotoxic CD8+ T cells became exhausted and CD4+ Tregs presented immunosuppressive characteristics. Macrophages played an important role in the tumor microenvironment. We identified three distinct macrophage subsets and emerged M2 polarization. We also found that cancer-associated fibroblasts exhibited heterogeneity and promoted GBC metastasis. Conclusions: In conclusion, our work provided a landscape view at the single-cell level and may clear the way for the therapy of GBC metastases.

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Cellular and molecular mechanisms that regulate mammalian digit tip regeneration

Open Biology ◽

10.1098/rsob.200194 ◽

2020 ◽

Vol 10 (9) ◽

pp. 200194

Author(s):

Mekayla A. Storer ◽

Freda D. Miller

Keyword(s):

Tissue Regeneration ◽

Molecular Mechanisms ◽

Cell Mass ◽

Cell Types ◽

Original Structure ◽

Mammalian Tissue ◽

Blastema Formation ◽

Different Cell Types ◽

Proliferating Cell ◽

Adult Mammal

Digit tip regeneration is one of the few examples of true multi-tissue regeneration in an adult mammal. The key step in this process is the formation of the blastema, a transient proliferating cell mass that generates the different cell types of the digit to replicate the original structure. Failure to form the blastema results in a lack of regeneration and has been postulated to be the reason why mammalian limbs cannot regrow following amputation. Understanding how the blastema forms and functions will help us to determine what is required for mammalian regeneration to occur and will provide insights into potential therapies for mammalian tissue regeneration and repair. This review summarizes the cellular and molecular mechanisms that influence murine blastema formation and govern digit tip regeneration.

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Brain-Derived Neurotrophic Factor in Central Nervous System Myelination: A New Mechanism to Promote Myelin Plasticity and Repair

International Journal of Molecular Sciences ◽

10.3390/ijms19124131 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4131 ◽

Cited By ~ 21

Author(s):

Jessica Fletcher ◽

Simon Murray ◽

Junhua Xiao

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neural Development ◽

Neurotrophic Factor ◽

Molecular Mechanisms ◽

Demyelinating Disease ◽

Cell Types ◽

Brain Derived Neurotrophic Factor ◽

Future Research ◽

Health And Disease

Brain-derived neurotrophic factor (BDNF) plays vitally important roles in neural development and plasticity in both health and disease. Recent studies using mutant mice to selectively manipulate BDNF signalling in desired cell types, in combination with animal models of demyelinating disease, have demonstrated that BDNF not only potentiates normal central nervous system myelination in development but enhances recovery after myelin injury. However, the precise mechanisms by which BDNF enhances myelination in development and repair are unclear. Here, we review some of the recent progress made in understanding the influence BDNF exerts upon the myelinating process during development and after injury, and discuss the cellular and molecular mechanisms underlying its effects. In doing so, we raise new questions for future research.

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Dynamin Superfamily at Pre- and Postsynapses: Master Regulators of Synaptic Transmission and Plasticity in Health and Disease

The Neuroscientist ◽

10.1177/1073858420974313 ◽

2020 ◽

pp. 107385842097431

Author(s):

Jorge Arriagada-Diaz ◽

Lorena Prado-Vega ◽

Ana M. Cárdenas Díaz ◽

Alvaro O. Ardiles ◽

Arlek M. Gonzalez-Jamett

Keyword(s):

Synaptic Transmission ◽

Neurological Disorders ◽

Synaptic Vesicles ◽

Cell Types ◽

Master Regulators ◽

Vesicle Recycling ◽

Cytoskeleton Remodeling ◽

The Central Nervous System ◽

Health And Disease ◽

Different Cell Types

Dynamin superfamily proteins (DSPs) comprise a large group of GTP-ases that orchestrate membrane fusion and fission, and cytoskeleton remodeling in different cell-types. At the central nervous system, they regulate synaptic vesicle recycling and signaling-receptor turnover, allowing the maintenance of synaptic transmission. In the presynapses, these GTP-ases control the recycling of synaptic vesicles influencing the size of the ready-releasable pool and the release of neurotransmitters from nerve terminals, whereas in the postsynapses, they are involved in AMPA-receptor trafficking to and from postsynaptic densities, supporting excitatory synaptic plasticity, and consequently learning and memory formation. In agreement with these relevant roles, an important number of neurological disorders are associated with mutations and/or dysfunction of these GTP-ases. Along the present review we discuss the importance of DSPs at synapses and their implication in different neuropathological contexts.

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