Response of vascular mesenchymal stem/progenitor cells to hyperlipidemia

Hyperlipidemia is a risk factor for atherosclerosis that is characterized by lipid accumulation, inflammatory cell infiltration, and smooth muscle cell proliferation. It is well known that hyperlipidemia is a stimulator for endothelial dysfunction and smooth muscle cell migration during vascular disease development. Recently, it was found that vessel wall contains a variable number of mesenchymal stem cells (MSCs) that are quiescent in physiological conditions, but can be activated by a variety of stimuli, e.g., increased lipid level or hyperlipidemia. Vascular MSCs displayed characteristics of stem cells which can differentiate into several types of cells, e.g., smooth muscle cells, adipocytic, chondrocytic, and osteocytic lineages. In vitro, lipid loading can induce MSC migration and chemokines secretion. After MSC migration into the intima, they play an essential role in inflammatory response and cell accumulation during the initiation and progression of atherosclerosis. In addition, MSC transplantation has been explored as a therapeutic approach to treat atherosclerosis in animal models. In this review, we aim to summarize current progress in characterizing the identity of vascular MSCs and to discuss the mechanisms involved in the response of vascular stem/progenitor cells to lipid loading, as well as to explore therapeutic strategies for vascular diseases and shed new light on regenerative medicine.     

Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.     

Knowledge translation: airway epithelial cell migration and respiratory diseases

Airway epithelial cell migration is essential for lung development and growth, as well as the maintenance of respiratory tissue integrity. This vital cellular process is also important for the repair and regeneration of damaged airway epithelium. More importantly, several lung diseases characterized by aberrant tissue remodeling result from the improper repair of damaged respiratory tissue. Epithelial cell migration relies upon extracellular matrix molecules and is further regulated by numerous local, neuronal, and hormonal factors. Under inflammatory conditions, cell migration can also be stimulated by certain cytokines and chemokines. Many well-known environmental factors involved in the pathogenesis of chronic lung diseases (e.g., cigarette smoking, air pollution, alcohol intake, inflammation, viral and bacterial infections) can inhibit airway epithelial cell migration. Further investigation of cellular and molecular mechanisms of cell migration with advanced techniques may provide knowledge that is relevant to physiological and pathological conditions. These studies may eventually lead to the development of therapeutic interventions to improve lung repair and regeneration and to prevent aberrant remodeling in the lung.     

Platelet–bacterial interactions

Many bacteria are capable of interacting with platelets and inducing platelet aggregation. This interaction may be a direct interaction between a bacterial surface protein and a platelet receptor or may be an indirect interaction where plasma proteins bind to the bacterial surface and subsequently bind to a platelet receptor. However, these interactions usually do not trigger platelet activation as a secondary co-signal is also required. This is usually due to specific antibody bound to the bacteria interacting with FcγRIIa on the platelet surface. Secreted bacterial products such as gingipains and lipopolysaccharide may also be capable of triggering platelet activation.     

The pathogenesis of cardiac fibrosis

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.     

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50% increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA.     

Regulation of phagocyte migration and recruitment by Src-family kinases

Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in signal transduction pathways regulating phagocytic cell migration and recruitment into inflammatory sites. Macrophages with a genetic deficiency of SFKs display marked alterations in cytoskeleton dynamics, polarization and migration. This same phenotype is found in cells with either a lack of SFK substrates and/or interacting proteins such as Pyk2/FAK, c-Cbl and p190RhoGAP. Notably, SFKs and their downstream targets also regulate monocyte recruitment into inflammatory sites. Depending on the type of assay used, neutrophil migration in vitro may be either dependent on or independent of SFKs. Also neutrophil recruitment in in vivo models of inflammation may be regulated differently by SFKs depending on the tissue involved. In this review we will discuss possible mechanisms by which SFKs may regulate phagocytic cell migratory abilities.     

Colloidal drug carriers: achievements and perspectives

Colloidal drug carriers such as liposomes and nanoparticles are able to modify the distribution of an associated substance. They can therefore be used to improve the therapeutic index of drugs by increasing their efficacy and/or reducing their toxicity. If these delivery systems are carefully designed with respect to the target and route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules such as peptides, proteins, genes, and oligonucleotides. They may also extend the therapeutic potential of established drugs such as doxorubicin and amphotericin B. This article discusses the use of colloidal, particulate carrier systems (25 nm to 1 μm in diameter) in such applications. In particular, systems which show diminished uptake by mononuclear phagocytes are described. Specific targeting of carriers to particular tissues or cells is also considered. Received 8 April 2002; received after revision 25 June 2002; accepted 26 June 2002     

Protective effects of hsp70 in inflammation

Inflammation results from the recruitement to a given tissue or organ and the activation of leucocytes, among which the monocytes-macrophages play a major role. These phagocytic cells produce high levels of reactive oxygen species (ROS) as well as cytokines. Whereas both ROS and cytokines have the potential to regulate the expression of heat shock (HS)/stress proteins (HSP), it appears that these proteins in turn have the ability to protect cells and tissues from the deleterious effects of inflammation. The mechanisms by which such protection occurs include prevention of ROS-induced DNA strand breaks and lipid peroxidation as well as protection from mitochondrial structure and function. In vivo, HS protects organs against a number of lesions associated with the increased production of ROS and/or cytokines. In an animal model for adult respiratory distress syndrome, an acute pulmonary inflammatory condition, HS completely prevented mortality. HSP (hsp70 in particular) may also exert protective effects in the immune system by contributing to the processing and presentation of bacterial and tumoral antigens. The analysis of the expression of hsp70 may prove of diagnostic and prognostic value in inflammatory conditions and therapeutical applications are being considered.     

DING proteins: numerous functions, elusive genes, a potential for health

DING proteins, named after their conserved N-terminus, form an overlooked protein family whose members were generally discovered through serendipity. It is characterized by an unusually high sequence conservation, even between distantly related species, and by an outstanding diversity of activities and ligands. They all share a demonstrated capacity to bind phosphate with high affinity or at least a predicted phosphate-binding site. However, DING protein genes are conspicuously absent from databases. The many novel family members identified in recent years have confirmed that DING proteins are ubiquitous not only in animals and plants but probably also in prokaryotes. At the functional level, there is increasing evidence that they participate in many health-related processes such as cancers as well as bacterial (Pseudomonas) and viral (HIV) infections, by mechanisms that are now beginning to be understood. They thus represent potent targets for the development of novel therapeutic approaches, especially against HIV. The few genomic sequences that are now available are starting to give some clues on why DING protein genes and mRNAs are well conserved and difficult to clone. This could open a new era of research, of both fundamental and applied importance.     

Platelet monoamine oxidase B: use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Senescence suppressors: their practical importance in replicative lifespan extension in stem cells

Recent animal and clinical studies report promising results for the therapeutic utilization of stem cells in regenerative medicine. Mesenchymal stem cells (MSCs), with their pluripotent nature, have advantages over embryonic stem cells in terms of their availability and feasibility. However, their proliferative activity is destined to slow by replicative senescence, and the limited proliferative potential of MSCs not only hinders the preparation of sufficient cells for in vivo application, but also draws a limitation on their potential for differentiation. This calls for the development of safe and efficient means to increase the proliferative as well as differentiation potential of MSCs. Recent advances have led to a better understanding of the underlying mechanisms and significance of cellular senescence, facilitating ways to manipulate the replicative lifespan of a variety of primary cells, including MSCs. This paper introduces a class of proteins that function as senescence suppressors. Like tumor suppressors, these proteins are lost in senescence, while their forced expression delays the onset of senescence. Moreover, treatments that increase the expression or the activity of senescence suppressors, therefore, cause expansion of the replicative and differentiation potential of MSCs. The nature of the activities and putative underlying mechanisms of the senescence suppressors will be discussed to facilitate their evaluation.     

Endothelial membrane reorganization during leukocyte extravasation

Leukocyte trafficking from the bloodstream to inflamed tissues across the endothelial barrier is an essential response in innate immunity. Leukocyte adhesion, locomotion, and diapedesis induce signaling in endothelial cells and this is accompanied by a profound reorganization of the endothelial cell surfaces that is only starting to be unveiled. Here we review the current knowledge on the leukocyte-mediated alterations of endothelial membrane dynamics and their role in promoting leukocyte extravasation. The formation of protein- and lipid-mediated cell adhesion nanodomains at the endothelial apical surface, the extension of micrometric apical membrane docking structures, which are derived from microvilli and embrace adhered leukocytes, as well as the vesicle-trafficking pathways that are required for efficient leukocyte diapedesis, are discussed. The coordination between these different endothelial membrane-remodeling events probably provides the road map for transmigrating leukocytes to find exit points in the vessel wall, in a context of severe mechanical and inflammatory stress. A better understanding of how vascular endothelial cells respond to immune cell adhesion should enable new therapeutic strategies to be developed that can abrogate uncontrolled leukocyte extravasation in inflammatory diseases.     

Platelet monoamine oxidase B: Use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Novel aspects and new roles for the serine protease plasmin

The serine protease plasmin is distributed throughout the human body in the form of the zymogen plasminogen. The plasminogen activation system is mostly recognized for its fibrinolytic activity but is also upregulated in chronic inflammatory diseases, including atherosclerosis and arthritis. Plasmin can bind to a variety of cells, including monocytes, through low-affinity binding sites and triggers aggregation of neutrophils, platelet degranulation and arachidonate release from endothelial cells. In monocytes, plasmin elicits full-scale proinflammatory activation, including lipid mediator release, chemotaxis and cytokine expression, as well as induction of other proinflammatory genes. The effects of plasmin are specific, require the active catalytic center and can be antagonized by lysine analogues, implying binding of the plasmin molecule to the cell membrane through its lysine binding sites. In view of the upregulation of the fibrinolytic genes in chronic inflammatory diseases, cell activation by plasmin is likely to play a major pathophysiological role, a view that is further supported by data from transgenic mice.Received 9 September 2003; received after revision 4 October 2003; accepted 13 October 2003     

Eosinophils in the pathogenesis of allergic airways disease

Eosinophils are traditionally thought to form part of the innate immune response against parasitic helminths acting through the release of cytotoxic granule proteins. However, they are also a central feature in asthma. From their development in the bone marrow to their recruitment to the lung via chemokines and cytokines, they form an important component of the inflammatory milieu observed in the asthmatic lung following allergen challenge. A wealth of studies has been performed in both patients with asthma and in mouse models of allergic pulmonary inflammation to delineate the role of eosinophils in the allergic response. Although the long-standing association between eosinophils and the induction of airway hyper-responsiveness remains controversial, recent studies have shown that eosinophils may also promote airway remodelling. In addition, emerging evidence suggests that the eosinophil may also serve to modulate the immune response. Here we review the highly co-ordinated nature of eosinophil development and trafficking and the evolution of the eosinophil as a multi-factoral leukocyte with diverse functions in asthma. Received 6 December 2006; received after revision 11 January 2007; accepted 15 February 2007     

Leukocyte recruitment in atherosclerosis: Potential targets for therapeutic approaches?

Atherosclerosis is a complex inflammatory disease involving cellular migration and interaction. Vascular injury in response to different cardiovascular risk factors enhances endothelial dysfunction, which in turn promotes the expression of inflammatory markers and transendothelial leukocyte migration. Recruitment of leukocytes from the blood stream into the vessel intima is a crucial step for the development of the disease. Recent findings have highlighted the role of chemokines, chemokine receptors, adhesion molecules, and gap junctions in this process by acting as chemoattractant, adhesive, or intercellular communication molecules. In this short review, we summarize new data concerning the different steps from leukocyte arrest to transendothelial migration and discuss potential new therapeutic approaches concerning these processes. Received 15 March 2006; received after revision 19 May 2006; accepted 13 June 2006     

To be disordered or not to be disordered: is that still a question for proteins in the cell?

There is ample evidence that many proteins or regions of proteins lack a well-defined folded structure under native-like conditions. These are called intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). Whether this intrinsic disorder is also their main structural characteristic in living cells has been a matter of intense debate. The structural analysis of IDPs became an important challenge also because of their involvement in a plethora of human diseases, which made IDPs attractive targets for therapeutic development. Therefore, biophysical approaches are increasingly being employed to probe the structural and dynamical state of proteins, not only in isolation in a test tube, but also in a complex biological environment and even within intact cells. Here, we survey direct and indirect evidence that structural disorder is in fact the physiological state of many proteins in the proteome. The paradigmatic case of α-synuclein is used to illustrate the controversial nature of this topic.     

Molecular pathways driving disease-specific alterations of intestinal epithelial cells

Due to the fact that chronic inflammation as well as tumorigenesis in the gut is crucially impacted by the fate of intestinal epithelial cells, our article provides a comprehensive overview of the composition, function, regulation and homeostasis of the gut epithelium. In particular, we focus on those aspects which were found to be altered in the context of inflammatory bowel diseases or colorectal cancer and also discuss potential molecular targets for a disease-specific therapeutic intervention.