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Journal of Controlled Release :... May 2018Paracrine cell communication plays a pivotal role for signal exchange between proximal cells in vivo. However, this localized, gradient type release of mediators at very... (Review)
Review
Paracrine cell communication plays a pivotal role for signal exchange between proximal cells in vivo. However, this localized, gradient type release of mediators at very low concentrations (pg/ml), relevant during physiological and pathological processes, is rarely reflected within in vitro approaches. This review gives an overview on state-of-the-art approaches, which transfer the paracrine cell-to-cell communication into in vitro cell culture model setups. The traditional methods like trans-well assays and more advanced microfluidic approaches are included. The review focusses on systems for localized release, mostly based on microparticles, which tightly mimic the paracrine interaction between single cells in 3D microenvironments. Approaches based on single microparticles, with the main focus on affinity-controlled storage and release of cytokines, are reviewed and their importance for understanding paracrine communication is highlighted. Various methods to study the cytokine release and their advantages and disadvantages are discussed. Basic principles of the release characteristics, like diffusion mechanisms, are quantitatively described, including the formation of resulting gradients around the local sources. In vitro cell experiments using such localized microparticle release systems in approaches to increase understanding of stem cell behavior within their niches and regulation of wound healing are highlighted as examples of successful localized release systems for mimicking paracrine cell communication.
Topics: Animals; Cell Culture Techniques; Cytokines; Humans; Microfluidics; Microspheres; Paracrine Communication; Signal Transduction; Stem Cells; Wound Healing
PubMed: 29601931
DOI: 10.1016/j.jconrel.2018.03.028 -
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 -
Molecular and Cellular Endocrinology Jun 2005The development and function of vertebrate ovary are primarily controlled by the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the... (Review)
Review
The development and function of vertebrate ovary are primarily controlled by the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the pituitary. However, most of the activities of FSH and LH are mediated or modulated by a variety of locally produced factors that form an intimate regulatory network within and between the follicles. As a top vertebrate model for genetic and developmental studies, the zebrafish has caught tremendous attention in the past two decades; however, its utility has quickly been extended to other areas including physiology. In the past few years, a variety of peptide growth factors have been identified and characterized in the zebrafish ovary including activin and epidermal growth factor (EGF), and lines of evidence point to the existence of an ovarian network of communication involving these factors. This article provides the state of the art of zebrafish as a model for analyzing ovarian development and its regulation.
Topics: Animals; Epidermal Growth Factor; Female; Oocytes; Ovarian Follicle; Paracrine Communication; Zebrafish
PubMed: 15921848
DOI: 10.1016/j.mce.2005.03.012 -
ELife Oct 2015Population averaging due to paracrine communication can arbitrarily reduce cellular response variability. Yet, variability is ubiquitously observed, suggesting limits to...
Population averaging due to paracrine communication can arbitrarily reduce cellular response variability. Yet, variability is ubiquitously observed, suggesting limits to paracrine averaging. It remains unclear whether and how biological systems may be affected by such limits of paracrine signaling. To address this question, we quantify the signal and noise of Ca(2+) and ERK spatial gradients in response to an in vitro wound within a novel microfluidics-based device. We find that while paracrine communication reduces gradient noise, it also reduces the gradient magnitude. Accordingly we predict the existence of a maximum gradient signal to noise ratio. Direct in vitro measurement of paracrine communication verifies these predictions and reveals that cells utilize optimal levels of paracrine signaling to maximize the accuracy of gradient-based positional information. Our results demonstrate the limits of population averaging and show the inherent tradeoff in utilizing paracrine communication to regulate cellular response fidelity.
Topics: Calcium Signaling; Cell Line; Humans; Lab-On-A-Chip Devices; MAP Kinase Signaling System; Models, Biological; Paracrine Communication; Signal Transduction; Wounds and Injuries
PubMed: 26448485
DOI: 10.7554/eLife.09652 -
Vitamins and Hormones 2019Aldosterone secretion by the zona glomerulosa of the adrenal cortex is controlled by circulating factors including the renin angiotensin system (RAS) and potassium.... (Review)
Review
Aldosterone secretion by the zona glomerulosa of the adrenal cortex is controlled by circulating factors including the renin angiotensin system (RAS) and potassium. Mineralocorticoid production is also regulated through an autocrine/paracrine mechanism by a wide variety of bioactive signals released in the vicinity of adrenocortical cells by chromaffin cells, nerve endings, cells of the immune system, endothelial cells and adipocytes. These regulatory factors include conventional neurotransmitters and neuropeptides. Their physiological role in the control of aldosterone secretion is not fully understood, but it is likely that they participate in the RAS-independent regulation of zona glomerulosa cells. Interestingly, recent observations indicate that autocrine/paracrine processes are involved in the pathophysiology of primary aldosteronism. The intraadrenal regulatory systems observed in aldosterone-producing adenomas (APA), although globally similar to those occurring in the normal adrenal gland, harbor alterations at different levels, which tend to strengthen the potency of paracrine signals to activate aldosterone secretion. Enhancement of paracrine stimulatory tone may participate to APA expansion and aldosterone hypersecretion together with somatic mutations of driver genes which activate the calcium signaling pathway and subsequently aldosterone synthase expression. Intraadrenal regulatory mechanisms represent thus promising pharmacological targets for the treatment of primary aldosteronism.
Topics: Adrenal Glands; Aldosterone; Humans; Paracrine Communication; Signal Transduction
PubMed: 30678861
DOI: 10.1016/bs.vh.2018.10.001 -
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 -
Molecular and Cellular Endocrinology Jun 2012Steroid hormones coordinate and control the development and function of many organs and are implicated in many pathological processes. Progesterone signaling, in... (Review)
Review
Steroid hormones coordinate and control the development and function of many organs and are implicated in many pathological processes. Progesterone signaling, in particular, is essential for several important female reproductive functions. Physiological effects of progesterone are mediated by its cognate receptor, expressed in a subset of cells in target tissues. Experimental evidence has accumulated that progesterone acts through both cell intrinsic as well as paracrine signaling mechanisms. By relegating the hormonal stimulus to paracrine signaling cascades the systemic signal gets amplified locally and signaling reaches different cell types that are devoid of hormone receptors. Interestingly, distinct biological responses to progesterone in different target tissues rely on several tissue-specific and some common paracrine factors that coordinate biological responses in different cell types. Evidence is forthcoming that the intercellular signaling pathways that control development and physiological functions are important in tumorigenesis.
Topics: Animals; Female; Humans; Paracrine Communication; Progesterone; Progestins; Signal Transduction
PubMed: 21945477
DOI: 10.1016/j.mce.2011.09.018 -
Cardiovascular Research May 2014Cardiac hypertrophy and fibrosis are two closely related adaptive response mechanisms of the myocardium to mechanical, metabolic, and genetic stress that finally... (Review)
Review
Cardiac hypertrophy and fibrosis are two closely related adaptive response mechanisms of the myocardium to mechanical, metabolic, and genetic stress that finally contribute to the development of heart failure (HF). This relation is based on a dynamic interplay between many cell types including cardiomyocytes and fibroblasts during disease progression. Both cell types secrete a variety of growth factors, cytokines, and hormones that influence hypertrophic cardiomyocyte growth and fibrotic fibroblast activation in a paracrine and autocrine manner. It has become evident that, aside proteinous signals, microRNAs (miRNAs) and possible other RNA species such as long non-coding RNAs are potential players in such a cell-to-cell communication. By directly acting as paracrine signals or by modulating downstream intercellular signalling mediators, miRNAs can act as moderators of the intercellular crosstalk. These small regulators can potentially be secreted in a 'mircrine' fashion, so that miRNAs can be assumed as the message itself. This review will summarize the recent findings about the paracrine crosstalk between cardiac fibroblasts and cardiomyocytes and addresses how miRNAs may be involved in this interplay. It also highlights therapeutic strategies targeting factors of pathological communication for the treatment of HF.
Topics: Animals; Cardiomegaly; Fibrosis; Heart Failure; Humans; MicroRNAs; Myocytes, Cardiac; Paracrine Communication
PubMed: 24562768
DOI: 10.1093/cvr/cvu039 -
European Journal of Heart Failure Nov 2015Cell-cell or inter-organ communication allows the exchange of information and messages, which is essential for the coordination of cell/organ functions and the... (Review)
Review
Cell-cell or inter-organ communication allows the exchange of information and messages, which is essential for the coordination of cell/organ functions and the maintenance of homeostasis. It has become evident that dynamic interactions of different cell types play a major role in the heart, in particular during the progression of heart failure, a leading cause of mortality worldwide. Heart failure is associated with compensatory structural and functional changes mostly in cardiomyocytes and cardiac fibroblasts, which finally lead to cardiomyocyte hypertrophy and fibrosis. Intercellular communication within the heart is mediated mostly via direct cell-cell interaction or the release of paracrine signalling mediators such as cytokines and chemokines. However, recent studies have focused on the exchange of genetic information via the packaging into vesicles as well as the crosstalk of lipids and other paracrine molecules within the heart and distant organs, such as kidney and adipose tissue, which might all contribute to the pathogenesis of heart failure. In this review, we discuss emerging communication networks and respective underlying mechanisms which could be involved in cardiovascular disease conditions and further emphasize promising therapeutic targets for drug development.
Topics: Disease Progression; Heart Failure; Humans; Intercellular Signaling Peptides and Proteins; MicroRNAs; Myocytes, Cardiac; Myofibroblasts; Paracrine Communication
PubMed: 26398116
DOI: 10.1002/ejhf.399 -
Current Opinion in Genetics &... Feb 2021Exosomes are secreted small extracellular vesicles (EVs) packaged with diverse biological cargo. They mediate complex intercellular communications among cells in... (Review)
Review
Exosomes are secreted small extracellular vesicles (EVs) packaged with diverse biological cargo. They mediate complex intercellular communications among cells in maintenance of normal physiology or to trigger profound disease progression. Increasing numbers of studies have identified exosome-mediated functions contributing to cancer progression, including roles in paracrine cell-to-cell communication, stromal reprogramming, angiogenesis, and immune responses. Despite the growing body of knowledge, the specific role of exosomes in mediating pre-cancerous conditions is not fully understood and their ability to transform a healthy cell is still controversial. Here we review recent studies describing functions attributed to exosomes in different stages of carcinogenesis. We also explore how exosomes ultimately contribute to the progression of a primary tumor to metastatic disease.
Topics: Carcinogenesis; Cell Communication; Exosomes; Extracellular Vesicles; Humans; Neoplasms; Paracrine Communication; Tumor Microenvironment
PubMed: 33477017
DOI: 10.1016/j.gde.2020.12.018