Current topics in membranes最新文献

Endothelial cells (ECs) are constantly subjected to an array of mechanical cues, especially shear stress, due to their luminal placement in the blood vessels. Blood flow can regulate various aspects of endothelial biology and pathophysiology by regulating the endothelial processes at the transcriptomic, proteomic, miRNomic, metabolomics, and epigenomic levels. ECs sense, respond, and adapt to altered blood flow patterns and shear profiles by specialized mechanisms of mechanosensing and mechanotransduction, resulting in qualitative and quantitative differences in their gene expression. Chromatin-regulatory proteins can regulate transcriptional activation by modifying the organization of nucleosomes at promoters, enhancers, silencers, insulators, and locus control regions. Recent research efforts have illustrated that SWI/SNF (SWItch/Sucrose Non-Fermentable) or BRG1/BRM-associated factor (BAF) complex regulates DNA accessibility and chromatin structure. Since the discovery, the gene-regulatory mechanisms of the BAF complex associated with chromatin remodeling have been intensively studied to investigate its role in diverse disease phenotypes. Thus far, it is evident that (1) the SWI/SNF complex broadly regulates the activity of transcriptional enhancers to control lineage-specific differentiation and (2) mutations in the BAF complex proteins lead to developmental disorders and cancers. It is unclear if blood flow can modulate the activity of SWI/SNF complex to regulate EC differentiation and reprogramming. This review emphasizes the integrative role of SWI/SNF complex from a structural and functional standpoint with a special reference to cardiovascular diseases (CVDs). The review also highlights how regulation of this complex by blood flow can lead to the discovery of new therapeutic interventions for the treatment of endothelial dysfunction in vascular diseases.

Fluorescence-based sensors play a fundamental role in biological research. These sensors can be based on fluorescent proteins, fluorescent probes or they can be hybrid systems. The availability of a very large dataset of fluorescent molecules, both genetically encoded and synthetically produced, together with the structural insights on many sensing domains, allowed to rationally design a high variety of sensors, capable of monitoring both molecular and global changes in living cells or in in vitro systems. The advancements in the fluorescence-imaging field helped researchers to obtain a deeper understanding of how and where specific changes occur in a cell or in vitro by combining the readout of the fluorescent sensors with the spatial information provided by fluorescent microscopy techniques. In this review we give an overview of the state of the art in the field of fluorescent biosensors and fluorescence imaging techniques, and eventually guide the reader through the choice of the best combination of fluorescent tools and techniques to answer specific biological questions. We particularly focus on sensors for probing the bioenergetics and physicochemical status of the cell.

Endothelial cells line the innermost layer of arterial, venous, and lymphatic vascular tree and accordingly are subject to hemodynamic, stretch, and stiffness mechanical forces. Normally quiescent, endothelial cells have a hemodynamic set point and become "activated" in response to disturbed hemodynamics, which may signal impending nutrient or gas depletion. Endothelial cells in the majority of tissue beds are normally inactivated and maintain vessel barrier functions, are anti-inflammatory, anti-coagulant, and anti-thrombotic. However, under aberrant mechanical forces, endothelial signaling transforms in response, resulting cellular changes that herald pathological diseases. Endothelial cell metabolism is now recognized as the primary intermediate pathway that undergirds cellular transformation. In this review, we discuss the various mechanical forces endothelial cells sense in the large vessels, microvasculature, and lymphatics, and how changes in environmental mechanical forces result in changes in metabolism, which ultimately influence cell physiology, cellular memory, and ultimately disease initiation and progression.

The first part of the paper describes two simple microscopic techniques that we use in our laboratory. One measures cell volumes in adherent cultures and the other measures cell dry mass; both measurements are done on the same instrument (a standard bright-field transmission microscope with only one or two narrow-band color filters added) and on the same cells. The reason for combining cell volume with dry mass is that the ratio of the two-dry mass concentration (MC)-is an important and insufficiently utilized biological parameter. We then describe a few applications of MC. The available experimental data strongly suggest its critical role in biological processes, including cell volume regulation. For example, most eukaryotic cells have surprisingly similar values of MC. Moreover, MC (and not cell volume) is tightly controlled in growing cell cultures at highly variable external osmolarities. We review the results showing that elevation of MC is a direct cause of shrinkage-induced apoptosis. Also, by focusing on MC, one can study heterogenous processes, such as necrotic swelling, or discriminate between apoptotic dehydration and the loss of cell fragments.

Endothelial cells (ECs), uniquely localized and strategically forming the inner lining of vascular wall, constitute the largest cell surface by area in the human body. The dynamic sensing and response of ECs to mechanical cues, especially shear stress, is crucial for maintenance of vascular homeostasis. It is well recognized that different flow patterns associated with atheroprotective vs atheroprone regions in the arterial tree, result in distinct EC functional phenotypes with differential transcriptome profiles. Mounting evidence has demonstrated an integrative and essential regulatory role of non-coding genome in EC biology. In particular, recent studies have begun to reveal the importance of enhancers and enhancer-derived transcripts in flow-regulated EC gene expression and function. In this minireview, we summarize studies in this area and discuss examples in support of the emerging importance of enhancers and enhancer(-derived) long non-coding RNAs (elncRNAs) in EC mechanosensing, with a focus on flow-responsive EC transcription. Finally, we will provide perspective and discuss standing questions to elucidate the role of these novel regulators in EC mechanobiology.

The importance of cell mechanics has long been recognized for the cell development and function. Biomechanics plays an important role in cell metabolism, regulation of mechanotransduction pathways and also modulation of nuclear response. The mechanical properties of the cell are likely determined by, among many others, the cytoskeleton elasticity, membrane tension and cell-substrate adhesion. This coordinated but complex mechanical interplay is required however, for the cell to respond to and influence in a reciprocal manner the chemical and mechanical signals from the extracellular matrix (ECM). In an effort to better and more fully understand the cell mechanics, the role of nuclear mechanics has emerged as an important contributor to the overall cellular mechanics. It is not too difficult to appreciate the physical connection between the nucleus and the cytoskeleton network that may be connected to the ECM through the cell membrane. Transmission of forces from ECM through this connection is essential for a wide range of cellular behaviors and functions such as cytoskeletal reorganization, nuclear movement, cell migration and differentiation. Unlike the cellular mechanics that can be measured using a number of biophysical techniques that were developed in the past few decades, it still remains a daunting challenge to probe the nuclear mechanics directly. In this paper, we therefore aim to provide informative description of the cell membrane and cytoskeleton mechanics, followed by unique computational modeling efforts to elucidate the nucleus-cytoskeleton coupling. Advances in our knowledge of complete cellular biomechanics and mechanotransduction may lead to clinical relevance and applications in mechano-diseases such as atherosclerosis, stem cell-based therapies, and the development of tissue engineered products.

Microvesicles are small, membrane-bound vesicles that are shed from the plasma membrane of cells into the extracellular space. Microvesicles contain a variety of cargo not typically thought to be released from cells, including receptor tyrosine kinases, cytosolic signaling proteins, and microRNAs, which are transferred from donor cells to recipient cells. The transfer of microvesicle cargo can result in the transformation of recipient cells thereby supporting disease progression, including modified fibroblast metabolism, epithelial cell contractility, vascular remodeling, and immune cell inflammatory signaling. Additionally, microvesicles are believed to play prominent roles in cell-cell communication and disease progression as they are detected at elevated concentrations in diseased tissues. As microvesicle uptake by recipient cells can modulate cell function to promote disease progression, understanding the mechanisms and mechanosensitivity of microvesicle release, internalization, and the resulting signaling is crucial to fully comprehend their functions in disease. Here, we review recent advances in the understanding of actomyosin-regulated microvesicle biogenesis, microvesicle uptake via pinocytosis, and the resulting cellular transformation. We discuss the effects of altered cell contractility, mode of cell migration, and extracellular matrix compliance on microvesicle signaling, with direct implications in disease progression and identifying future therapeutic targets.

Bioactive omega-3 polyunsaturated fatty acids have been shown to reduce the risk of death in patients with cardiovascular disease and alleviate the symptoms of other inflammatory diseases. However, the mechanisms of action of these effects remain unclear. It has been postulated that omega-3 polyunsaturated fatty acids modify cell membranes by incorporation into the membrane and altering the signaling properties of cellular receptors. In this chapter, we explore the effects of omega-3 polyunsaturated fatty acids on cell membrane structure and function. We present a review of the current evidence for the health benefits of these compounds and explore the molecular mechanisms through which omega-3 polyunsaturated fatty acids interact with membrane lipids and modulate bilayer structure. Using computational models of multicomponent phospholipid bilayers, we assess the consequences of incorporation of these fatty acids on membrane lipid packing, water permeation, and membrane structure.

Vascular beds are anatomically and functionally compartmentalized into arteries, capillaries, and veins. The bulk of the vasculature consists of the dense, anastomosing capillary network, composed of capillary endothelial cells (cECs) that are intimately associated with the parenchyma. Despite their abundance, the ion channel expression and function and Ca²⁺ signaling behaviors of capillaries have only recently begun to be explored in detail. Here, we discuss the established and emerging roles of ion channels and Ca²⁺ signaling in cECs. By mining a publicly available RNA-seq dataset, we outline the wide variety of ion channel genes that are expressed in these cells, which potentially imbue capillaries with a broad range of sensing and signal transduction capabilities. We also underscore subtle but critical differences between cEC and arteriolar EC ion channel expression that likely underlie key functional differences in ECs at these different levels of the vascular tree. We focus our discussion on the cerebral vasculature, but the findings and principles being elucidated in this area likely generalize to other vascular beds.