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Results for “tissue microenvironment”

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At least 523 records · Page 29Linked to original sources

PubMed2005

Hypoxia inhibits the migratory capacity of human monocyte-derived dendritic cells.

Hypoxia, a prominent characteristic of inflammatory tissue lesions and solid tumour microenvironments, is a crucial stimulus capable of modulating the expression of specific genes involved in leucocyte recruitment. Although studies have shown that hypoxia can affect leucocyte migration by influencing the expression of migration-related genes, such as matrix metalloproteinases (MMP) and their endogenous tissue inhibitors of matrix metalloproteinases (TIMP), it remains unclear whether hypoxia can affect the migration of dendritic cells (DC). In this study, we showed that human monocyte-derived DC under hypoxic conditions in a transwell system have significantly reduced migratory capacity compared to normoxic controls. A moderate phenotypic change of hypoxic DC was observed. In hypoxic DC, we detected a twofold increase in TIMP-1 transcript levels, and downregulated expression of MMP-9 and membrane type 1-MMP genes by threefold and 17-fold, respectively. Our results suggest that hypoxia may inhibit DC migratory activity by regulating the balance between MMP and TIMP gene expression.

Cell Differentiation↗

PubMed2006

Modelling the buried human body environment in upland climes using three contrasting field sites.

Despite an increasing literature on the decomposition of human remains, whether buried or exposed, it is important to recognise the role of specific microenvironments which can either trigger or delay the rate of decomposition. Recent casework in Northern England involving buried and partially buried human remains has demonstrated a need for a more detailed understanding of the effect of contrasting site conditions on cadaver decomposition and on the microenvironment created within the grave itself. Pigs (Sus scrofa) were used as body analogues in three inter-related taphonomy experiments to examine differential decomposition of buried human remains. They were buried at three contrasting field sites (pasture, moorland, and deciduous woodland) within a 15 km radius of the University of Bradford, West Yorkshire, UK. Changes to the buried body and the effect of these changes on hair and associated death-scene textile materials were monitored as was the microenvironment of the grave. At recovery, 6, 12 and 24 months post-burial, the extent of soft tissue decomposition was recorded and samples of fat and soil were collected for gas chromatography mass spectrometry (GCMS) analysis. The results of these studies demonstrated that (1) soil conditions at these three burial sites has a marked effect on the condition of the buried body but even within a single site variation can occur; (2) the process of soft tissue decomposition modifies the localised burial microenvironment in terms of microbiological load, pH, moisture and changes in redox status. These observations have widespread application for the investigation of clandestine burial and time since deposition, and in understanding changes within the burial microenvironment that may impact on biomaterials such as hair and other associated death scene materials.

Animals↗

PubMed2001

Muscle-based gene therapy and tissue engineering for the musculoskeletal system.

The recent expansion of molecular biology techniques has opened the gates for a rapid advancement in our knowledge of disease mechanisms. These techniques, in addition to advances in cell biology and polymer chemistry, are resulting in novel approaches to treating musculoskeletal disorders. Surgeons, who have traditionally used the tools of excision and reconstruction to treat patients, might now serve as surgical 'gardeners', who create microenvironments that are conducive for tissue regeneration. This review will update readers on the principles and current advances in muscle-based gene therapy and tissue engineering for the musculoskeletal system.

Journal Article↗

PubMed2006

The application of stem cells in the treatment of ischemic diseases.

Ischemia causes oxygen deprivation, cell injury and related organ dysfunction. Although ischemic injury may be local, it involves many biochemical changes in different cell types. The ability of stem cells to differentiate into different cell lineages provides the possibility of their use in treating a variety of diseases requiring tissue repair or reconstitution, such as stroke, ischemic retinopathy, myocardial infarction, ischemic disorders of the liver, ischemic renal failure, and ischemic limb dysfunction. Several cell types including embryonic stem cells, various progenitor and stem cells of hematopoietic or mesenchymal origin have been used in attempts to reconstitute injured tissue. Xenologous or autologous stem cells may be administered either through the peripheral vascular system or directly by regional injection. The stem cells are then guided to the infarct site by homing signals. Either by cell differentiation or paracrine effects, stem cells or progenitor cells participate in the reconstruction of a favorable microenvironment resulting in neovascularization and tissue regeneration that eventually improve the physiological function of organs with ischemic damage.

Animals↗

PubMed2006

Use of neopterin as a bone marrow hematopoietic and stromal cell growth factor in tissue-engineered devices.

The in vitro response of early haematopoietic progenitors or stem cells (CD34+)--common for myeloid (granulocyte, eosinophil, megakaryocyte) and marrow stromal cell lineages, to neopterin, exogenously added to the liquid mouse bone marrow cultures, at doses 12.5-25 microg/ml culture medium, has been studied. The results obtained show a significant stimulation of common--myeloid and stromal/ mesenchymal progenitor cell proliferation and differentiation, as early as 24h to the 96h after the in vitro treatment with neopterin. On day 4 of cultivation the granulocyte/macrophageal proliferation and differentiation has been attenuated giving place to the marrow stromal/mesenchymal cell growth and differentiation. A functional role of neopterin as hematopoietic growth factor--essential for the proliferation and differentiation of bone marrow common (hematopoietic and stromal) progenitors is not yet clear and remains to be elucidated. The in vitro and ex vivo applying of neopterin--alone or in specific combinations with other cytokines (e.g. FGF-2) for the induction of marrow stromal/mesenchymal cell proliferation and differentiation, merits further investigations with regards to its future use in regenerative medicine. The results provide a theoretical basis for the application of neopterin in tissue-engineered devices: incorporated into biodegradable polymer microparticles (with encapsulated early bone marrow progenitors and other special supplements), it could be experimentally applied for fast and easy induction of endothelial, osteoblastic/osteogenic, neuronal and other cell lineage differentiation as well as for improving tissue trophical processes and reparative microenvironment.

Animals↗

PubMed1986

In vivo and in vitro modulation of megakaryocytopoiesis and stromal colony formation by lithium.

The ability of lithium to influence in vivo and in vitro megakaryocytopoiesis and the hematopoietic microenvironment from marrow and splenic tissues was investigated. For three consecutive days, mice were injected intraperitoneally with ultrapure lithium chloride (1.6 mg/kg body weight). Animals were killed on days 1 through 4 and thereafter on alternating days until day 16. Megakaryocytopoiesis was evaluated by culturing marrow and splenic cells for their megakaryocyte stem cell (CFU-M) content. The marrow and splenic microenvironment was determined by measuring stromal colonies. Increases in marrow CFU-M were noted on the first 3 days after Li, with the maximum effect on day 2 (180% of control). A second wave of megakaryocytopoiesis began on day 6 and peaked on day 10 (165% of control). Splenic megakaryocytopoiesis was also stimulated by Li; maximum production occurred on day 10 (330% of control). Splenic stromal colony formation was elevated on the 12 days after Li. Numbers of marrow stromal colonies were elevated on days 6, 10, and 12. The increased numbers of marrow- and splenic-derived CFU-M elevated the level of circulating platelets for 10 days after Li. Dose-response Li (0.01 to 10 mmol/L) studies performed in vitro demonstrate that Li effectively increased the number of both CFU-M and stromal colony-forming cells in the presence of optimal concentrations of conditioned media used to stimulate the formation of CFU-M. Furthermore, when stromal colonies were used as feeder layers overlaid with normal nonadherent marrow cells, Li-stimulated stromal colonies supported a greater number of CFU-Ms than did normal, non-Li-treated stromal cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Interactions at the blood/material interface.

The complex interactions occurring at the blood/material interface of implanted blood-contacting biomaterials largely determine the clinical efficacy of small diameter vascular grafts. Physical characteristics of the material such as chemical composition, electrical charge, surface texture, elastic modulus, and porosity all affect many responses at the interfaces with blood, surrounding tissues, and adjacent artery. Some responses begin instantaneously (deposition of plasma proteins and platelets) while other reactions are somewhat delayed (deposition of leukocytes and monocytes, and migration of endothelial cells and smooth muscle cells). Each of these elements may become activated and release bioactive substances which further affect the behavior of the other entities in this complex and dynamic microenvironment. It is precisely these tissue reactions that regulate thrombogenicity and the development of pseudointimal hyperplasia.

Adhesiveness↗

PubMed1993

Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition.

Conventional virgin lymphocytes of a given class show relatively homogeneous recirculation through secondary lymphoid tissues, whereas memory/effector populations are composed of distinct subsets with differential, often tissue-selective migratory capability. In keeping with these observations, CD45RAhigh/ROlow "virgin" T cells in human peripheral blood uniformly express the peripheral lymph node homing receptor (HR) L-selectin, whereas among the CD45RAlow/ROhigh "memory/effector" subset, the expression of this HR is bimodal. To investigate the mechanisms responsible for the generation of memory/effector T cell subsets with differential homing potential, we developed a multiparameter flow cytometric technique that defines a common pathway of post-thymic T cell differentiation in secondary lymphoid tissues. Our analyses indicate that the virgin to memory T cell transition is characterized by a stepwise, unidirectional progression through distinct CD45RA+/RO+ intermediates that allow the in vivo discrimination of early, middle, and late transitional T cells. In normal peripheral blood, few T cells with a transitional phenotype are identified, but in secondary lymphoid tissues, 2 to 10% of T cells have this phenotype, including those CD45RA+ T cells that 1) are morphologically blasts, 2) are in S or G2/M phase of the cell cycle, or 3) express activation Ag. General adhesion molecules (LFA-1, LFA-3, ICAM-1) are uniformly up-regulated concordant with changes in T cell expression of CD45RA/RO in all tissues examined. Early in the transition, L-selectin is also uniformly up-regulated, but in subsequent stages, T cell expression of this HR is preferentially down-regulated in mucosal lymphoid tissues, and retained in peripheral lymph node. Differential regulation of L-selectin can also be demonstrated in vitro by the activation of virgin T cells in the presence of specific cytokines--IL-2 induces L-selectin down-regulation, whereas IL-6 and particularly TGF-beta 1 promote L-selectin up-regulation. Taken together, these findings support the hypothesis that local microenvironments within particular secondary lymphoid tissues influence HR expression at the time of CD45RA/RO conversion, and thereby contribute to the formation of CD45RAlow/ROhigh memory/effector T cell populations with tissue-selective homing behavior.

Adult↗

PubMed2006

Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms.

The tumor microenvironment is notably enriched with a broad spectrum of proteases. The proteolytic specificities of peptide substrates provide modular chemical tools for the rational design of cell-impermeable prodrugs that are specifically activated by proteases extracellularly in the tumor microenvironment. Targeting cell-impermeable prodrug activation to tumor microenvironment will significantly reduce drug toxicity to normal tissues. The activated prodrug attacks both tumor and stroma cells through a "bystander effect" without selectively deleting target-producing cells, therefore further minimizing resistance and toxicity. Here, we showed that legumain, the only asparaginyl endopeptidase of the mammalian genome, is highly expressed by neoplastic, stromal, and endothelial cells in solid tumors. Legumain is present extracellularly in the tumor microenvironment, associated with matrix as well as cell surfaces and functional locally in the reduced pH of the tumor microenvironment. A novel legumain-activated, cell-impermeable doxorubicin prodrug LEG-3 was designed to be activated exclusively in the tumor microenvironment. Upon administration, there is a profound increase of the end-product doxorubicin in nuclei of cells in tumors but little in other tissues. This tumor microenvironment-activated prodrug completely arrested growth of a variety of neoplasms, including multidrug-resistant tumor in vivo and significantly extended survival without evidence of myelosuppression or cardiac toxicity. The tumor microenvironment-activated prodrug design can be extended to other proteases and chemotherapeutic compounds and provides new potentials for the rational development of more effective functionally targeted cancer therapeutics.

Animals↗

PubMed2005

Do tissue levels of autoantigenic aminoacyl-tRNA synthetase predict clinical disease?

The etiologies of most autoimmune diseases are not completely understood. Aminoacyl-tRNA synthetases (AARS) are a family of heterogenous enzymes responsible for protein synthesis and whose secondary functions include a role in autoimmune myositis. A subset of patients with idiopathic inflammatory myopathies demonstrate autoantibody against specific cytoplasmic AARS and the human asparaginyl-tRNA synthetase (AsnRS) has been shown to be a potent chemokine that interacts with CCR3 chemokine receptors. One way in which a chemotactic cytoplasmic enzyme might contribute to tissue inflammation is if it were abundant in a specific injured tissue and thereby released to the microenvironment at times of cellular damage. To test this hypothesis, the relative levels of AsnRS mRNA were studied in six human tissues. A 1.6 kbF RNA probe identified highly variable levels of the corresponding mRNA in Northern blot analysis of human lung, brain, heart, skeletal muscle, pancreas and liver. The highest levels of signal were noted in muscle and pancreas. Polyclonal antibody raised against recombinant human AsnRS identified abundant antigenic material in the pancreas, in particular in islet cells. Thus, the local abundance of an endogenous pro-inflammatory autoantigen may provide one explanation for perpetuation or exacerbation of tissue specific immune-mediated pathologies.

Amino Acyl-tRNA Synthetases↗

PubMed1992

Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

To study the role of the thymus in the cellular pathogenesis of myasthenia gravis (MG) we transplanted thymus tissue fragments from MG thymuses beneath the kidney capsule of severe combined immunodeficiency (SCID) mice. Immunocytochemical studies documented that the human thymus tissues are accepted as long-term grafts in the host SCID mice, with human lymphocytes, thymic stroma, and thymic myoid cells demonstrable in transplanted thymus for at least 15 weeks after transplantation. Human anti-acetylcholine receptor antibodies became detectable 1 to 2 weeks after transplantation, and in most chimeras the titers increased over at least 11 weeks to reach levels typically found in severe human MG. Human Ig deposits were detected at skeletal muscle end-plates, demonstrating that the human (auto)antibodies bound to murine acetylcholine receptor. In contrast, transfers of dissociated thymus cells only lead to a transient increase of anti-acetylcholine receptor antibodies. Our data prove that myasthenia gravis thymus is able to induce and maintain autoantibody production in immunodeprived host animals, and that this tissue contains all cellular components required for autoantibody production. Transplantation of solid thymus tissue seems to transfer an autoimmune microenvironment, which will allow direct studies of the mechanism of autosensitization inside the thymus.

Animals↗

PubMed1996

The use of micromachined surfaces to investigate the cell behavioural factors essential to osseointegration.

OBJECTIVE: Although currently available implants can be used to achieve osseointegration under well-defined conditions, a greater understanding of cell behaviour is required to improve the designs and embark on actual tissue engineering. MATERIALS AND METHODS: We employed micromachined substrata to investigate some of the main behavioural responses of osteoblasts from rat fetal calvaria to surface topography. In particular, confocal laser scanning microscopy (CLSM), differential interference contrast microscopy, time-lapse cinemicrography, immunofluorescence, digital radiography and image analysis were used to investigate cell adhesion, cell shape and cytoskeleton distribution, tissue organization, cell differentiation, and microenvironment. RESULTS AND CONCLUSIONS: A grooved surface permitted the attachment of more cells than a smooth one. Cell shape and cytoskeleton were strikingly influenced as early as 20 min after cell attachment, when the cytoskeleton begins to align with the topography. Some grooved surfaces appeared to promote osteogenesis in vitro as assessed by the production of bone-like nodules. Moreover, these nodules align with the topography in vitro, and preliminary results indicate that bone-like tissue also aligns with grooves when such surfaces are implanted in vivo.

Actins↗

PubMedDate not supplied

The role of lymphotoxin in development and maintenance of secondary lymphoid tissues.

Secondary lymphoid organs provide the necessary microenvironment for the cooperation of antigen-specific T- and B-lymphocytes and antigen-presenting cells in order to initiate an efficient immune response. Remarkable progress in understanding of the mechanisms of lymphoid organogenesis was achieved due to the analysis of various gene-targeted mice. This review primarily focuses on the role of lymphotoxin (LT) in development, maturation and maintenance of secondary lymphoid organs.

Animals↗

PubMed2001

Muscle-based gene therapy and tissue engineering.

The development of new biological approaches based on cell and gene therapies, in combination with tissue engineering, may create innovative ways to treat various tissues of the musculoskeletal system. It is vital for practicing orthopaedic surgeons to understand the terminology, fundamental concepts, and current research in this burgeoning field so that they may practice their discipline in its fullest form. Such techniques, coupled with advances in cell biology and polymer chemistry, are resulting in novel approaches to treating musculoskeletal disorders in which surgeons, who have traditionally used the tools of excision and reconstruction to treat patients, may now serve as surgical gardeners who create microenvironments that are conducive for tissue regeneration. Gene therapy and tissue engineering applications for bone healing, articular disorders, and skeletal muscle diseases and injuries are currently being explored. This review is intended to update readers on the principles and current advances in muscle-based gene therapy and tissue engineering for the musculoskeletal system.

Animals↗

PubMed1991

Optimization of the microenvironment for mammalian cell culture in flexible collagen microspheres in a fluidized-bed bioreactor.

Flexible, three-dimensional, collagen Microspheres have been developed to actively promote a natural, optimal microenvironment for large-scale tissue culture of mammalian cells. The transport of nutrients into and cell products out of the Microspheres is enhanced by forced convective flow, which is the result of the tumbling of Microspheres and the dynamic properties of media flow in the fluidized-bed bioreactor. The collagen Microspheres have important characteristics of composition and morphology essential for optimal cell-matrix and cell-cell interactions. These interactions lead to high cell density and productivity through the dynamic modification of the microenvironment by cell-derived extracellular constituents. The collagen and Microsphere/fluidized-bed system provides the means to control and optimize the diffusive and contact components of the cells' microenvironment. Adaptation of cells to this microenvironment often results in dramatic increases in cell-specific productivity. Production of biotherapeutics in this process can be routinely performed in serum-free media, often leading to high productivity and product quality.

Animals↗

PubMed1998

Chondrogenesis in a cell-polymer-bioreactor system.

Chondrogenesis was studied under controlled in vitro conditions using a cell-polymer-bioreactor system. Bovine calf articular chondrocytes were seeded onto biodegradable polymer scaffolds and cultured in rotating bioreactor vessels. Concomitant increases in the amounts of glycosaminoglycan (GAG) and type II collagen resulted in cell-polymer constructs with continuous cartilaginous matrix over their entire cross sections (6.7 mm diameter x 5 mm thick) after 40 days of cultivation. As compared to natural calf cartilage, constructs had comparable cellularities, 68% as much GAG and 33% as much type II collagen per gram wet weight. The progression of chondrogenesis in chondrocyte-polymer constructs was similar to that suggested previously for precursor cells in vitro and developing limbs in vivo. In particular, the polymer scaffold provided a three-dimensional structure that could be seeded with chondrocytes at high cell densities in order to establish cell-to-cell contacts and initiate cartilage tissue development, whereas the bioreactor vessel provided a permissive microenvironment for chondrogenesis. This work demonstrates the promise of using tissue engineered constructs for in vitro studies of cell interactions and differentiation.

Animals↗

PubMed1997

Potential of microsensor-based feedback bioactuators for biophysical cancer treatment.

Solid tumors usually exhibit a poorly organized vascularization and a deviant energy metabolism which result in an acidic pH and large hypoxic areas in the tumor microenvironment. A lot of cell biological data support the hypothesis that such physico-chemical conditions are promoters of the microevolution of malignant cells, inhibitors of the immune response, and co-factors for tumor cell invasion. Our experimental in vitro analyses and computer simulations indicate that the efficiency of immunotherapies and classical methods for cancer treatment might be improved if a physico-chemical microenvironment could be restored which reflects that found in normal tissue. In order to monitor and manipulate the tumor microenvironment, we suggest utilizing silicon-based feedback bioactuators which are controlled by on-line microsensors. These miniaturized bioactuators play the role of 'pH clamps' and can be implanted directly at the sites of inoperable tumors and metastases where they can reconstitute normal physico-chemical conditions. The drug application scheme can be precisely controlled by an integrated microprocessor. The paper summarizes the current state of development of such microsensor-based feedback bioactuators and outlines their potential for biophysical cancer treatment.

Adaptation, Physiological↗

PubMed1993

Long-term survival of autologous adrenal medulla grafts in the great omentum of the rat.

The omentum, a rich source for trophic and angiogenic factors, was explored as a potential intermediate transplant site to facilitate long-term survival of chromaffin tissue. Autologous rat adrenal medullas were grafted into omental pockets. All grafts became densely vascularized. The grafted chromaffin tissue exhibited strong immunoreactivities for tyrosine hydroxylase, synaptophysin and chromogranin A throughout the observation period of 16 weeks. The expression of these markers implies that grafted chromaffin cells retained the key enzyme for catecholamine biosynthesis and the organelles required for catecholamine secretion. Moreover, intermediate transplant of chromaffin tissue to the omentum could provide a favourable conditioning microenvironment thus augmenting the potential for survival of functional chromaffin tissue.

Adrenal Medulla↗