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The Journal of Surgical Research Apr 2024Dynamic cell-cell interactions shape the tumor microenvironment to regulate tumor growth and invasiveness. Myofibroblasts are gastrointestinal stromal cells that are...
INTRODUCTION
Dynamic cell-cell interactions shape the tumor microenvironment to regulate tumor growth and invasiveness. Myofibroblasts are gastrointestinal stromal cells that are upregulated in the setting of colorectal cancer (CRC) and may play an important role in tumor-stromal cell communication. Angiogenin is a 14-kDa ribonuclease that regulates myofibroblast function and has been implicated in myofibroblast-CRC cell communication in mouse models. However, its role in human patients has not been well established.
METHODS
Open access, annotated single-cell RNA sequencing data of paired normal human colon and CRC tissue were available in the National Center for Biotechnology Information Gene Expression Omnibus Database. We supplemented and verified these data by analyzing scRNA-seq data from an independent set of paired normal human colon and CRC tissue. CellChat was used to quantitatively infer biologically meaningful cell-cell communication networks from scRNA-seq data. PLXNB2 and α-2 actin (ACTA2) are cell surface angiogenin receptors that regulate angiogenin signaling. Ligand-receptor interactions involving angiogenin, PLXNB2, and ACTA2 were analyzed between cell populations in each sample.
RESULTS
We found no difference in overall angiogenin expression comparing normal colon and CRC tissue. In normal colon tissue, myofibroblasts do not express angiogenin or the PLXNB2 receptor. In the presence of CRC, there was a striking increase in the number of myofibroblast cells within the surrounding stroma. CRC-associated myofibroblasts were characterized by a significant upregulation of both angiogenin and PLXNB2 receptor expression (P < 0.05), while no difference was seen in ACTA2. CRC cells not only use angiogenin for autocrine signaling but also communicate with myofibroblasts via the PLXNB2 receptor.
CONCLUSIONS
Compared to normal human colon tissue, CRC tissue is associated with an enrichment of myofibroblasts that exhibit upregulated expression of angiogenin and the angiogenin receptor PLXNB2. CRC cells engage in autocrine signaling via angiogenin and paracrine signaling with myofibroblasts via PLXNB2. Angiogenin appears to be directly involved in tumor-stromal cell communication in human CRC tissue and may play an important role in disease progression.
Topics: Animals; Humans; Mice; Cell Communication; Colorectal Neoplasms; Myofibroblasts; Ribonuclease, Pancreatic; Signal Transduction; Tumor Microenvironment
PubMed: 38295715
DOI: 10.1016/j.jss.2023.12.036 -
Journal of Cellular Physiology Apr 2024In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously...
In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice-a developmental juncture marking the onset of SSC differentiation-participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression-an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.
Topics: Animals; Male; Mice; Autocrine Communication; Cell Differentiation; Exosomes; Glial Cell Line-Derived Neurotrophic Factor; Mice, Inbred ICR; Paracrine Communication; Sertoli Cells; Spermatogonia
PubMed: 38291718
DOI: 10.1002/jcp.31202 -
Kidney Research and Clinical Practice Jan 2024The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while...
The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while detaining plasma proteins according to size and charge selectivity. Structurally, the fenestrated endothelial cells, which align the capillary loops, are in close proximity to mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and are separated from the endothelial compartment by the glomerular basement membrane. Podocyte-endothelial cell communication or crosstalk is required for the development and maintenance of an efficient filtration process in physiological conditions. In pathological situations, communication also has an essential role in promoting or delaying disease progression. Podocytes and endothelial cells can secrete signaling molecules, which act as crosstalk effectors and, through binding to their target receptors, can trigger bidirectional paracrine or autocrine signal transduction. Moreover, the emerging evidence of extracellular vesicles derived from various cell types engaging in cell communication has also been reported. In this review, we summarize the principal pathways involved in the development and maintenance of the GFB and the progression of kidney disease, particularly in kidney transplantation.
PubMed: 38062623
DOI: 10.23876/j.krcp.23.071 -
Nephrology, Dialysis, Transplantation :... Apr 2024Kidney fibrosis is a common outcome of a wide variety of chronic kidney diseases, in which virtually all kinds of renal resident and infiltrating cells are involved. As... (Review)
Review
Kidney fibrosis is a common outcome of a wide variety of chronic kidney diseases, in which virtually all kinds of renal resident and infiltrating cells are involved. As such, well-orchestrated intercellular communication is of vital importance in coordinating complex actions during renal fibrogenesis. Cell-cell communication in multicellular organisms is traditionally assumed to be mediated by direct cell contact or soluble factors, including growth factors, cytokines and chemokines, through autocrine, paracrine, endocrine and juxtacrine signaling mechanisms. Growing evidence also demonstrates that extracellular vesicles, lipid bilayer-encircled particles naturally released from almost all types of cells, can act as a vehicle to transfer a diverse array of biomolecules including proteins, mRNA, miRNA and lipids to mediate cell-cell communication. We recently described a new mode of intercellular communication via building a special extracellular niche by insoluble matricellular proteins. Kidney cells, upon injury, produce and secrete different matricellular proteins, which incorporate into the local extracellular matrix network, and regulate the behavior, trajectory and fate of neighboring cells in a spatially confined fashion. This extracellular niche-mediated cell-cell communication is unique in that it restrains the crosstalk between cells within a particular locality. Detailed delineation of this unique manner of intercellular communication will help to elucidate the mechanism of kidney fibrosis and could offer novel insights in developing therapeutic intervention.
Topics: Cell Communication; Humans; Fibrosis; Animals; Kidney Diseases; Kidney
PubMed: 38040652
DOI: 10.1093/ndt/gfad257 -
Phytomedicine : International Journal... Jan 2024Traditional Chinese medicine prescription sini decoction (SND) can alleviate inflammation, improve microcirculation, and modulate immune status in sepsis patients....
BACKGROUND
Traditional Chinese medicine prescription sini decoction (SND) can alleviate inflammation, improve microcirculation, and modulate immune status in sepsis patients. However, its underlying mechanisms remain unclear, and therapeutic effects may vary among individuals.
PURPOSE
Through a comprehensive and systematic network pharmacology analysis, the purpose of this study is to investigate the therapeutic mechanisms of SND in treating sepsis.
METHODS
An analysis of WGCNA identified CX3CR1 as a key gene influencing sepsis prognosis. A drug-active component-target network for SND was created using the traditional Chinese medicine systems pharmacology (TCMSP) database and Cytoscape software. Shared targets between SND and CX3CR1 high-expression gene modules were found through the GEO database. Gene module functionality was analyzed using GO, KEGG, GSEA, and GSVA. Unsupervised clustering of sepsis patients was performed based on the ferroptosis gene set, and immune cell interactions and mechanisms were explored using CIBERSORT, single-cell sequencing, and intercellular communication analysis.
RESULTS
This study demonstrates that high expression of CX3CR1 improves survival rates in sepsis patients and is associated with immune cell signaling pathways. SND contains 116 active components involved in oxidative stress and lipid metabolism pathways. HMOX1, a co-expressed gene in SND and CX3CR1 high-expression gene module, plays a crucial role in sepsis survival. Unsupervised clustering analysis classified sepsis patients into three clusters based on the ferroptosis gene set, revealing differences in immune cell expression and involvement in heme metabolism pathways. Notably, intercellular interactions among immune cells primarily occur through paracrine and autocrine mechanisms in MIF, GALECTIN, and IL16 signaling pathways, modulating the immune-inflammatory microenvironment in sepsis.
CONCLUSIONS
This study identifies CX3CR1 as a crucial molecule impacting sepsis prognosis through WGCNA analysis. It reveals that SND's active component, quercetin and kaempferol, target HMOX1 via related pathways to regulate heme metabolism, reduce inflammation, inhibit ferroptosis, and improve immune function, ultimately improving sepsis prognosis. These findings offer a solid pharmacological foundation and potential therapeutic targets for SND in treating sepsis.
Topics: Humans; Network Pharmacology; Multiomics; Drugs, Chinese Herbal; Sepsis; Inflammation; Heme; Molecular Docking Simulation
PubMed: 38029626
DOI: 10.1016/j.phymed.2023.155212 -
BioRxiv : the Preprint Server For... Nov 2023In patients with severe acute respiratory distress syndrome (ARDS) associated with sepsis, lung recovery is considerably delayed, and mortality is much high. More...
BACKGROUND
In patients with severe acute respiratory distress syndrome (ARDS) associated with sepsis, lung recovery is considerably delayed, and mortality is much high. More insight into the process of lung regeneration in ARDS patients is needed. Exosomes are important cargos for intercellular communication by serving as autocrine and/or paracrine. Cutting-edge exomics (exosomal proteomics) makes it possible to study the mechanisms of re-alveolarization in ARDS lungs.
AIMS
This study aimed to identify potential regenerative niches by characterizing differentially expressed proteins in the exosomes of bronchioalveolar lavage (BAL) in ARDS patients.
METHODS
We purified exosomes from BAL samples collected from ARDS patients by NIH-supported ALTA and SPIROMICS trials. The abundance of exosomal proteins/peptides was quantified using liquid chromatography-mass spectrometry (LC-MS). Differentially expressed exosomal proteins between healthy controls and ARDS patients were profiled for functional annotations, cell origins, signaling pathways, networks, and clinical correlations.
RESULTS
Our results show that more exosomal proteins were identified in the lungs of late-stage ARDS patients. Immune cells and lung epithelial stem cells were major contributors to BAL exosomes in addition to those from other organs. We enriched a wide range of functions, stem cell signals, growth factors, and immune niches in both mild and severe patients. The differentially expressed proteins that we identified were associated with key clinical variables. The severity-associated differences in protein-protein interaction, RNA crosstalk, and epigenetic network were observed between mild and severe groups. Moreover, alveolar type 2 epithelial cells could serve as both exosome donors and recipients via autocrine and paracrine mechanisms.
CONCLUSIONS
This study identifies novel exosomal proteins associated with diverse functions, signaling pathways, and cell origins in ARDS lavage samples. These differentiated proteins may serve as regenerative niches for re-alveolarization in injured lungs.
PubMed: 38014329
DOI: 10.1101/2023.11.13.566908 -
Frontiers in Immunology 2023Renal cell carcinoma (RCC) is one of the most malignant urological tumors. Currently, there is a lack of molecular markers for early diagnosis of RCC. The 5-year... (Review)
Review
Renal cell carcinoma (RCC) is one of the most malignant urological tumors. Currently, there is a lack of molecular markers for early diagnosis of RCC. The 5-year survival rate for early-stage RCC is generally favorable; however, the prognosis takes a significant downturn when the tumor progresses to distant metastasis. Therefore, the identification of molecular markers for RCC is crucial in enhancing early diagnosis rates. Exosomes are a type of extracellular vesicle (EV) typically ranging in size from 30 nm to 150 nm, which contain RNA, DNA, proteins, lipids, etc. They can impact neighboring receptor cells through the autocrine or paracrine pathway, influence cellular communication, and regulate the local immune cells, consequently shaping the tumor immune microenvironment and closely associating with tumor development. The clinical application of exosomes as tumor markers and therapeutic targets has ignited significant interest within the research community. This review aims to provide a comprehensive summary of the advancements in exosome research within the context of RCC.
Topics: Humans; Carcinoma, Renal Cell; Exosomes; Biomarkers, Tumor; Proteins; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37942325
DOI: 10.3389/fimmu.2023.1271669 -
Molecular Cancer Research : MCR Feb 2024Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide....
UNLABELLED
Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from noncarrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells may differ from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than noncarrier breast tissues with more integrin receptor-expressing stromal cells.
IMPLICATIONS
These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.
Topics: Humans; Female; BRCA1 Protein; BRCA2 Protein; Ligands; Mutation; Genes, BRCA1; Breast Neoplasms; Germ-Line Mutation; Gene Expression Profiling; Integrins; Genetic Predisposition to Disease; Tumor Microenvironment
PubMed: 37878345
DOI: 10.1158/1541-7786.MCR-23-0489 -
The International Journal of... Dec 2023Remodeling of the extracellular matrix (ECM) is a key hallmark of cancer progression. A critical component of ECM remodeling is the assembly of the glycoprotein...
Remodeling of the extracellular matrix (ECM) is a key hallmark of cancer progression. A critical component of ECM remodeling is the assembly of the glycoprotein fibronectin (FN) into insoluble fibrils, which provide a scaffold for invading vascular endothelial cells and escaping cancer cells, as well as a framework for collagen deposition and oncogenic cytokine tethering. FN fibril assembly is induced by Transforming Growth Factor-β1 (TGF-β1), which was originally identified for its role in malignant transformation. Addition of exogenous TGF-β1 drives FN fibril assembly while also upregulating endogenous TGF-β1 expression and autocrine signaling. In the current study, we sought to determine if autocrine TGF-β1 signaling plays a role in FN fibril formation in either MCF10A mammary epithelial cells, which behave similarly to healthy epithelia, or malignant MDA- MB-231 breast cancer cells. Our results show two interesting findings: first, malignant MDA-MB- 231 cells assemble less FN into fibrils, despite expressing and secreting more soluble FN; second, autocrine TGF-β1 signaling is required for FN fibril formation in MCF10A epithelial cells, even in the presence of exogenous, active TGF-β1. This suggests that autocrine TGF-β1 is signaling through distinct pathways from active exogenous TGF-β1. We hypothesized that this signaling was mediated by interactions between the TGF-β1 latency associated peptide (LAP) and α integrins; indeed, incubating MCF10As with soluble LAP, even in the absence of the active TGF-β1 ligand, partially recovered FN fibril assembly. Taken together, these data suggests that autocrine TGF-β1 plays a critical role in FN fibril assembly, and this interaction is mediated by LAP-integrin signaling.
Topics: Fibronectins; Transforming Growth Factor beta1; Endothelial Cells; Autocrine Communication; Epithelial Cells
PubMed: 37866655
DOI: 10.1016/j.biocel.2023.106478 -
CNS & Neurological Disorders Drug... Oct 2023Muscle skeletal striated cells secrete a wide range of proteins called myokines or "exerkines", which in turn perform autocrine, paracrine, or endocrine functions. For...
Muscle skeletal striated cells secrete a wide range of proteins called myokines or "exerkines", which in turn perform autocrine, paracrine, or endocrine functions. For being able to act in the communication between skeletal muscle, adipose tissue, and mainly the brain, exerkines play a prominent role and potential influence on health promotion. Furthermore, we detected in the literature that one of these potential therapeutic substances derived from muscle contraction is a molecule derived from glycolytic metabolism that in the past was largely marginalized, the lactate. Currently, studies are dedicated to examining the target structures for exerkines that may contribute to the maintenance and restoration of mental health. Thus, lactate appears to be recognized as a critical mediator of exercise-related changes and their health benefits, particularly in their role in communication and coordination between organs. It is inferred that the BDNF expression mechanism can be induced by lactate, which in turn derives from the activation of SIRT pathways 1 and 2 and activates the PGC1-α cascade. The behavior of lactate concentration is intensity-dependent, directly related to the type of fast-twitch fibers (type IIb) and the recruitment of these fibers would potentiate the responses in the brain. In this sense, high-intensity exercise would establish itself as an important strategy to be considered. Despite this understanding, there is still much to be done. However, lactate appears to be a highly promising exerkine for future research initiatives and a potential biomarker to reduce illness and promote mental health.
PubMed: 37842902
DOI: 10.2174/0118715273250928231009054658