-
Endocrine Reviews Aug 2020Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes,... (Review)
Review
Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases, and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine, or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with, for example, cancer, diabetes, or neurodegenerative diseases.
Topics: Brain; Cytokines; Diabetes Mellitus; Exercise; Humans; Muscle Cells; Muscle, Skeletal; Neoplasms; Neurodegenerative Diseases
PubMed: 32393961
DOI: 10.1210/endrev/bnaa016 -
International Journal of Molecular... Jan 2023Exosomes are a subtype of membrane-contained vesicles 40-200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA,... (Review)
Review
Exosomes are a subtype of membrane-contained vesicles 40-200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA, miRNA, lncRNA, and DNA, exosomes are able to perform such vital functions as maintaining cellular homeostasis, removing cellular debris, and facilitating intercellular and interorgan communication. Exosomes travel in all body fluids and deliver their molecular messages in autocrine, paracrine as well as endocrine manners. In recent years, there has been an increased interest in studying exosomes as diagnostic markers and therapeutic targets, since in many disease conditions this machinery becomes dysregulated or hijacked by pathological processes. Additionally, delivery of exosomes and exosomal miRNA has already been shown to improve systemic metabolism and inhibit progression of cancer development in mice. However, the subcellular machinery of exosomes, including their biogenesis, release and uptake, remains largely unknown. This review will bring molecular details of these processes up to date with the goal of expanding the knowledge basis for designing impactful exosome experiments in the future.
Topics: Animals; Mice; Exosomes; MicroRNAs; Biological Transport
PubMed: 36674857
DOI: 10.3390/ijms24021337 -
International Journal of Molecular... Jun 2021Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the... (Review)
Review
Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.
Topics: Animals; Autocrine Communication; Biological Transport; Cation Transport Proteins; Disease Susceptibility; Hepcidins; Homeostasis; Humans; Iron; Ligands; Metabolic Networks and Pathways; Paracrine Communication; Protein Binding; Signal Transduction; Tissue Distribution
PubMed: 34204327
DOI: 10.3390/ijms22126493 -
Cardiovascular Research Apr 2021Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct... (Review)
Review
Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies.
Topics: Angiogenesis Inducing Agents; Angiogenic Proteins; Animals; Autocrine Communication; Cell Lineage; Cell Movement; Cell Proliferation; Endothelial Progenitor Cells; Humans; Inflammation Mediators; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Paracrine Communication; Phenotype; Recovery of Function; Regeneration; Signal Transduction
PubMed: 33063086
DOI: 10.1093/cvr/cvaa287 -
International Journal of Molecular... Oct 2020Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the... (Review)
Review
Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal vascular disorders, such as retinopathy of prematurity, retinal vein occlusion, and diabetic retinopathy. Understanding the cellular and molecular mechanisms of pericyte-endothelial interaction and perturbation can facilitate the design of therapeutic intervention for the prevention and treatment of retinal vascular disorders. Pericyte-endothelial interactions are indispensable for the integrity and functionality of retinal neurovascular unit (NVU), including vascular cells, retinal neurons, and glial cells. The essential autocrine and paracrine signaling pathways, such as Vascular endothelial growth factor (VEGF), Platelet-derived growth factor subunit B (PDGFB), Notch, Angipointein, Norrin, and Transforming growth factor-beta (TGF-β), have been well characterized for the regulation of pericyte-endothelial interactions in the neo-vessel formation processes (vasculogenesis and angiogenesis) during embryonic development. They also play a vital role in stabilizing and remodeling mature vasculature under pathological conditions. Awry signals, aberrant metabolisms, and pathological conditions, such as oxidative stress and inflammation, can disrupt the communication between pericytes and endothelial cells, thereby resulting in the breakdown of the blood-retinal barrier (BRB) and other microangiopathies. The emerging evidence supports extracellular exosomes' roles in the (mis)communications between the two cell types. This review summarizes the essential knowledge and updates about new advancements in pericyte-EC interaction and communication, emphasizing the retinal microvasculature.
Topics: Animals; Blood-Retinal Barrier; Endothelial Cells; Exosomes; Humans; Microvessels; Models, Animal; Neovascularization, Physiologic; Pericytes; Retina; Retinal Diseases; Retinal Vessels; Signal Transduction
PubMed: 33049983
DOI: 10.3390/ijms21197413 -
Frontiers in Immunology 2023Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T... (Review)
Review
Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T cells accumulate, is a key factor in AA. However, the exact functional mechanism remains unclear. Therefore, AA treatment has poor efficacy maintenance and high relapse rate after drug withdrawal. Recent studies show that immune-related cells and molecules affect AA. These cells communicate through autocrine and paracrine signals. Various cytokines, chemokines and growth factors mediate this crosstalk. In addition, adipose-derived stem cells (ADSCs), gut microbiota, hair follicle melanocytes, non-coding RNAs and specific regulatory factors have crucial roles in intercellular communication without a clear cause, suggesting potential new targets for AA therapy. This review discusses the latest research on the possible pathogenesis and therapeutic targets of AA.
Topics: Humans; Alopecia Areata; CD8-Positive T-Lymphocytes; Cytokines; Autoimmunity
PubMed: 37153617
DOI: 10.3389/fimmu.2023.1148359 -
Hepatology (Baltimore, Md.) Jan 2021Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense... (Review)
Review
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.
Topics: Bile Duct Neoplasms; Cancer-Associated Fibroblasts; Cholangiocarcinoma; Disease Progression; Extracellular Vesicles; Humans; Lymphocytes, Tumor-Infiltrating; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 32500550
DOI: 10.1002/hep.31410 -
Nature Sep 2019A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster...
A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Disease Progression; Glioma; Humans; Mice; Microscopy, Electron, Transmission; Neurons; Receptors, AMPA; Synapses
PubMed: 31534219
DOI: 10.1038/s41586-019-1564-x -
Science Translational Medicine Jan 2023Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in...
Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3-neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.
Topics: Humans; Mice; Animals; Non-alcoholic Fatty Liver Disease; Hepatic Stellate Cells; Autocrine Communication; Fibrosis; Liver Cirrhosis; Liver
PubMed: 36599008
DOI: 10.1126/scitranslmed.add3949 -
Science (New York, N.Y.) Mar 2023Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways...
Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.
Topics: Astrocytes; Genetic Testing; High-Throughput Screening Assays; Microfluidic Analytical Techniques; Microglia; Amphiregulin; Autocrine Communication; Gene Expression; Humans
PubMed: 36893254
DOI: 10.1126/science.abq4822