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International Journal of Molecular... Aug 2023The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and... (Review)
Review
The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer.
Topics: Humans; Urinary Bladder; Tumor Microenvironment; Endothelial Cells; Neoplasms; Urinary Bladder Neoplasms; Pericytes
PubMed: 37569686
DOI: 10.3390/ijms241512311 -
Acta Neurologica Belgica Jun 2024The functional structure of the blood-brain barrier (BBB) deteriorates after stroke by developing diffuse microvascular and neurovascular dysfunction and loss of white... (Review)
Review
The functional structure of the blood-brain barrier (BBB) deteriorates after stroke by developing diffuse microvascular and neurovascular dysfunction and loss of white matter integrity. This causes nervous tissue injury and causes sensory and motor disabilities in stroke patients. Improving the integrity of the BBB and neurovascular remodeling after stroke can promote post-stroke injury conditions. Pericytes are contractile cells abundant in the BBB and sandwiched between astrocytes and endothelial cells of the microvessels. Stroke could lead to the degeneration of pericytes in the BBB. However, recent evidence shows that promoting pericytes enhances BBB integrity and neurovascular remodeling. Furthermore, pericytes achieve multipotent properties under hypoxic conditions, allowing them to transdifferentiate into the brain resident cells such as microglia. Microglia regulate immunity and inflammatory response after stroke. The current review studies recent findings in the intervening mechanisms underlying the regulatory effect of pericytes in BBB recovery after stroke.
Topics: Pericytes; Humans; Blood-Brain Barrier; Ischemic Stroke; Animals
PubMed: 37805645
DOI: 10.1007/s13760-023-02391-y -
Circulation Sep 2023
Topics: Humans; Pericytes; Myocardial Infarction; Heart
PubMed: 37695834
DOI: 10.1161/CIRCULATIONAHA.123.065676 -
Matrix Biology : Journal of the... Sep 2023Angiogenesis, the formation of the new blood vessels from pre-existing vasculature, is an essential process occurring under both normal and pathological conditions, such...
Angiogenesis, the formation of the new blood vessels from pre-existing vasculature, is an essential process occurring under both normal and pathological conditions, such as inflammation and cancer. This complex process is regulated by several cytokines, growth factors and extracellular matrix components modulating endothelial cell and pericyte function. In this study, we discovered that the extracellular matrix glycoprotein Elastin Microfibril Interfacer 2 (Emilin2) plays a prominent role in pericyte physiology. This work was originally prompted by the observations that tumor-associated vessels from Emilin2 mice display less pericyte coverage, impaired vascular perfusion, and reduced drug efficacy, suggesting that Emilin2 could promote vessel maturation and stabilization affecting pericyte recruitment. We found that Emilin2 affects different mechanisms engaged in pericyte recruitment and vascular stabilization. First, human primary endothelial cells challenged with recombinant Emilin2 synthesized and released ∼ 2.1 and 1.2 folds more PDGF-BB and HB-EGF, two cytokines known to promote pericyte recruitment. We also discovered that Emilin2, by directly engaging αβ and αβ integrins, highly expressed in pericytes, served as an adhesion substrate and haptotactic stimulus for pericytes. Moreover, Emilin2 evoked increased NCadherin expression via the sphingosine-1-phosphate receptor, leading to enhanced vascular stability by fostering interconnection between endothelial cells and pericytes. Finally, restoring pericyte coverage in melanoma and ovarian tumor vessels developed in Emilin2 mice improved drug delivery to the tumors. Collectively, our results implicate Emilin2 as a prominent regulator of pericyte function and suggest that Emilin2 expression could represent a promising maker to predict the clinical outcome of patients with melanoma, ovarian, and potentially other forms of cancer.
Topics: Humans; Mice; Animals; Pericytes; Endothelial Cells; Becaplermin; Cytokines; Melanoma; Glycoproteins
PubMed: 37579864
DOI: 10.1016/j.matbio.2023.08.002 -
The Journal of Clinical Investigation Dec 2023Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells,...
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.
Topics: Animals; Humans; Infant; Mice; Endothelial Cells; Lung; Lymphangioleiomyomatosis; Mechanistic Target of Rapamycin Complex 1; Mesoderm; Tuberous Sclerosis; Tumor Suppressor Proteins; Vascular Remodeling; T-Box Domain Proteins; Tuberous Sclerosis Complex 2 Protein; In Vitro Techniques
PubMed: 38127441
DOI: 10.1172/JCI172116 -
Seminars in Cancer Biology Nov 2023Epithelial-to-mesenchymal transition or transformation (EMT) is a cell shape-changing process that is utilized repeatedly throughout embryogenesis and is critical to the... (Review)
Review
Epithelial-to-mesenchymal transition or transformation (EMT) is a cell shape-changing process that is utilized repeatedly throughout embryogenesis and is critical to the attainment of a precise body plan. In the adult, EMT is observed under both normal and pathological conditions, such as during normal wounding healing, during development of certain fibrotic states and vascular anomalies, as well as in some cancers when malignant cells progress to become more aggressive, invasive, and metastatic. Epithelia derived from any of the three embryonic germ layers can undergo EMT, including those derived from mesoderm, such as endothelial cells (sometimes termed Endo-MT) and those derived from endoderm such as fetal liver stroma. At the cellular level, EMT is defined as the transformation of epithelial cells towards a mesenchymal phenotype and is marked by attenuation of expression of epithelial markers and de novo expression of mesenchymal markers. This process is induced by extracellular factors and can be reversible, resulting in mesenchymal-to-epithelial transformation (MET). It is now clear that a cell can simultaneously express properties of both epithelia and mesenchyme, and that such transitional cell-types drive tumor cell heterogeneity, an important aspect of cancer progression, development of a stem-like cell state, and drug resistance. Here we review some of the earliest studies demonstrating the existence of EMT during embryogenesis and discuss the discovery of the extracellular factors and intracellular signaling pathways that contribute to this process, with components of the TGFβ signaling superfamily playing a prominent role. We mention early controversies surrounding in vivo EMT during embryonic development and in adult diseased states, and the maturation of the field to a stage wherein targeting EMT to control disease states is an aspirational goal.
Topics: Pregnancy; Female; Adult; Humans; Epithelial-Mesenchymal Transition; Endothelial Cells; Epithelial Cells; Neoplasms; Embryonic Development
PubMed: 37852342
DOI: 10.1016/j.semcancer.2023.10.003 -
Developmental Cell Sep 2023Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin (Eomes) and Brachyury...
Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin (Eomes) and Brachyury sharing partially redundant functions. Gross differences in mutant embryonic phenotypes suggest specific functions of each TF. To date, the molecular details of separated lineage-specific gene regulation by Eomes and Brachyury remain poorly understood. Here, we combine mouse embryonic and stem-cell-based analyses to delineate the non-overlapping, lineage-specific transcriptional activities. On a genome-wide scale, binding of both TFs overlaps at promoters of target genes but shows specificity for distal enhancer regions that is conferred by differences in Tbx DNA-binding motifs. The unique binding to enhancer sites instructs the specification of anterior mesoderm (AM) and DE by Eomes and caudal mesoderm by Brachyury. Remarkably, EOMES antagonizes BRACHYURY gene regulatory functions in coexpressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives.
Topics: Mice; Animals; Gastrulation; T-Box Domain Proteins; Mesoderm; Fetal Proteins; Gene Expression Regulation, Developmental; Mammals
PubMed: 37633271
DOI: 10.1016/j.devcel.2023.07.023 -
Journal of Atherosclerosis and... Sep 2023There are still many patients suffering from ischemic stroke and related disabilities worldwide. To develop a treatment that promotes functional recovery after acute... (Review)
Review
There are still many patients suffering from ischemic stroke and related disabilities worldwide. To develop a treatment that promotes functional recovery after acute ischemic stroke, we need to elucidate endogenous tissue repair mechanisms. The concept of a neurovascular unit (NVU) indicates the importance of a complex orchestration of cell-cell interactions and their microenvironment in the physiology and pathophysiology of various central nervous system diseases, particularly ischemic stroke. In this concept, microvascular pericytes play a crucial role in regulating the blood-brain barrier integrity, cerebral blood flow (CBF), and vascular stability. Recent evidence suggests that pericytes are also involved in the tissue repair leading to functional recovery following acute ischemic stroke through the interaction with other cell types constituting the NVU; pericytes may organize CBF recovery, macrophage-mediated clearance of myelin debris, intrainfarct fibrosis, and periinfarct astrogliosis and remyelination. In this review, we will discuss the physiological and pathophysiological functions of pericytes, their involvement in the molecular mechanisms underlying tissue repair and functional recovery after ischemic stroke, and a therapeutic strategy to promote endogenous regeneration.
Topics: Humans; Pericytes; Ischemic Stroke; Stroke; Blood-Brain Barrier; Macrophages
PubMed: 37394570
DOI: 10.5551/jat.RV22007 -
Stem Cell Research & Therapy Oct 2023Understanding mechanisms and manifestations of cardiovascular risk factors, including diabetes, on vascular cells such as endothelial cells, pericytes, and vascular... (Review)
Review
Understanding mechanisms and manifestations of cardiovascular risk factors, including diabetes, on vascular cells such as endothelial cells, pericytes, and vascular smooth muscle cells, remains elusive partly due to the lack of appropriate disease models. Therefore, here we explore different aspects for the development of advanced 3D in vitro disease models that recapitulate human blood vessel complications using patient-derived induced pluripotent stem cells, which retain the epigenetic, transcriptomic, and metabolic memory of their patient-of-origin. In this review, we highlight the superiority of 3D blood vessel organoids over conventional 2D cell culture systems for vascular research. We outline the key benefits of vascular organoids in both health and disease contexts and discuss the current challenges associated with organoid technology, providing potential solutions. Furthermore, we discuss the diverse applications of vascular organoids and emphasize the importance of incorporating all relevant cellular components in a 3D model to accurately recapitulate vascular pathophysiology. As a specific example, we present a comprehensive overview of diabetic vasculopathy, demonstrating how the interplay of different vascular cell types is critical for the successful modelling of complex disease processes in vitro. Finally, we propose a strategy for creating an organ-specific diabetic vasculopathy model, serving as a valuable template for modelling other types of vascular complications in cardiovascular diseases by incorporating disease-specific stressors and organotypic modifications.
Topics: Humans; Endothelial Cells; Organoids; Induced Pluripotent Stem Cells; Pericytes; Diabetes Mellitus
PubMed: 37817281
DOI: 10.1186/s13287-023-03521-2