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PubMedDate not supplied

Recent progress in understanding the relationships among aging, replicative senescence, cell turnover and cancer.

The link between aging and cancer is more than just the increasing accumulation of mutations with time. Recent research provides evidence that senescent cells are not merely passive bystanders, but may promote cancer through degradation of the tissue microenvironment. Another critical factor in the relationship between aging and cancer is p53 function; its activity level is apparently finely tuned to suppress cancer while regulating both apoptosis and the replacement of damaged cells through stem cell proliferation. The deacetylase activity of the sir2 gene product plays a role in longevity regulation in invertebrates, and also regulates p53 function in mammals, implying yet another link between aging and cancer in mammals.

Aging↗
PubMed2002

[Mesenchymal stem cells and related factors].

Mesenchymal stem cells possess the ability to differentiate into osteoblasts, chondroblasts, lipoblasts, myoblasts and so on, which can be used in the formation of hematopoietic microenvironment, tissue repairing and gene therapy. Growth factors such as TGF-beta, IGF-I, BMP and FGF can influence on the differentiation of MSC and they cooperate with each other. MSCs support hematopoiesis by secreting cytokines including G-CSF, SCF, LIF, M-CSF, IL-6, IL-11 and are related to some diseases. MSC would demonstrate important effect on gene engineering.

Animals↗
PubMed1992

Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy.

Angiogenesis, the growth of blood capillaries, is regulated by soluble growth factors and insoluble extracellular matrix (ECM) molecules. Soluble angiogenic mitogens act over large distances to initiate capillary growth whereas changes in ECM govern whether individual cells will grow, differentiate, or involute in response to these stimuli in the local tissue microenvironment. Analysis of this local control mechanism has revealed that ECM molecules switch capillary endothelial cells between differentiation and growth by both binding specific transmembrane integrin receptors and physically resisting cell-generated mechanical loads that are applied to these receptors. Control of capillary endothelial cell form and function therefore may be exerted by altering the mechanical properties of the ECM as well as its chemical composition. Understanding of this mechanochemical control mechanism has led to the development of new angiogenesis inhibitors that may be useful for the treatment of cancer.

Animals↗
PubMed2004

An unexpected role for hypoxic response: oxygenation and inflammation.

The eradication of invading microorganisms depends initially on innate immunity mechanisms that preexist in all individuals and act within minutes of infection. Pathogen spread is often countered by an inflammatory response that recruits more effector molecules and cells of the innate immune system from local blood vessels, while inducing clotting farther downstream so that pathogens cannot spread throughout the blood. If a microorganism crosses an epithelial barrier and begins to replicate in the tissues of the host, it is, in some cases, immediately recognized by the mononuclear phagocytes, or macrophages, that reside in tissues. Macrophages mature continuously from circulating monocytes that leave the circulation to migrate into tissues throughout the body. The second major family of phagocytes, the neutrophils or polymorphonuclear leukocytes (PMNs) are short-lived cells that are abundant cells in the blood but are not present in healthy tissues. Both phagocytic cell types play a key role in innate immunity because they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response. This infiltration of neutrophils and later macrophages to the site of bacterial infection is tightly linked with the need of these immune defense cells to respond to the tissue microenvironment.

Animals↗
PubMed2003

Mechanisms of specific immunotherapy: current knowledge.

Induction of specific unresponsiveness (tolerance) in peripheral T cells by IL-10 and/or TGF-beta and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy of allergy and natural exposure to allergens in healthy individuals. IL-10 and TGF-beta elicit tolerance in T cells and thereby control the suppression and development of antigen-specific immunity. Both cytokines also play an important role on the generation of a non-inflammatory IgG4 and IgA type of allergen--specific antibodies during the course of specific immunotherapy. Histamine plays an important role in upper and lower airway inflammation. In addition to its well-characterized effects in the acute inflammatory and allergic responses, histamine regulates several aspects of antigen-specific immune response development. Histamine affects the maturation of dendritic cells and alters their T cell polarizing capacity. Histamine regulates antigen specific Th1 and Th2 cells as well as related antibody isotype responses. Histamine and four different known histamine receptors (HR) display a very complex system and their expression changes according to the stage of cell differentiation as well as microenvironmental influences.

Antibody Formation↗
PubMed1992

IL-4 suppresses cytokine gene expression induced by IFN-gamma and/or IL-2 in murine peritoneal macrophages.

The effect of IL-4 on inflammatory gene expression in murine peritoneal macrophages stimulated with IFN-gamma in combination with IL-2 has been examined. These agents cooperatively induce the expression of mRNA for TNF-alpha and IP-10. Murine rIL-4 suppresses cytokine mRNA expression depending on the stimulus used and the mRNA being measured. Expression of TNF-alpha mRNA in macrophages stimulated with IFN-gamma, IL-2, or the combination is markedly suppressed by IL-4 whereas LPS-induced TNF-alpha mRNA is unaffected. In contrast, IP-10 mRNA expression is more sensitive to suppression by IL-4 when stimulated by LPS than by IFN-gamma/IL-2. IL-4-mediated suppression does not alter the time course of mRNA expression. Treatment of IFN-gamma/IL-2-stimulated macrophages with cycloheximide blocks the suppressive effect of IL-4, suggesting that de novo synthesis of an intermediate protein is part of the suppressive mechanism. The IL-4-mediated suppression of IFN-gamma/IL-2-driven TNF-alpha gene expression appears to be mediated at the level of transcription. These findings support a role for IL-4 as an antiinflammatory cytokine and suggest that macrophage inflammatory function will be dependent on the precise stimulus composition of the tissue microenvironment.

Animals↗
PubMed1992

[Studying the mast cell. Recent data].

In the light of recently published data, the mast cell can now be viewed as a key cell, not only in allergic reactions such as immediate hypersensitivity responses, but also in a broad spectrum of other biologic responses including host-parasite interactions, nonspecific inflammatory reactions, fibrosis, angiogenesis, tissue reconstruction, and wound healing. Nevertheless the molecular basis for the intervention of mast cells in many of these biologic responses is still unclear. Very recent studies have demonstrated that mast cells are capable of producing a wide range of cytokines, a property which may influence various physiologic, immunologic and disease processes. Furthermore, although substantial differences have been reported between mast cells located in different tissues, the reasons and mechanisms underlying this heterogeneity long remained obscure. The recent development of two original experimental approaches, i.e., in vitro culture of mast cells, mainly derived from mouse bone marrow precursors, and replenishment of mast cell-deficient mice, has provided new insight into the mechanisms by which tissue microenvironment influence of regulation mast cell phenotype. Extrapolation to humans of data obtained in rodents is, however, hazardous. In the review presented here, the most recent data from the literature provide the basis for outlining avenues of research which can be expected, in the near or remote future, to solve what mast cell experts term "the riddle of the mast cells".

Animals↗
PubMed2006

[The role of matrix metalloproteinases in tumor invasion and metastasis].

The complicated process of invasion and metastasis consists of a long series of sequential and interrelated steps. The outcome of the process is dependent on both: the tumour cells and the properties of tissue microenvironments. Many investigators are interested in the influence of extracellular matrix components on that process. Especially matrix metalloproteinases (MMPs)--family of zinc-dependent enzymes, which take part in the coordination of extracellular matrix synthesis and breakdown seems to play crucial role in this process. A positive correlation between different type of MMPs and specific tumors has been demonstrated in many studies. In this article we summarize the current views on the role of MMPs in cancer invasion and metastasis.

Animals↗
PubMed1987

Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol.

Dendritic cells have been isolated from human tonsillar tissue and shown to act as accessory cells in a mitogenic response. The dendritic cells will induced receptors for the active metabolite of vitamin D3, 1,25(OH)2D3, in the responder E+ T cells. The dendritic cells themselves constitutively express receptors for the metabolite, and this distinguishes them from other non-T cells in lymphomedullary tissue. Expression of the 1,25(OH)2D3 receptor may be a dendritic cell property that facilitates their accessory cell role within the tissue microenvironment.

Calcitriol↗
PubMed1994

Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. I. Mechanism and evidence of functional significance.

Tenidap is a novel anti-inflammatory and antiarthritic agent that in clinical studies of rheumatoid arthritis patients, displays symptomatic efficacy superior to nonsteroidal anti-inflammatory drugs (NSAIDs) and equivalent to combinations of NSAIDs and second line agents. Clinical and preclinical biochemical studies have demonstrated that tenidap combines cytokine modulation with suppression of prostaglandin biosynthesis. To better understand tenidap's mechanism of action, in vitro studies of intracellular pH (pHi) were conducted. In cells loaded with the pH-sensitive fluorescence dye 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein, tenidap, but not NSAIDs, caused a rapid and sustained acidification of the cytoplasmic compartment. Tenidap did not act as a proton ionophore, as it did not dissipate the low pH within lysosomes. Mammalian cells regulate pHi through the concerted action of a number of specific transport proteins, including sodium-proton antiporters and chloride-bicarbonate exchangers. Tenidap did not alter pHi via inhibition of the sodium-proton antiporter, but inhibited activity of chloride-bicarbonate exchangers, as did UK5099, a known anion-transport inhibitor that also lowers pHi. This similar activity suggests that the pHi change is coupled to anion transport inhibition. As a result of the pHi change, tenidap affected pH-dependent cellular activities. Tenidap inhibited mannose 6-phosphate receptor-mediated endocytosis, inhibited protein synthesis, and stimulated accumulation of the amino acid leucine. Effects on these cellular processes rapidly reversed when tenidap was removed from the culture medium. Tenidap's in vitro activities were highly dependent on the medium composition; protein content, pH, and bicarbonate concentration all were important factors that influenced activity. These results indicate that tenidap is a potent anion-transport inhibitor and modulator of pHi. Within the appropriate cell or tissue microenvironment, these activities may contribute to tenidap's novel therapeutic profile.

Animals↗
PubMedDate not supplied

Adhesion molecule interaction with extracellular matrix.

The role of extracellular matrix (ECM) proteins in supporting tissue structure and modulating cell moltility or phagocytosis is well established. Recent demonstration of complex in vitro interactions between lymphocytes and ECM components mediated by an array of cell surface adhesion receptors supports the role ECM may play in physiological functioning of the immune system in vivo, e.g. cell activation, migration and positioning in specific tissue microenvironments. Thus, ECM components and their lymphocyte adhesion ligands should be considered as active participants in the host immune responses, including that triggered by transplantation of an MHC-incompatible organ graft.

Animals↗
PubMed1977

The role of committed and uncommitted hematopoietic stem cells as targets for Rauscher and Friend leukemia virus.

The study of Friend and Rauscher murine leukemia viruses has produced a variety of evidence regarding the nature of the target cell(s). These viruses produce in mice leukemias with a strong erythroid component. However, they are also pancytotic in their action, with demonstrable effects on differentiating myeloid and thromboid cells, the immuno-responsive cells, and the peripheral lymphoid cells as well. In addition, it has been noted that a variety of factors can influence disease expression, including the variety of mouse strain, the hematopoietic cell line being observed, and the tissue microenvironment in which leukemogenesis is taking place, as well as the viral substrain itself. The data available indicates that the target cells are definitely to be found among the most primitive of the hematopoietic progenitor cells of both the marrow and the spleen. However, from an analysis of this data it would appear that the virus target is not exclusively limited to a single type of hematopoietic precursor cell. Rather it is suggested that there is a closely related family of targets, consisting of the uncommitted pluripotent stem cell and the committed progenitor stem cells of the erythroid, myeloid, thromboid and immune cell lines. The evidence for each of these types of hematopoietic cells is reviewed.

Animals↗
PubMed1997

Nitric oxide inhibits IgE-mediated degranulation of mast cells and is the principal intermediate in IFN-gamma-induced suppression of exocytosis.

IFN-gamma regulates various aspects of rodent peritoneal mast cell function, including mediator release, cell growth, TNF-alpha-mediated cytotoxicity, and MHC class II expression. We investigated whether the suppressive action of IFN-gamma on IgE/Ag-mediated degranulation of mast cells is mediated via synthesis of nitric oxide. Incubation of mouse peritoneal cells with L-NMMA, an inhibitor of nitric oxide synthase, or in medium lacking the nitric oxide precursor L-arginine reversed the inhibitory effect of IFN-gamma on Ag-induced serotonin release. Furthermore, the nitric oxide donors sodium nitroprusside and S-nitrosoglutathione inhibited degranulation, and this effect was direct, since it was seen equally on purified and unfractionated mast cells and occurred independently of IFN-gammaR expression. Additional experiments revealed that accessory cells in peritoneal cell populations were the principal target for the action of IFN-gamma and the main source of nitric oxide; the cytokine was more potent on unfractionated compared with purified mast cells, and IFN-gamma induced detectable nitrite production in mixed peritoneal cells, but not in purified mast cells. These studies show that IFN-gamma induces nitric oxide production in peritoneal cell populations, and that synthesized nitric oxide directly inhibits the IgE-mediated secretory function of mast cells. The activation of nitric oxide-producing cells in the tissue microenvironment may be important in the control of mast cell-dependent allergic reactions.

Animals↗
PubMed1998

The role of cellular senescence in skin aging.

Higher organisms contain two types of cells: postmitotic cells, which never divide, and mitotic (or mitotically competent) cells, which can divide. Postmitotic cells include mature nerve, muscle, and fat cells, some of which persist for life. Mitotic cells include epithelial and stromal cells of organs such as the skin. Because postmitotic and mitotic cells differ in their proliferative capacity, they may age by different mechanisms. Normal somatic mitotically competent cells do not divide indefinitely. The process that limits the cell division number is termed cellular or replicative senescence. Replicative senescence is thought to be a powerful, albeit imperfect, tumor suppressive mechanism. It is also thought to contribute to organismic aging. Senescent cells undergo three phenotypic changes: they irreversibly arrest growth, they acquire resistance to apoptotic death, and they acquire altered differentiated functions. The growth arrest is very likely critical for the role of replicative senescence in tumor suppression, but may be less important for the aging of organs such as the skin. On the other hand, the altered differentiation may be critical for compromising the function and integrity of organs like the skin during aging. Senescent keratinocytes and fibroblasts appear to accumulate with age in human skin. Moreover, senescent cells express genes that have long-range, pleiotropic effects - degradative enzymes, growth factors, and inflammatory cytokines. Thus, relatively few senescent cells might compromise skin function and integrity. Moreover, by altering the tissue microenvironment, senescent cells may also contribute to the rise in cancer that occurs with age.

Cell Differentiation↗
PubMedDate not supplied

Tissue barriers, immunosuppressive microenvironments, and privileged sites: the eye's point of view.

Immune privilege exists at numerous sites in the body. It is becoming increasingly clear that privilege is extended to foreign tissues implanted at privileged sites by active regulatory mechanisms, rather than because implanted tissues are hidden from recognition by cells of the immune system. Recent experimental analysis of privilege has focused on regional tissue factors that participate in creating the privileged status. Local barriers are being more fully described, barriers that restrict, but do not prevent, afferent and efferent communication between a privileged site and the systemic immune apparatus. In addition, cytokines and mediators are being discovered at local sites, and these agents appear to create novel microenvironments that act on migrating cells of the lymphoreticular system and thereby modify both the induction and expression of immunity to antigenic materials that are introduced into, or arise within, privileged sites. This review summarizes many recent studies, and attempts to place in the broader context of systemic immunity what has been learned in the recent past about the unique forms of immunity that attend foreign tissue grafts and other types of antigenic materials placed experimentally in privileged sites. Particular emphasis is placed on reconciling (a) the requirements of various organs and tissues for immune protection against invading pathogens with (b) the vulnerability of certain organs and tissues to immunopathogenic processes that inadvertently inflict tissue injury and dysfunction.

Animals↗
PubMed2006

Modeling evaluation of the fluid-dynamic microenvironment in tissue-engineered constructs: a micro-CT based model.

Natural cartilage remodels both in vivo and in vitro in response to mechanical stresses, hence mechanical stimulation is believed to be a potential tool to modulate extra-cellular matrix synthesis in tissue-engineered cartilage. Fluid-induced shear is known to enhance chondrogenesis in engineered cartilage constructs. The quantification of the hydrodynamic environment is a condition required to study the biochemical response to shear of 3D engineered cell systems. We developed a computational model of culture medium flow through the microstructure of a porous scaffold, during direct- perfused culture. The 3D solid model of the scaffold micro-geometry was reconstructed from 250 micro-computed tomography (micro-CT) images. The results of the fluid dynamic simulations were analyzed at the central portions of the fluid domain, to avoid boundary effects. The average, median and mode shear stress values calculated at the scaffold walls were 3.48, 2.90, and 2.45 mPa respectively, at a flow rate of 0.5 cm(3)/min, perfused through a 15 mm diameter scaffold, at an inlet fluid velocity of 53 microm/s. These results were compared to results estimated using a simplified micro-scale model and to results estimated using an analytical macro-scale porous model. The predictions given by the CT-based model are being used in conjunction with an experimental bioreactor model, in order to quantify the effects of fluid-dynamic shear on the growth modulation of tissue-engineered cartilage constructs, to potentially enhance tissue growth in vitro.

Bioreactors↗