secreted factors
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Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 344
Author(s):  
Natalia Diaz-Garrido ◽  
Josefa Badia ◽  
Laura Baldomà

Gut bacteria release extracellular vesicles (BEVs) as an intercellular communication mechanism that primes the host innate immune system. BEVs from E. coli activate dendritic cells (DCs) and subsequent T-cell responses in a strain-specific manner. The specific immunomodulatory effects were, in part, mediated by differential regulation of miRNAs. This study aimed to deepen understanding of the mechanisms of BEVs to drive specific immune responses by analyzing their impact on DC-secreted cytokines and exosomes. DCs were challenged with BEVs from probiotic and commensal E. coli strains. The ability of DC-secreted factors to activate T-cell responses was assessed by cytokine quantification in indirect DCs/naïve CD4+ T-cells co-cultures on Transwell supports. DC-exosomes were characterized in terms of costimulatory molecules and miRNAs cargo. In the absence of direct cellular contacts, DC-secreted factors triggered secretion of effector cytokines by T-cells with the same trend as direct DC/T-cell co-cultures. The main differences between the strains influenced the production of Th1- and Treg-specific cytokines. Exosomes released by BEV-activated DCs were enriched in surface proteins involved in antigen presentation and T-cell activation, but differed in the content of immune-related miRNA, depending on the origin of the BEVs. These differences were consistent with the derived immune responses.


2022 ◽  
Author(s):  
Reilly L Allison ◽  
Jacob W Adelman ◽  
Jenica Abrudan ◽  
Raul A Urrutia ◽  
Michael T Zimmermann ◽  
...  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte conditioned medium and microglial conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons.


2021 ◽  
Author(s):  
Andreia Fernandes ◽  
Vahid Hosseini ◽  
Viola Vogel ◽  
Robert Lovchik

Shear stress is extremely important for endothelial cell (EC) function. The popularity of 6-well plates on orbital shakers to impose shear stress on ECs has increased among biologists due to their low cost and simplicity. One characteristic of such a platform is the heterogeneous flow profile within a well. While cells in the periphery are exposed to a laminar and high-velocity pulsatile flow that mimics physiological conditions, the flow in the center is disturbed and imposes low shear stress on the cells, which is characteristic of atheroprone regions. For studies where such heterogeneity is not desired, we present a simple cell-patterning technique to selectively prevent cell growth in the center of the well and facilitate the exclusive collection and analysis of cells in the periphery. This guarantees that cell phenotypes will not be influenced by secreted factors from cells exposed to other shear profiles nor that interesting results may be obscured by mixing cells from different regions. We also present a multi-staining platform that compartmentalizes each well into 5 smaller independent regions: four at the periphery and one in the center. This is ideal for studies that aim to grow cells on the whole well surface, for comparison with previous work and minimal interference in the cell culture, but require screening of markers by immunostaining afterwards. It allows to compare different regions of the well, reduces antibody-related costs, and allows the exploration of multiple markers essential for high-content screening of cell response. By increasing the versatility of the 6-well plate on an orbital shaker system, we hope that these two solutions motivate biologists to pursue studies on EC mechanobiology and beyond.


2021 ◽  
Author(s):  
Patricia Dias-Carvalho ◽  
Flavia Martins ◽  
Susana Mendonca ◽  
Andreia Ribeiro ◽  
Ana Luisa Machado ◽  
...  

Genetic alterations influence the malignant potential of cancer cells, and so does the tumor microenvironment. Herein, we combined the study of KRAS oncogenic effects in colorectal cancer cells with the influence of fibroblasts derived factors. Results revealed that mutant KRAS regulates cell fate through both autonomous and non autonomous signaling mechanisms. Specifically, processes such as proliferation and cell-cell aggregation were autonomously controlled by mutant KRAS independently of the stimulation with fibroblasts conditioned media. However, cancer cell invasion revealed to be a KRAS dependent non-autonomous effect, resulting from the cooperation between fibroblasts-derived HGF and mutant KRAS regulation of C-MET expression. C-MET downregulation upon KRAS silencing rendered cells less responsive to HGF and thus less invasive. Yet, in one cell line, KRAS inhibition triggered invasion upon stimulation with fibroblasts conditioned media. Inhibition of PIK3CA oncogene did not promoted invasion, thus showing a KRAS specific effect. Moreover, the invasive capacity also depended on the HGF-C-MET axis. Overall, our study awards oncogenic KRAS an important role in modulating the response to fibroblast-secreted factors either by promoting or impairing invasion, and depicts the HGF-C-MET axis as a putative therapeutic target to impair the invasive properties of mutant KRAS cancer cells.


2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Toru Hanamura ◽  
Jessica L. Christenson ◽  
Kathleen I. O’Neill ◽  
Emmanuel Rosas ◽  
Nicole S. Spoelstra ◽  
...  

Abstract Purpose Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity. Methods Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype. Results Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes. Conclusion KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers.


2021 ◽  
Author(s):  
Lauren M. Sparks ◽  
Bret H. Goodpaster ◽  
Bryan C. Bergman

Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot – most likely due to its limited accessibility – is the intermuscular adipose depot (IMAT). Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include: 1) sex and related circulating hormone levels, 2) race and ethnicity and 3) lifestyle factors (e.g. diet and physical activity level). IMAT quantity <i>per se</i> may not be the driving factor in the etiology of insulin resistance and type 2 diabetes but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as RNAseq, ATACseq and DNA methylation at the single cell and single nuclei levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.


2021 ◽  
Author(s):  
Lauren M. Sparks ◽  
Bret H. Goodpaster ◽  
Bryan C. Bergman

Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot – most likely due to its limited accessibility – is the intermuscular adipose depot (IMAT). Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include: 1) sex and related circulating hormone levels, 2) race and ethnicity and 3) lifestyle factors (e.g. diet and physical activity level). IMAT quantity <i>per se</i> may not be the driving factor in the etiology of insulin resistance and type 2 diabetes but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as RNAseq, ATACseq and DNA methylation at the single cell and single nuclei levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.


2021 ◽  
Vol 8 ◽  
Author(s):  
Eunhye Kim ◽  
Lian Cai ◽  
Sang-Hwan Hyun

Stem cell factor (SCF), also known as c-Kit ligand, plays an important role in the proliferation of primordial germ cells and the survival of oocytes during follicular development. The aim of this study was to investigate the effect of SCF/c-Kit signaling on in vitro maturation (IVM) of porcine oocytes by analyzing nuclear and cytoplasmic maturation, oocyte size, cumulus cell expansion, and developmental competence to the blastocyst stage. Moreover, mRNA expression patterns of porcine cumulus cells and oocytes were evaluated using qRT-PCR. Following 42 h of IVM, 10 and 50 ng/mL SCF-treated groups exhibited significantly (P &lt; 0.05) increased polar body extrusion rates and intracellular glutathione levels compared with the control group. The cumulus expansion index significantly (P &lt; 0.05) increased in all SCF-treated groups compared with the control samples. mRNA levels of the proapoptotic gene Bax and apoptosis-related cysteine peptidase Caspase3 were lower in SCF-treated cumulus cells than in the control group. Notably, the diameter of oocytes after IVM, the mRNA expression of well-known oocyte-secreted factors (GDF9 and BMP15), and an oocyte-specific protein essential for ovulation and oocyte health (YBX2) were significantly (P &lt; 0.05) higher in SCF-treated than in non-treated oocytes. Inhibition of c-Kit during porcine IVM using ACK2, an antagonistic blocker of c-Kit, significantly (P &lt; 0.05) decreased the polar body extrusion rate compared with the control, as well as blastocyst formation rate compared with the 10 ng/mL SCF-treated group. In conclusion, the effect of SCF/c-Kit-mediated signaling during porcine IVM could be ascribed to the reduced expression of apoptosis-related genes and higher expression of oocyte-specific/secreted factors.


Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4821
Author(s):  
Cinthia Carolina Stempin ◽  
Romina Celeste Geysels ◽  
Sunmi Park ◽  
Luz Maria Palacios ◽  
Ximena Volpini ◽  
...  

Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.


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