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Stem Cell Research & Therapy Jan 2021Stem cells can be used for regenerative medicine and as treatments for disease. The application of tissue engineering-related transplantation, stem cells, and local... (Review)
Review
Stem cells can be used for regenerative medicine and as treatments for disease. The application of tissue engineering-related transplantation, stem cells, and local changes in the microenvironment is expected to solve major medical problems. Currently, most studies focus on tissue repair and regeneration, and mesenchymal stem cells (MSCs) are among the most common research topics. MSCs are applicable as seed cells, and they represent one of the current hot topics in regenerative medicine research. However, due to storage limitations and because cell senescence occurs during in vitro expansion, their clinical application is challenging. Exosomes, which are secreted by MSCs through paracrine signalling, not only have the same effects as MSCs, but they also have the advantages of targeted delivery, low immunogenicity, and high repairability. This article reviews the acquisition methods, characteristics, biological functions, and clinical applications of exosomes.
Topics: Exosomes; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Paracrine Communication; Regenerative Medicine; Tissue Engineering
PubMed: 33468232
DOI: 10.1186/s13287-021-02138-7 -
Nature Cell Biology Aug 2013Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated...
Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
Topics: Animals; Cell Line, Tumor; Cellular Senescence; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Inflammasomes; Interleukin-1; Mice; Models, Animal; Paracrine Communication; Protein Binding; Signal Transduction; Transforming Growth Factor beta1
PubMed: 23770676
DOI: 10.1038/ncb2784 -
Critical Care (London, England) Apr 2020Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a... (Review)
Review
Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a bidirectional interaction between the brain and the heart. In support of this theory, AIS patients are extremely vulnerable to severe cardiac complications. Sympathetic hyperactivity, hypothalamic-pituitary-adrenal axis, the immune and inflammatory responses, and gut dysbiosis have been identified as the main pathological mechanisms involved in brain-heart axis dysregulation after AIS. Moreover, evidence has confirmed that the main causes of mortality after AIS include heart attack, congestive heart failure, hemodynamic instability, left ventricular systolic dysfunction, diastolic dysfunction, arrhythmias, electrocardiographic anomalies, and cardiac arrest, all of which are more or less associated with poor outcomes and death. Therefore, intensive care unit admission with continuous hemodynamic monitoring has been proposed as the standard of care for AIS patients at high risk for developing cardiovascular complications. Recent trials have also investigated possible therapies to prevent secondary cardiovascular accidents after AIS. Labetalol, nicardipine, and nitroprusside have been recommended for the control of hypertension during AIS, while beta blockers have been suggested both for preventing chronic remodeling and for treating arrhythmias. Additionally, electrolytic imbalances should be considered, and abnormal rhythms must be treated. Nevertheless, therapeutic targets remain challenging, and further investigations might be essential to complete this complex multi-disciplinary puzzle. This review aims to highlight the pathophysiological mechanisms implicated in the interaction between the brain and the heart and their clinical consequences in AIS patients, as well as to provide specific recommendations for cardiovascular management after AIS.
Topics: Brain; Heart; Humans; Ischemia; Paracrine Communication; Stroke
PubMed: 32317013
DOI: 10.1186/s13054-020-02885-8 -
Circulation Jun 2021Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts...
BACKGROUND
Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts at the epicardium and advances transmurally. Mutations in genes encoding desmosome proteins, including DSP (desmoplakin), are major causes of ACM.
METHODS
To delineate contributions of the epicardium to the pathogenesis of ACM, the allele was conditionally deleted in the epicardial cells in mice upon expression of tamoxifen-inducible Cre from the locus. Wild type (WT) and were crossed to Rosa26 (R26) dual reporter mice to tag the epicardial-derived cells with the EGFP (enhanced green fluorescent protein) reporter protein. Tagged epicardial-derived cells from adult :R26 and : R26 mouse hearts were isolated by fluorescence-activated cell staining and sequenced by single-cell RNA sequencing.
RESULTS
WT1 (Wilms tumor 1) expression was progressively restricted postnatally and was exclusive to the epicardium by postnatal day 21. Expression of was reduced in the epicardial cells but not in cardiac myocytes in the mice. The mice exhibited premature death, cardiac dysfunction, arrhythmias, myocardial fibro-adipogenesis, and apoptosis. Single-cell RNA sequencing of ≈18 000 EGFP-tagged epicardial-derived cells identified genotype-independent clusters of endothelial cells, fibroblasts, epithelial cells, and a very small cluster of cardiac myocytes, which were confirmed on coimmunofluorescence staining of the myocardial sections. Differentially expressed genes between the paired clusters in the 2 genotypes predicted activation of the inflammatory and mitotic pathways-including the TGFβ1 (transforming growth factor β1) and fibroblast growth factors-in the epicardial-derived fibroblast and epithelial clusters, but predicted their suppression in the endothelial cell cluster. The findings were corroborated by analysis of gene expression in the pooled RNA-sequencing data, which identified predominant dysregulation of genes involved in epithelial-mesenchymal transition, and dysregulation of 146 genes encoding the secreted proteins (secretome), including genes in the TGFβ1 pathway. Activation of the TGFβ1 and its colocalization with fibrosis in the :R26 mouse heart was validated by complementary methods.
CONCLUSIONS
Epicardial-derived cardiac fibroblasts and epithelial cells express paracrine factors, including TGFβ1 and fibroblast growth factors, which mediate epithelial-mesenchymal transition, and contribute to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of ACM. The findings uncover contributions of the epicardial-derived cells to the pathogenesis of ACM.
Topics: Animals; Cardiomyopathies; Disease Models, Animal; Humans; Mice; Paracrine Communication; Pericardium; Sequence Analysis, RNA; Single-Cell Analysis; Survival Analysis
PubMed: 33726497
DOI: 10.1161/CIRCULATIONAHA.120.052928 -
The Journal of Experimental Medicine Feb 2021Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages,...
Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN-mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.
Topics: Animals; Autocrine Communication; CRISPR-Cas Systems; Cell Death; Cell Line; HEK293 Cells; Humans; Interferon Type I; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Paracrine Communication; RAW 264.7 Cells; Rifampin; Signal Transduction; Tuberculosis
PubMed: 33125053
DOI: 10.1084/jem.20200887 -
Cellular and Molecular Gastroenterology... 2019Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the... (Review)
Review
Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the gut lumen. Food signals stimulate the release of hormones into the paracellular space where they either act locally or are taken up into the blood and circulate to distant organs. It recently was recognized that many EECs possess basal processes known as neuropods that not only contain hormones but also connect to nerves. This review describes how neuropods contribute to EEC function beyond typical hormonal actions. For example, gastrointestinal hormones not only act on distant organs, but, through neuropods, some act locally to stimulate other mucosal cells such as intestinal stem cells, enterocytes, or other EECs. With the recent discovery that EECs communicate directly with enteric nerves, EECs not only have the ability to sense food and bacteria in the gastrointestinal tract, but can communicate these signals directly to the nervous system.
Topics: Animals; Cell Communication; Enteroendocrine Cells; Humans; Models, Biological; Neurons; Paracrine Communication; Signal Transduction
PubMed: 30710726
DOI: 10.1016/j.jcmgh.2019.01.006 -
Journal of Experimental & Clinical... Feb 2022Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis....
BACKGROUND
Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.
METHODS
To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08-2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.
RESULTS
SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.
CONCLUSIONS
PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a "nerve-repair like effect", induce a high level of autophagy of cancer cells, provide a "beacon" for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.
Topics: Adenocarcinoma; Animals; Autophagy; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Female; Humans; Mice; Neoplasm Invasiveness; Nerve Growth Factor; Paracrine Communication; Rats; Schwann Cells; Transfection; Tumor Microenvironment
PubMed: 35109895
DOI: 10.1186/s13046-021-02198-w -
Current Opinion in Pharmacology Jun 2017Skeletal muscle cells are highly abundant and metabolically active and are known to 'communicate' their energy demands to other organs through active secretion.... (Review)
Review
Skeletal muscle cells are highly abundant and metabolically active and are known to 'communicate' their energy demands to other organs through active secretion. Muscle-derived secretory proteins include a variety of cytokines and peptides collectively referred to as 'myokines' that exert autocrine, paracrine or endocrine effects. Analyses of the skeletal muscle secretome revealed that numerous myokines are secreted in response to contraction or strength training, and that these factors not only regulate energy demand but also contribute to the broad beneficial effects of exercise on cardiovascular, metabolic, and mental health. Herein we review recent studies on the myokines that regulate muscle function and those that mediate cross talk between skeletal muscle and other organs including adipose tissue, liver, pancreas, the cardiovascular system, brain, bones, and skin.
Topics: Adipogenesis; Animals; Brain; Cardiovascular System; Humans; Muscle, Skeletal; Osteogenesis; Paracrine Communication; Skin
PubMed: 28605657
DOI: 10.1016/j.coph.2017.05.005 -
The Journal of Steroid Biochemistry and... Feb 2020The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such... (Review)
Review
The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO. This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5α-dihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.
Topics: Humans; Intracellular Space; Male; Paracrine Communication; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Steroids; Tumor Microenvironment
PubMed: 31614208
DOI: 10.1016/j.jsbmb.2019.105499 -
Expert Review of Cardiovascular Therapy 2016Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen... (Review)
Review
Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen fibrillogenesis with scar tissue formation at sites of repair irrespective of the etiologic origins of injury or tissue involved. MyoFb can persist long after healing is complete, where their ongoing turnover of collagen accounts for a progressive structural remodeling of an organ (a.k.a. fibrosis, sclerosis or cirrhosis). Such persistent metabolic activity is derived from a secretome consisting of requisite components in the de novo generation of angiotensin (Ang) II. Autocrine and paracrine signaling induced by tissue AngII is expressed via AT1 receptor ligand binding to respectively promote: i) regulation of myoFb collagen synthesis via the fibrogenic cytokine TGF-β1-Smad pathway; and ii) dedifferentiation and protein degradation of atrophic myocytes immobilized and ensnared by fibrillar collagen at sites of scarring. Several cardioprotective strategies in the prevention of fibrosis and involving myofibroblasts are considered. They include: inducing myoFb apoptosis through inactivation of antiapoptotic proteins; AT1 receptor antagonist to interfere with auto-/paracrine myoFb signaling or to induce counterregulatory expression of ACE2; and attacking the AngII-AT1R-TGF-β1-Smad pathway by antibody or the use of triplex-forming oligonucleotides.
Topics: Angiotensin II; Collagen; Fibroblasts; Fibrosis; Humans; Myofibroblasts; Paracrine Communication; Wound Healing
PubMed: 26818589
DOI: 10.1586/14779072.2016.1147348