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Methods in Molecular Biology (Clifton,... 2021The epithelial-mesenchymal transition (EMT) is a key process required for building the early body plan of metazoa. It involves coordinated and precisely timed changes in...
The epithelial-mesenchymal transition (EMT) is a key process required for building the early body plan of metazoa. It involves coordinated and precisely timed changes in multiple cell processes such as de-adhesion, motility, invasion, and cell polarity. While much has been learned about how embryos deploy epithelial-mesenchymal transitions since Betty Hay named the process decades ago, a number of things are still not well understood. Here I will discuss some of the big questions that remain, including how is all of this controlled, how does each of the cell biological events work, and how are they so nicely coordinated with one another?
Topics: Animals; Cell Adhesion; Cell Movement; Cell Polarity; Embryo, Nonmammalian; Epithelial-Mesenchymal Transition; Epithelium; Gastrulation; Humans; Mesoderm
PubMed: 32939708
DOI: 10.1007/978-1-0716-0779-4_2 -
Current Biology : CB Sep 2021At the initial stage of carcinogenesis, newly emerging transformed cells are often eliminated from epithelial layers via cell competition with the surrounding normal...
At the initial stage of carcinogenesis, newly emerging transformed cells are often eliminated from epithelial layers via cell competition with the surrounding normal cells. For instance, when surrounded by normal cells, oncoprotein RasV12-transformed cells are extruded into the apical lumen of epithelia. During cancer development, multiple oncogenic mutations accumulate within epithelial tissues. However, it remains elusive whether and how cell competition is also involved in this process. In this study, using a mammalian cell culture model system, we have investigated what happens upon the consecutive mutations of Ras and tumor suppressor protein Scribble. When Ras mutation occurs under the Scribble-knockdown background, apical extrusion of Scribble/Ras double-mutant cells is strongly diminished. In addition, at the boundary with Scribble/Ras cells, Scribble-knockdown cells frequently undergo apoptosis and are actively engulfed by the neighboring Scribble/Ras cells. The comparable apoptosis and engulfment phenotypes are also observed in Drosophila epithelial tissues between Scribble/Ras double-mutant and Scribble single-mutant cells. Furthermore, mitochondrial membrane potential is enhanced in Scribble/Ras cells, causing the increased mitochondrial reactive oxygen species (ROS). Suppression of mitochondrial membrane potential or ROS production diminishes apoptosis and engulfment of the surrounding Scribble-knockdown cells, indicating that mitochondrial metabolism plays a key role in the competitive interaction between double- and single-mutant cells. Moreover, mTOR (mechanistic target of rapamycin kinase) acts downstream of these processes. These results imply that sequential oncogenic mutations can profoundly influence cell competition, a transition from loser to winner. Further studies would open new avenues for cell competition-based cancer treatment, thereby blocking clonal expansion of more malignant populations within tumors.
Topics: Animals; Apoptosis; Cell Competition; Drosophila; Epithelium; Mammals; Mutation
PubMed: 34314674
DOI: 10.1016/j.cub.2021.06.064 -
Frontiers in Endocrinology 2024Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These... (Review)
Review
Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.
Topics: Humans; Endothelium, Vascular; Diabetic Angiopathies; Animals; Oxidative Stress
PubMed: 38645427
DOI: 10.3389/fendo.2024.1359255 -
The keratin-desmosome scaffold of internal epithelia in health and disease - The plot is thickening.Current Opinion in Cell Biology Feb 2024Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the... (Review)
Review
Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the epidermis is well recognized, our review focuses on their emerging importance in internal epithelia. The significance of keratin-desmosome scaffolds (KDSs) in the intestine is highlighted by transgenic mouse models and individuals with inflammatory bowel disease who display profound KDS alterations. In lung, high K8 expression defines a transitional cell subset during regeneration, and K8 variants are associated with idiopathic pulmonary fibrosis. Inherited variants in desmosomal proteins are overrepresented in idiopathic lung fibrosis, and familiar eosinophilic esophagitis. K18 serum fragments are established hepatocellular injury markers that correlate with the extent of histological inflammation. K17 expression is modified in multiple tumors, and K17 levels might be of prognostic relevance. These data should spur further studies on biological roles of these versatile tissue protectors and efforts on their therapeutic targeting.
Topics: Mice; Animals; Keratins; Desmosomes; Cytoskeleton; Epithelium; Intermediate Filaments
PubMed: 38000362
DOI: 10.1016/j.ceb.2023.102282 -
Proceedings of the National Academy of... Feb 2023Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion...
Arteriolar smooth muscle cells (SMCs) and capillary pericytes dynamically regulate blood flow in the central nervous system in the face of fluctuating perfusion pressures. Pressure-induced depolarization and Ca elevation provide a mechanism for regulation of SMC contraction, but whether pericytes participate in pressure-induced changes in blood flow remains unknown. Here, utilizing a pressurized whole-retina preparation, we found that increases in intraluminal pressure in the physiological range induce contraction of both dynamically contractile pericytes in the arteriole-proximate transition zone and distal pericytes of the capillary bed. We found that the contractile response to pressure elevation was slower in distal pericytes than in transition zone pericytes and arteriolar SMCs. Pressure-evoked elevation of cytosolic Ca and contractile responses in SMCs were dependent on voltage-dependent Ca channel (VDCC) activity. In contrast, Ca elevation and contractile responses were partially dependent on VDCC activity in transition zone pericytes and independent of VDCC activity in distal pericytes. In both transition zone and distal pericytes, membrane potential at low inlet pressure (20 mmHg) was approximately -40 mV and was depolarized to approximately -30 mV by an increase in pressure to 80 mmHg. The magnitude of whole-cell VDCC currents in freshly isolated pericytes was approximately half that measured in isolated SMCs. Collectively, these results indicate a loss of VDCC involvement in pressure-induced constriction along the arteriole-capillary continuum. They further suggest that alternative mechanisms and kinetics of Ca elevation, contractility, and blood flow regulation exist in central nervous system capillary networks, distinguishing them from neighboring arterioles.
Topics: Pericytes; Calcium; Calcium Channels, L-Type; Arterioles; Central Nervous System; Calcium, Dietary
PubMed: 36802432
DOI: 10.1073/pnas.2216421120 -
Cells Dec 2021Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical... (Review)
Review
Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.
Topics: Airway Remodeling; Cell Differentiation; Epithelial-Mesenchymal Transition; Epithelium; Humans; Lung; Mesenchymal Stem Cells; Organogenesis; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa
PubMed: 34943975
DOI: 10.3390/cells10123467 -
Cell Metabolism Jul 2024Adipose tissue plasticity is orchestrated by molecularly and functionally diverse cells within the stromal vascular fraction (SVF). Although several mouse and human...
Adipose tissue plasticity is orchestrated by molecularly and functionally diverse cells within the stromal vascular fraction (SVF). Although several mouse and human adipose SVF cellular subpopulations have by now been identified, we still lack an understanding of the cellular and functional variability of adipose stem and progenitor cell (ASPC) populations across human fat depots. To address this, we performed single-cell and bulk RNA sequencing (RNA-seq) analyses of >30 SVF/Lin- samples across four human adipose depots, revealing two ubiquitous human ASPC (hASPC) subpopulations with distinct proliferative and adipogenic properties but also depot- and BMI-dependent proportions. Furthermore, we identified an omental-specific, high IGFBP2-expressing stromal population that transitions between mesothelial and mesenchymal cell states and inhibits hASPC adipogenesis through IGFBP2 secretion. Our analyses highlight the molecular and cellular uniqueness of different adipose niches, while our discovery of an anti-adipogenic IGFBP2+ omental-specific population provides a new rationale for the biomedically relevant, limited adipogenic capacity of omental hASPCs.
Topics: Humans; Adipogenesis; Omentum; Insulin-Like Growth Factor Binding Protein 2; Stromal Cells; Female; Male; Middle Aged; Adipose Tissue; Adult; Epithelium; Stem Cells; Mesenchymal Stem Cells; Aged; Animals
PubMed: 38729152
DOI: 10.1016/j.cmet.2024.04.017 -
Der Pathologe Dec 2021Bladder cancer ranks among the top ten most common tumor types worldwide and represents a growing healthcare problem, accounting for a large part of total healthcare... (Review)
Review
BACKGROUND
Bladder cancer ranks among the top ten most common tumor types worldwide and represents a growing healthcare problem, accounting for a large part of total healthcare costs. Chemotherapy is effective in a subset of patients, while causing severe side effects. Tumor pathogenesis and drug resistance mechanisms are largely unknown. Precision medicine is failing in bladder cancer, as bladder tumors are genetically and molecularly very heterogeneous. Currently, therapeutic decision-making depends on assessing a single fragment of surgically acquired tumor tissue.
OBJECTIVE
New preclinical model systems for bladder cancer are indispensable for developing therapeutic strategies tailored to individual patient and tumor characteristics. Organoids are small 3D tissue cultures that simulate small-size organs "in a dish" and tumoroids are a special type of cancer organoid (i.e., malignant tissue).
MATERIALS AND METHODS
Since 2016, we have collaborated with the renowned Hubrecht Institute to provide proof of concept of tissue-based bladder tumoroids mimicking parental tumors. We have developed a living biobank containing bladder organoids and tumoroids grown from over 50 patient samples, which reflect crucial aspects of bladder cancer pathogenesis.
RESULTS
Histological and immunofluorescence analysis indicated that the heterogeneity and subclassification of tumoroids mimicked those of corresponding parental tumor samples. Thus, urothelial tumoroids mimic crucial aspects of bladder cancer pathogenesis.
CONCLUSION
Research with urothelial tumoroids will open up new avenues for bladder cancer pathogenesis and drug-resistance research as well as for precision medicine approaches.
Topics: Carcinoma, Transitional Cell; Humans; Organoids; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium
PubMed: 34623463
DOI: 10.1007/s00292-021-00988-9 -
Stem Cell Research & Therapy Dec 2020The corneal endothelium located on the posterior corneal surface is responsible for regulating stromal hydration. This is contributed by a monolayer of corneal... (Review)
Review
The corneal endothelium located on the posterior corneal surface is responsible for regulating stromal hydration. This is contributed by a monolayer of corneal endothelial cells (CECs), which are metabolically active in a continuous fluid-coupled efflux of ions from the corneal stroma into the aqueous humor, preventing stromal over-hydration and preserving the orderly arrangement of stromal collagen fibrils, which is essential for corneal transparency. Mature CECs do not have regenerative capacity and cell loss due to aging and diseases results in irreversible stromal edema and a loss of corneal clarity. The current gold standard of treatment for this worldwide blindness caused by corneal endothelial failure is the corneal transplantation using cadaveric donor corneas. The top indication is Fuchs corneal endothelial dystrophy/degeneration, which represents 39% of all corneal transplants performed. However, the global shortage of transplantable donor corneas has restricted the treatment outcomes, hence instigating a need to research for alternative therapies. One such avenue is the CEC regeneration from endothelial progenitors, which have been identified in the peripheral endothelium and the adjacent transition zone. This review examines the evidence supporting the existence of endothelial progenitors in the posterior limbus and summarizes the existing knowledge on the microanatomy of the transitional zone. We give an overview of the isolation and ex vivo propagation of human endothelial progenitors in the transition zone, and their growth and differentiation capacity to the corneal endothelium. Transplanting these bioengineered constructs into in vivo models of corneal endothelial degeneration will prove the efficacy and viability, and the long-term maintenance of functional endothelium. This will develop a novel regenerative therapy for the management of corneal endothelial diseases.
Topics: Cell- and Tissue-Based Therapy; Cornea; Corneal Transplantation; Endothelial Cells; Endothelium, Corneal; Humans
PubMed: 33276809
DOI: 10.1186/s13287-020-02046-2 -
International Journal of Molecular... Oct 2021Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the... (Review)
Review
Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the primary tumor and disseminate through the intraperitoneal fluid. The peritoneal mesothelial cell (PMC) monolayer that lines the abdominal cavity is the first barrier encountered by OvCA cells. Subsequent progression of tumors through the peritoneum leads to the accumulation into the peritoneal stroma of a sizeable population of carcinoma-associated fibroblasts (CAFs), which is mainly originated from a mesothelial-to-mesenchymal transition (MMT) process. A common characteristic of OvCA patients is the intraperitoneal accumulation of ascitic fluid, which is composed of cytokines, chemokines, growth factors, miRNAs, and proteins contained in exosomes, as well as tumor and mesothelial suspended cells, among other components that vary in proportion between patients. Exosomes are small extracellular vesicles that have been shown to mediate peritoneal metastasis by educating a pre-metastatic niche, promoting the accumulation of CAFs via MMT, and inducing tumor growth and chemoresistance. This review summarizes and discusses the pivotal role of exosomes and MMT as mediators of OvCA peritoneal colonization and as emerging diagnostic and therapeutic targets.
Topics: Ascitic Fluid; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cytokines; Epithelial-Mesenchymal Transition; Epithelium; Exosomes; Female; Humans; Intercellular Signaling Peptides and Proteins; Ovarian Neoplasms; Peritoneal Neoplasms; Peritoneum
PubMed: 34768926
DOI: 10.3390/ijms222111496