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Journal of Cellular and Molecular... Jun 2024Gastric cancer (GC) remains a prominent malignancy that poses a significant threat to human well-being worldwide. Despite advancements in chemotherapy and immunotherapy,...
Gastric cancer (GC) remains a prominent malignancy that poses a significant threat to human well-being worldwide. Despite advancements in chemotherapy and immunotherapy, which have effectively augmented patient survival rates, the mortality rate associated with GC remains distressingly high. This can be attributed to the elevated proliferation and invasive nature exhibited by GC. Our current understanding of the drivers behind GC cell proliferation remains limited. Hence, in order to reveal the molecular biological mechanism behind the swift advancement of GC, we employed single-cell RNA-sequencing (scRNA-seq) to characterize the tumour microenvironment in this study. The scRNA-seq data of 27 patients were acquired from the Gene Expression Omnibus database. Differential gene analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were employed to investigate 38 samples. The copy number variation level exhibited by GC cells was determined using InferCNV. The CytoTRACE, Monocle and Slingshot analysis were used to discern the cellular stemness and developmental trajectory of GC cells. The CellChat package was utilized for the analysis of intercellular communication crosstalk. Moreover, the findings of the data analysis were validated through cellular functional tests conducted on the AGS cell line and SGC-7901 cell line. Finally, this study constructed a risk scoring model to evaluate the differences of different risk scores in clinical characteristics, immune infiltration, immune checkpoints, functional enrichment, tumour mutation burden and drug sensitivity. Within the microenvironment of GC, we identified the presence of 8 cell subsets, encompassing NK_T cells, B_Plasma cells, epithelial cells, myeloid cells, endothelial cells, mast cells, fibroblasts, pericytes. By delving deeper into the characterization of GC cells, we identified 6 specific tumour cell subtypes: C0 PSCA+ tumour cells, C1 CLDN7+ tumour cells, C2 UBE2C+ tumour cells, C3 MUC6+ tumour cells, C4 CHGA+ tumour cells and C5 MUC2+ tumour cells. Notably, the C2 UBE2C+ tumour cells demonstrated a close association with cell mitosis and the cell cycle, exhibiting robust proliferative capabilities. Our findings were fortified through enrichment analysis, pseudotime analysis and cell communication analysis. Meanwhile, knockdown of the transcription factor CREB3, which is highly active in UBE2C+ tumour cells, significantly impedes the proliferation, migration and invasion of GC cells. And the prognostic score model constructed with CREB3-related genes showcased commendable clinical predictive capacity, thus providing valuable guidance for patients' prognosis and clinical treatment decisions. We have identified a highly proliferative cellular subgroup C2 UBE2C+ tumour cells in GC for the first time. The employment of a risk score model, which is based on genes associated with UBE2C expression, exhibits remarkable proficiency in predicting the prognosis of GC patients. In our investigation, we observed that the knockdown of the transcription factor CREB3 led to a marked reduction in cellular proliferation, migration and invasion in GC cell line models. Implementing a stratified treatment approach guided by this model represents a judicious and promising methodology.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Cell Proliferation; Single-Cell Analysis; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Gene Expression Profiling; DNA Copy Number Variations; Biomarkers, Tumor; Cell Communication
PubMed: 38894657
DOI: 10.1111/jcmm.18373 -
The Journal of Clinical Investigation Jun 2024While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β-cells and contributes to diabetes. However, the...
While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β-cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β-cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β-cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatments with either Cxcl1 or IL-1β restored the mature β-cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
PubMed: 38885342
DOI: 10.1172/JCI179335 -
Biomedicine & Pharmacotherapy =... Jun 2024The tumor microenvironment (TME) is a combination of tumor cells and indigenous host stroma, which consists of tumor-infiltrating immune cells, endothelial cells,... (Review)
Review
The tumor microenvironment (TME) is a combination of tumor cells and indigenous host stroma, which consists of tumor-infiltrating immune cells, endothelial cells, fibroblasts, pericytes, and non-cellular elements. Tumor-associated macrophages (TAMs) represent the major tumor-infiltrating immune cell type and are generally polarized into two functionally contradictory subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. Macrophage polarization refers to how macrophages are activated at a given time and space. The interplay between the TME and macrophage polarization can influence tumor initiation and progression, making TAM a potential target for cancer therapy. Here, we review the latest investigations on factors orchestrating macrophage polarization in the TME, how macrophage polarization affects tumor progression, and the perspectives in modulating macrophage polarization for cancer immunotherapy.
PubMed: 38878638
DOI: 10.1016/j.biopha.2024.116930 -
Stem Cell Reports Jun 2024Functionality of the blood-brain barrier (BBB) relies on the interaction between endothelial cells (ECs), pericytes, and astrocytes to regulate molecule transport within...
Functionality of the blood-brain barrier (BBB) relies on the interaction between endothelial cells (ECs), pericytes, and astrocytes to regulate molecule transport within the central nervous system. Most experimental models for the BBB rely on freshly isolated primary brain cells. Here, we explored human induced pluripotent stem cells (hiPSCs) as a cellular source for astrocytes in a 3D vessel-on-chip (VoC) model. Self-organized microvascular networks were formed by combining hiPSC-derived ECs, human brain vascular pericytes, and hiPSC-derived astrocytes within a fibrin hydrogel. The hiPSC-ECs and pericytes showed close interactions, but, somewhat unexpectedly, addition of astrocytes disrupted microvascular network formation. However, continuous fluid perfusion or activation of cyclic AMP (cAMP) signaling rescued the vascular organization and decreased vascular permeability. Nevertheless, astrocytes did not affect the expression of proteins related to junction formation, transport, or extracellular matrix, indicating that, despite other claims, hiPSC-derived ECs do not entirely acquire a BBB-like identity in the 3D VoC model.
PubMed: 38876110
DOI: 10.1016/j.stemcr.2024.05.006 -
Frontiers in Neurology 2024Severe acute respiratory syndrome corona virus 2 (SARS CoV-2) is the cause of Corona virus disease 2019 (COVID-19), which turned into a pandemic in late 2019 and early...
Severe acute respiratory syndrome corona virus 2 (SARS CoV-2) is the cause of Corona virus disease 2019 (COVID-19), which turned into a pandemic in late 2019 and early 2020. SARS CoV-2 causes endothelial cell destruction and swelling, microthrombosis, constriction of capillaries, and malfunction of pericytes, all of which are detrimental to capillary integrity, angiogenesis, and healing processes. Cytokine storming has been connected to COVID-19 disease. Hypoxemia and tissue hypoxia may arise from impaired oxygen diffusion exchange in the lungs due to capillary damage and congestion. This personal view will look at how inflammation and capillary damage affect blood and tissue oxygenation, cognitive function, and the duration and intensity of COVID-19 disease. The general effects of microvascular injury, hypoxia, and capillary damage caused by COVID-19 in key organs are also covered in this point of view. Once initiated, this vicious cycle leads to diminished capillary function, which exacerbates inflammation and tissue damage, and increased inflammation due to hypoxia. Brain damage may result from low oxygen levels and high cytokines in brain tissue. In this paper we give a summary in this direction with focus on the role of the neuropeptide Substance P. On the basis of this, we discuss selected approaches to the question: "How Substance P is involved in the etiology of the COVID-19 and how results of our research could improve the prevention or therapy of corona? Thereby pointing out the role of Substance P in the post-corona syndrome and providing novel concepts for therapy and prevention.
PubMed: 38872816
DOI: 10.3389/fneur.2024.1370454 -
IScience Jun 2024Systemic sclerosis (SSc) is a chronic disease characterized by fibrosis and vascular abnormalities in the skin and internal organs, including the lung. SSc-associated...
Systemic sclerosis (SSc) is a chronic disease characterized by fibrosis and vascular abnormalities in the skin and internal organs, including the lung. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death in SSc patients. Pericytes are key regulators of vascular integrity and endothelial function. The role that pericytes play in SSc-PF remains unclear. We compared the transcriptome of pericytes from SSc-PF lungs (SScL) to pericytes from normal lungs (NORML). We identified 1,179 differentially expressed genes in SScL pericytes. Pathways enriched in SScL pericytes included prostaglandin, PI3K-AKT, calcium, and vascular remodeling signaling. Decreased cyclic AMP production and altered phosphorylation of AKT in response to prostaglandin E2 in SScL pericytes demonstrate the functional consequence of changes in the prostaglandin pathway that may contribute to fibrosis. The transcriptomic signature of SSc lung pericytes suggests that they promote vascular dysfunction and contribute to the loss of protection against lung inflammation and fibrosis.
PubMed: 38868196
DOI: 10.1016/j.isci.2024.110010 -
Brain Research Bulletin Nov 2023This study was designed to investigate the role of pericytes in the pathogenesis of perioperative neurocognitive disorder (PND).
AIMS
This study was designed to investigate the role of pericytes in the pathogenesis of perioperative neurocognitive disorder (PND).
METHODS
In this study, we established a PND model via sevoflurane anesthesia and tibial fracture surgery in 2-month-old and 16-month-old male C57BL/6 mice. On the third postoperative day, the mice were subjected to behavioral testing or sacrificed to collect brain tissue. The progression of hippocampal blood-brain barrier (BBB) disruption and neuroinflammation was detected using transmission electron microscope and immunofluorescence. We also used western blotting to measure the levels of plasma-derived protein immunoglobulin G (IgG) and albumin in the hippocampus to assess the leakage of the BBB.
RESULTS
Aged mice did not experience age-related cognitive decline and BBB disruption compared with younger mice but only increased glial cell activity. Anesthesia/Surgery damaged cognitive function, reduced pericyte coverage, decreased the length of capillaries and levels of occludin and claudin-5, destroyed the structure of the BBB, exacerbated IgG and albumin accumulation in the hippocampus, and enhanced the activation of microglia and astrocytes in the hippocampus of aged mice. However, these negative effects did not occur in young mice.
CONCLUSION
Our study showed that the loss of pericytes led to increased BBB permeability and neuroinflammation after anesthesia/surgery in aged mice, ultimately resulting in cognitive dysfunction.
Topics: Animals; Blood-Brain Barrier; Pericytes; Male; Mice; Mice, Inbred C57BL; Hippocampus; Cognitive Dysfunction; Cognition; Aging; Sevoflurane; Anesthesia
PubMed: 38867419
DOI: 10.1016/j.brainresbull.2023.110799 -
Science Progress 2024Pericytes (PCs) are versatile cells integral to the microcirculation wall, exhibiting specific stem cell traits. They are essential in modulating blood flow, ensuring... (Review)
Review
Pericytes (PCs) are versatile cells integral to the microcirculation wall, exhibiting specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, maintaining homeostasis, and aiding tissue repair process. Given their involvement in numerous disease-related pathological and physiological processes, the regulation of PCs has emerged as a focal point of research. Adenomyosis is characterized by the presence of active endometrial glands and stroma encased by an enlarged and proliferative myometrial layer, further accompanied by fibrosis and new blood vessel formation. This distinct pathological condition might be intricately linked with PCs. This article comprehensively reviews the markers associated with PCs, their contributions to angiogenesis, blood flow modulation, and fibrotic processes. Moreover, it provides a comprehensive overview of the current research on adenomyosis pathophysiology, emphasizing the potential correlation and future implications regarding PCs and the development of adenomyosis.
Topics: Adenomyosis; Pericytes; Humans; Female; Neovascularization, Pathologic; Animals; Fibrosis; Endometrium; Myometrium; Biomarkers
PubMed: 38863331
DOI: 10.1177/00368504241257126 -
Pharmacological Research Jul 2024Melatonin, a versatile hormone produced by the pineal gland, has garnered considerable scientific interest due to its diverse functions. In the eye, melatonin regulates... (Review)
Review
Melatonin, a versatile hormone produced by the pineal gland, has garnered considerable scientific interest due to its diverse functions. In the eye, melatonin regulates a variety of key processes like inhibiting angiogenesis by reducing vascular endothelial growth factor levels and protecting the blood-retinal barrier (BRB) integrity by enhancing tight junction proteins and pericyte coverage. Melatonin also maintains cell health by modulating autophagy via the Sirt1/mTOR pathways, reduces inflammation, promotes antioxidant enzyme activity, and regulates intraocular pressure fluctuations. Additionally, melatonin protects retinal ganglion cells by modulating aging and inflammatory pathways. Understanding melatonin's multifaceted functions in ocular health could expand the knowledge of ocular pathogenesis, and shed new light on therapeutic approaches in ocular diseases. In this review, we summarize the current evidence of ocular functions and therapeutic potential of melatonin and describe its roles in angiogenesis, BRB integrity maintenance, and modulation of various eye diseases, which leads to a conclusion that melatonin holds promising treatment potential for a wide range of ocular health conditions.
Topics: Melatonin; Humans; Animals; Eye Diseases; Eye; Blood-Retinal Barrier
PubMed: 38862072
DOI: 10.1016/j.phrs.2024.107253 -
Open Biology Jun 2024Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A...
Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.
Topics: Pericytes; Humans; Animals; SARS-CoV-2; COVID-19; Mice; Endothelial Cells; Risk Factors; Lipopolysaccharides; Apolipoprotein E4; Apolipoprotein E3; Inflammation
PubMed: 38862017
DOI: 10.1098/rsob.230349