scholarly journals Lipopolysaccharide Stimulates p38-dependent Induction of Antiviral Genes in Neutrophils Independently of Paracrine Factors

2003 ◽  
Vol 278 (18) ◽  
pp. 15693-15701 ◽  
Author(s):  
Kenneth C. Malcolm ◽  
G. Scott Worthen
Keyword(s):  
Paracrine Factors ◽  
Antiviral Genes

scholarly journals Single-cell RNA sequencing of human fetal epicardium reveals novel markers and regulators of EMT

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T.J Streef ◽  
T Van Herwaarden ◽  
A.M Smits ◽  
M.J Goumans
Keyword(s):  
Cell Culture ◽  
Single Cell ◽  
Rna Sequencing ◽  
Public Institution ◽  
Funding Source ◽  
Injury Response ◽  
Post Injury ◽  
Paracrine Factors ◽  
Adult Heart ◽  
Single Cell Rna Sequencing

Abstract Background The heart is covered by the epicardium, consisting of epithelial cells and a mesenchymal layer. The epicardium has been shown to be essential during cardiac development by contributing cells through epithelial-to-mesenchymal transition (EMT) and the secretion of paracrine factors. In the adult, the epicardium conveys a cardioprotective response after myocardial infarction, albeit suboptimal compared to the epicardial contribution to heart development. Although the developing epicardium has been characterised in mice and zebrafish, knowledge on the human fetal epicardium derives mostly from cell culture models. Therefore, direct analysis of the human fetal epicardium is vital as it provides new insights into the cellular and biochemical interactions within the developing heart, which can potentially contribute to enhancing the post-injury response. Aim To study the human fetal epicardium using single-cell RNA sequencing (scRNA seq) in order to determine its cellular compositionThe data are further explored to e.g.identify regulators of epicardial EMT. Methods Epicardial layers were isolated from four fetal human hearts (14–15 weeks gestation, obtained under informed consent and according to local ethical approval). Tissue was digested, and single live cells were sorted into 384-wells plates and sequenced. Data analysis was performed using R-packages RaceID3 and StemID2. Findings were validated using qPCR and immunohistochemistry. Results Analysis of 2024 cells reveals a clear clustering of the epicardial epithelium and the mesenchymal population. Importantly, we found that “classical” markers, such as Wilms' Tumor 1 and T-box transcription factor 18, are not specific enough to reliably identify the epicardium, but our analysis has provided markers that do allow for robust identification of the epicardium. Additionally, we were able to identify epicardial subpopulations based on their expression profile, and we are currently investigating these using immunohistochemistry in human fetal and adult heart tissue sections. To establish the regulation of epicardial activation we are focussing on the process of EMT within our dataset using RaceID2. From our analysis, several regulators of epicardial EMT are proposed that will be followed up on in vitro. Conclusions We identify various novel markers of the fetal epithelial epicardium, as well as characterizing markers of the mesenchymal layer. We also identified novel factors involved in epicardial EMT, and these are currently being validated in our cell-culture model. These data can provide new insights into the post-injury response in the adult heart. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Dutch Heart Foundation

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

scholarly journals Use of paracrine factors from stem cells to treat local radiation burns in rats

2018 ◽  
Vol Volume 11 ◽  
pp. 69-76
Author(s):  
A Temnov ◽  
T Astrelina ◽  
Konstantin Rogov ◽  
B Moroz ◽  
Vladimir Lebedev ◽  
...  
Keyword(s):  
Stem Cells ◽  
Paracrine Factors ◽  
Local Radiation

scholarly journals Microrna-130a Downregulates HCV Replication through an atg5-Dependent Autophagy Pathway

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 338 ◽  
Author(s):  
Xiaoqiong Duan ◽  
Xiao Liu ◽  
Wenting Li ◽  
Jacinta A. Holmes ◽  
Annie J. Kruger ◽  
...  
Keyword(s):  
Immune Responses ◽  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Pyruvate Metabolism ◽  
Host Immune Responses ◽  
Qrt Pcr ◽  
Antiviral Genes ◽  
Autophagy Pathway ◽  
Host Antiviral Response

We previously identified that miR-130a downregulates HCV replication through two independent pathways: restoration of host immune responses and regulation of pyruvate metabolism. In this study, we further sought to explore host antiviral target genes regulated by miR-130a. We performed a RT² Profiler™ PCR array to identify the host antiviral genes regulated by miR-130a. The putative binding sites between miR-130a and its downregulated genes were predicted by miRanda. miR-130a and predicted target genes were over-expressed or knocked down by siRNA or CRISPR/Cas9 gRNA. Selected gene mRNAs and their proteins, together with HCV replication in JFH1 HCV-infected Huh7.5.1 cells were monitored by qRT-PCR and Western blot. We identified 32 genes that were significantly differentially expressed more than 1.5-fold following miR-130a overexpression, 28 of which were upregulated and 4 downregulated. We found that ATG5, a target gene for miR-130a, significantly upregulated HCV replication and downregulated interferon stimulated gene expression. miR-130a downregulated ATG5 expression and its conjugation complex with ATG12. ATG5 and ATG5-ATG12 complex affected interferon stimulated gene (ISG) such as MX1 and OAS3 expression and subsequently HCV replication. We concluded that miR-130a regulates host antiviral response and HCV replication through targeting ATG5 via the ATG5-dependent autophagy pathway.

Role of physical forces in compensatory growth of the lung

1989 ◽  
Vol 257 (4) ◽  
pp. L179-L189 ◽  
Author(s):  
D. E. Rannels
Keyword(s):  
Cell Shape ◽  
Compensatory Growth ◽  
Normal Lung ◽  
Physical Factors ◽  
Physical Force ◽  
Isolated Cells ◽  
Paracrine Factors ◽  
Extracellular Matrix Components ◽  
Hormonal Modulation ◽  
Physical Forces

In many species, partial resection of the lung leads to rapid compensatory growth of the remaining tissue to restore normal lung mass and function. The response to partial pneumonectomy is closely controlled; both its rate and nature are subject to hormonal modulation. Physical factors, particularly distortion of the lung by altered inflation, are likely involved in regulation of the response, although the details of the regulatory mechanisms are not understood. In a number of tissues including the lung, application of external physical force leads to both acute and long-term changes in metabolism. In some cases these include cell growth and division, along with increased production of extracellular matrix components. Similar responses have been described after application of stress to isolated cells in culture. Independent lines of investigation have defined dramatic influences of cell shape on growth, differentiation, and metabolism, but stress-strain relationships at the cellular or subcellular levels are poorly defined. The mechanisms by which changes in cell shape are transduced to intracellular signals likely depend on receptor-mediated interactions with the cytoskeleton, but strain-associated transduction pathways may involve stretch-sensitive ion channels, G protein-dependent reactions, the action of locally produced autocrine or paracrine factors, or a combination of these factors. These observations suggest a general model of the response to pneumonectomy that may be used to formulate specific hypotheses as a basis for future investigations. This approach will provide insight into the mechanisms by which physical forces influence growth and metabolism in the lung and other tissues.

scholarly journals Human adventitial pericytes secrete bioactive factors exerting distinct biological effects on cardiac cells: hints for cardiac repair

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Avolio ◽  
G Mangialardi ◽  
S Slater ◽  
V.V Alvino ◽  
K Heesom ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Stromal Cells ◽  
Synthetic Peptides ◽  
Biological Effect ◽  
Biological Effects ◽  
Biological Properties ◽  
Cardiac Cells ◽  
Mass Spectrometry Analysis ◽  
Funding Source ◽  
Paracrine Factors

Abstract Background Pericytes are attracting much attention as potential candidates for successful cell therapy of myocardial ischaemia. Intramyocardially delivered adventitial pericytes (APCs) secrete paracrine factors which stimulate angiogenesis and recruitment of cardiac stromal cells, reduce fibrosis and promote cardiomyocyte proliferation and viability. However, factors responsible for these biological effects have not been elucidated yet. Purpose To exploit the components of APC secretome exerting a biological effect on cardiac cells with the aim to discover new druggable targets with potential therapeutic activity. Methods and results APCs were derived from saphenous veins of adult patients (n=13, 68±11 yrs, all with coronary artery disease - CAD). The APC-conditioned medium (CM) stimulated the proliferation of human iPS-derived cardiomyocytes compared with unconditioned medium (UCM) (EdU incorporation, 1.3-fold increases, P=0.004). Stimulation with APC-CM increased the number of mitotic figures in cardiomyocytes (Aurora B, 1.5-fold increases compared to UCM, P=0.002). Furthermore, APC-CM abrogated the hypoxia-induced apoptosis in cardiomyocytes (2-fold increase in Caspase 3/7 activity in hypoxic cells exposed to UCM compared to normoxic cells, P=0.002). We also found that APC-CM stimulates the migration of human cardiac stromal cells (CSCs) obtained from healthy donors (n=6, 54±11 yrs) in both a transwell and scratch migration assays (n=6, P<0.01 and P<0.05 vs UCM respectively). Interestingly, APC-CM activated also the migration of HUVECs (n=6, P<0.01 vs UCM) but did not attract fibroblasts. Next, we aimed to identify the biologically active components of the APC-CM. Depletion of exosomes and heat and RNase treatments did not abolish the pro-migratory action of the APC-CM, while this was abrogated by Proteinase K. Fractionation of the APC-CM based on the MW indicated that the bioactive peptides have MW >30KDa. The pro-migratory fractions of the APC-CM obtained from size exclusion chromatography underwent mass spectrometry analysis (n=3 APCs). This identified 14 proteins uniquely present in the pro-migratory fractions. The two most relevant candidates were SPARC and TGFBI, both confirmed by ELISA. Intriguingly, the recombinant SPARC and TGFBI failed to reproduce the biological effect of APC-CM on CSC migration, suggesting that the secreted proteins may carry unique post-translational modifications not found in synthetic peptides. Further analyses are being carried out to reveal the biological properties of the endogenous SPARC and TGFBI. Conclusions This study suggests a fascinating approach based on the use of the active component of the APC-CM as a surrogate of APC therapy. If the biological properties of the cellular proteins will be successfully reproduced in synthetic peptides in vitro, this innovative approach may extend the benefits of APC therapy to all those patients with CAD for whom cell therapy is not an available option. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation programme grant “Unravelling mechanism of stem cell depletion for the preservation of regenerative fitness in patients with diabetes”

scholarly journals Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Nami Mohammadian Khonsari ◽  
Sahar Mohammad Poor Nami ◽  
Benyamin Hakak-Zargar ◽  
Tessa Voth
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Hormone Receptors ◽  
Bone Growth ◽  
Synergistic Effects ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Pathogenic Mutation ◽  
Paracrine Factors ◽  
Severe Short Stature

Abstract Background Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. Case presentation We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient’s phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient’s father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. Conclusion We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

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