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PubMed2007

Fabrication of three-dimensional tissues.

The goal of tissue engineering is to restore or replace the lost functions of diseased or damaged organs. Ideally, engineered tissues should provide nutrient transport, mechanical stability, coordination of multicellular processes, and a cellular microenvironment that promotes phenotypic stability. To achieve this goal, many engineered tissues require both macro- (approximately cm) and micro- (approximately 100 microm) scale architectural features. In recent years, techniques from the manufacturing world have been adapted to create scaffolds for tissue engineering with defined three-dimensional architectures at physiologically relevant length scales. This chapter reviews three-dimensional fabrication techniques for tissue engineering, including: acellular scaffolds, cellular assembly, and hybrid scaffold/cell constructs.

Biocompatible Materials↗

PubMed2002

Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy.

PURPOSE: (1) To determine whether exposure of phosphatidylserine (PS) occurs on vascular endothelium in solid tumors in mice. (2) To determine whether PS exposure can be induced on viable endothelial cells in tissue culture by conditions present in the tumor microenvironment. METHODS AND MATERIALS: Externalized PS in vivo was detected by injecting mice with a monoclonal anti-PS antibody and examining frozen sections of tumors and normal tissues for anti-PS antibody bound to vascular endothelium. Apoptotic cells were identified by anti-active caspase-3 antibody or by TUNEL assay. PS exposure on cultured endothelial cells was determined by 125I-annexin V binding. RESULTS: Anti-PS antibody bound specifically to vascular endothelium in six tumor models. The percentage of PS-positive vessels ranged from 4% to 40% in different tumor types. Vascular endothelium in normal organs was unstained. Very few tumor vessels expressed apoptotic markers. Hypoxia/reoxygenation, acidity, inflammatory cytokines, thrombin, or hydrogen peroxide induced PS exposure on cultured endothelial cells without causing loss of viability. CONCLUSIONS: Vascular endothelial cells in tumors, but not in normal tissues, externalize PS. PS exposure might be induced by tumor-associated oxidative stress and activating cytokines. PS is an abundant and accessible marker of tumor vasculature and could be used for tumor imaging and therapy.

Animals↗

PubMed1993

The nonlymphoid microenvironment of reactive follicles and lymphomas of follicular origin as defined by immunohistology on paraffin-embedded tissues.

Twenty-five reactive lymph nodes, 10 palatine tonsils, and 72 B-cell non-Hodgkin's lymphomas (NHLs) of supposed follicular origin were investigated in an immunohistologic study of fixed, paraffin-embedded tissues using a panel of monoclonal antibodies reactive with antigens resistant against fixation and paraffin-embedding techniques together with polyclonal antibodies. The results concerning the microenvironmental organization of reactive lymphoid follicles confirmed that the distribution of CD21+ and CD23+ dendritic reticulum cells, vimentin+ fibroblastic reticulum cells, and CD68+ tingible-body macrophages is heterogeneous with reference to their immunostaining patterns and topographic localization within the germinal center and mantle zone. Moreover, a close microenvironmental similarity between the follicular lymphomas of supposed germinal center or mantle zone origin and their normal counterparts was noted. The study of the microenvironment of the B-zone small lymphocytic lymphoma cases, showing the same distribution patterns for the nonlymphoid cells as seen in mantle zone lymphomas, corroborated the supposed follicular origin of this unusual variant of small lymphocytic lymphoma. In conclusion, this study shows that monoclonal antibodies recognizing CD21, CD23, and CD68 antigens may be valuable additions to vimentin, S-100 protein, laminin, and type IV collagen antibodies for investigating the microenvironmental organization of lymphoid tissues in both normal and neoplastic conditions.

Biomarkers↗

PubMed2003

The blood-brain barrier and its role in immune privilege in the central nervous system.

The blood-brain barrier (BBB) provides both anatomical and physiological protection for the central nervous system (CNS), strictly regulating the entry of many substances and blood borne cells into the nervous tissue. Increased understanding of how the unique microenvironment in the CNS influences the BBB is crucial for developing novel therapeutic approaches to CNS diseases. In this review, we discuss those characteristics of the BBB that play an important role in maintaining immune privilege in the CNS, as well as factors that regulate immune cell invasion through the BBB and thereby modulate immune responses in the nervous tissue. In general, immune cell invasion across the BBB is highly restricted and carefully regulated. A florid invasion of activated white blood cells can create a predominantly proinflammatory local environment in the CNS, leading to immune-mediated diseases of the nervous tissue. Recent developments in cellular and molecular biological methods have allowed closer analysis of BBB function, and led to an improved understanding of the active role of the BBB in immune-mediated diseases of the CNS.

Animals↗

PubMedDate not supplied

[Regulatory proteins of vertebrate eye tissues].

In our work the new proteins likely belonged to the microenvironment of pigmented epithelium cells and retinal neurons in mammalian eye were studied. We attempted to understand the role of these proteins in the maintenance of normal morphological and functional state of these eye tissues. Earlier for the first time we identified the adhesion molecules with physico-chemical and biological properties much different from other known cell adhesion molecules of bovine eye. Probably, they represent one family of low molecular weigh, highly glicosylated proteins, that express biological activity in extremely low doses--10(-10) mg/ml. The homogeneity of studying proteins is confirmed by HPLC and SDS-electrophoresis in PAAG. It is shown also that these proteins are N-glycosylated, because they contain mannose and N-acetilglucosamine residues. They demonstrate as well a high calcium-binding activity, with Kd corresponded to 10(-4)-10(-6) mg/ml. For a study of the biological effect of these glycoproteins in extremely low doses, a new experimental model was proposed and developed. It was the cultivation in vitro of the posterior part of the eye obtained from the newt Pleurodeles waltl. In short-time culture system it was demonstrated that the studied glycoproteins could stabilize pigment epithelium cell differentiation and cellular interactions in the neural retina in vitro. In addition, glycoproteins, obtained from the pigmented epithelium of bovine eye could decrease the rate of bipolar cell apoptosis in the neural retina. Therefore, the novel adhesion glycoproteins, expressing their biological activity in extremely low doses, pretend to be the regulatory molecules with vivid gomeostatic effects necessary for the delicate adjustment of cell behavior action and function in sensory tissues.

Animals↗

PubMed1990

Evidence for morphologic diversity of human mast cells. An ultrastructural study of mast cells from multiple body sites.

The ultrastructural features of 502 mast cells, including 34,187 granules, were studied from seven human tissue sites (lung, skin, colon, stomach, small bowel, breast parenchyma, and axillary lymph nodes). Granule areas and substructure were detailed according to the microenvironment (lung alveoli, lung bronchi, bowel mucosa, bowel submucosa, breast skin, breast parenchyma, and axillary lymph nodes). Although completely closed, discrete scrolls were present in some mast cell granules at all tissue locations, they were present more frequently in granules from bowel mucosa and lung (scroll-rich morphology). In contrast, most of the mast cell granules from skin, breast parenchyma, axillary lymph nodes, and bowel submucosa were rimmed by incomplete scrolls forming parallel lamellae; centrally, amorphous granular material and/or grating/lattice-like structures occurred (scroll-poor morphology). In breast, the latter granules had a mean granule area almost twice that of all other sites. Individual mast cells having granules with both scroll-rich and scroll-poor features were common in all tissue sites and microenvironments. In fact, 7.8% of mast cells had granules showing at least one completely closed, discrete scroll and grating/lattice-like structures, sometimes within the same granule. These observations indicate that mixed forms occur and that there is considerable morphologic diversity between the predominant mast cell found in mucosa and lung (scroll-rich morphology) and the predominant mast cell found in skin, breast parenchyma, axillary lymph nodes, and bowel submucosa (scroll-poor morphology).

Breast↗

PubMed2026

Unbiased Spatial Proteomics Uncovers Hepatic in Situ Regulation in Alcohol-Associated Hepatitis.

Alcohol-associated hepatitis (AH) is an acute inflammatory form of alcohol-associated liver disease. Previous studies have explored molecular mechanisms associated with AH pathogenesis through bulk liver tissue analysis; however, the heterogeneity of liver tissue and hence the spatial regulation within the AH liver microenvironment remained unaddressed. Here, an unbiased spatial proteomics analysis on the pathologic regions (PRs) of AH liver tissue is presented, including immune cell infiltration foci, lipid droplets, chicken-wire fibrosis, and fibrotic bands. Through combining a highly efficient nanodroplet processing in one pot for trace samples platform with ultrasensitive liquid chromatography-mass spectrometry, this study identified and quantified a total of 5186 unique proteins from PRs isolated in 200-μm-long × 200-μm-wide × 10-μm-thick areas. This in-depth spatial proteome coverage allowed us to discover mechanistic regulations within individual PRs, including compromised resolution of inflammation with infiltrated neutrophils at infiltration foci, increase of mitochondrial and peroxisomal fatty acid β-oxidation at lipid droplets, and differential cellular and extracellular regulations between chicken-wire fibrosis and fibrotic bands. Overall, this study demonstrated a new capability for AH research, revealed the significance of understanding spatial regulation within AH liver tissue, and further facilitated the development of therapeutic strategies at high resolution.

Proteomics↗

PubMed2006

Regulating activation of transplanted cells controls tissue regeneration.

Current approaches to tissue regeneration are limited by the death of most transplanted cells and/or resultant poor integration of transplanted cells with host tissue. We hypothesized that transplanting progenitor cells within synthetic microenvironments that maintain viability, prevent terminal differentiation, and promote outward migration would significantly enhance their repopulation and regeneration of damaged host tissue. This hypothesis was addressed in the context of muscle regeneration by transplanting satellite cells to muscle laceration sites on a delivery vehicle releasing factors that induce cell activation and migration (hepatocyte growth factor and fibroblast growth factor 2) or transplantation on materials lacking factor release. Controls included direct cell injection into muscle, the implantation of blank scaffolds, and scaffolds releasing factors without cells. Injected cells demonstrated a limited repopulation of damaged muscle and led to a slight improvement in muscle regeneration, as expected. Delivery of cells on scaffolds that did not promote migration resulted in no improvement in muscle regeneration. Strikingly, delivery of cells on scaffolds that promoted myoblast activation and migration led to extensive repopulation of host muscle tissue and increased the regeneration of muscle fibers at the wound and the mass of the injured muscle. This previously undescribed strategy for cell transplantation significantly enhances muscle regeneration from transplanted cells and may be broadly applicable to the various tissues and organ systems in which provision and instruction of a cell population competent to participate in regeneration may be clinically useful.

Animals↗

PubMed1983

Antigen presenting cells in situ: their identification and involvement in immunopathology.

Macrophages and other dendritic non-lymphoid cells have been shown to be functionally capable of presenting antigen to induce lymphocyte responses. These cells can now be studied in situ and distinguished, one from another, within normal tissues and sites of cellular infiltration. Analysis of the microenvironment within which these cells are found can be made with immunohistological methods using monoclonal antibodies (McAbs) and cytochemical techniques. In some cases McAbs are specific for particular types of antigen presenting cell. Using such reagents, evidence is accumulating that these cells may be intimately involved in the pathogenesis of immunoregulatory disorders. What is now required is a more definitive correlation between functional capacity and cell phenotype established with cells isolated from blood, and from normal and pathological tissues. If this is possible the immunopathologist may be able, not only to analyse complex microenvironments but also directly determine the interactions and mechanisms at play within the diseased tissues.

Antibodies, Monoclonal↗

PubMed2004

Microenvironmental interactions and survival of CLL B-cells.

Chronic Lymphocytic Leukemia (CLL) B cells display characteristics consistent with a defect in programmed cell death (apoptosis) and exhibit prolonged survival in vivo. When recovered from peripheral blood or lymphoid tissues from the patient and cultured in vitro, these malignant cells rapidly undergo spontaneous apoptosis. This observation suggests that the selective survival advantage enjoyed by CLL B-cells is not entirely autonomous, raising the possibility of manipulating CLL B-cell survival by iatrogenic means. The extended survival of the neoplastic B-cells creates a permissive soil on which oncogene activation, genetic instability and accumulation of gene mutations favoring disease progression can occur. In addition, such survival-promoting microenvironments can rescue leukemia cells from cytotoxic therapy, giving way to disease relapse. Survival of CLL B-cells is influenced by interactions with non-leukemia cells in the microenvironment of lymph nodes, marrow and other tissues. CLL B-cells have developed many different ways to escape undergoing apoptosis. These include: (a) expression of survival receptor as well as their ligands, giving rise to autocrine survival pathways which are leukemia cell specific; (b) defects in plasma membrane receptor cell signaling, triggered by death receptors such as Fas- and TRAIL; and (c) constitutively active survival signaling pathways such as NFkappaB and PI3K/Akt. Here we discuss some of the molecular mechanisms by which interaction with other cells and factors in the microenvironment provides survival advantages to CLL B-cells in specific in vivo niches, and we suggest some strategies for overcoming these anti-apoptotic mechanisms for improving treatment of CLL.

Animals↗

PubMed2002

Impact of tumor hypoxia and anemia on radiation therapy outcomes.

Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.

Anemia↗

PubMed1991

Synovial tissue macrophage as a source of the chemotactic cytokine IL-8.

Cells of the synovial microenvironment may recruit neutrophils (PMN) and lymphocytes into synovial fluid, as well as lymphocytes into the synovial tissues, of arthritic patients. We have investigated the production of the chemotactic cytokine IL-8 by using sera, synovial fluid, synovial tissue, and macrophages and fibroblasts isolated from synovial tissues from 75 arthritic patients. IL-8 levels were higher in synovial fluid from rheumatoid (RA) patients (mean +/- SE, 14.37 +/- 5.8 ng/ml), compared with synovial fluid from osteoarthritis patients (0.135 +/- 17 ng/ml) (p less than 0.05) or from patients with other arthritides (5.52 +/- 5.11 ng/ml). IL-8 from RA sera was 8.44 +/- 2.33 ng/ml, compared with nondetectable levels found in normal sera. IL-8 levels from RA sera and synovial fluid were strongly positively correlated (r = 0.96, p less than 0.05). Moreover, RA synovial fluid chemotactic activity for PMN in these fluids was inhibited 40 +/- 5% upon incubation with neutralizing polyclonal antibody to IL-8. Synovial tissue fibroblasts released only small amounts of constitutive IL-8 but could be induced to produce IL-8 by stimulation with either IL-1 beta, TNF-alpha, or LPS. In contrast, unlike normal PBMC or alveolar macrophages, macrophages isolated from RA synovial tissue constitutively expressed both IL-8 mRNA and antigenic IL-8. RA synovial macrophage IL-8 expression was not augmented by incubation with either LPS, TNF-alpha, or IL-1 beta. Immunohistochemical analysis of synovial tissue showed that a greater percentage of RA macrophages than osteoarthritis macrophages reacted with anti-IL-8. Whereas macrophages were the predominant cell for immunolocalization of IL-8, less than 5% of synovial tissue fibroblasts were positive for immunolocalized IL-8. These results suggest that macrophage-derived IL-8 may play an important role in the recruitment of PMN in synovial inflammation associated with RA.

Animals↗

PubMed1997

Expression of granzyme B by cytotoxic T lymphocytes in the lymph nodes of HIV-infected patients.

During HIV infection the architecture of secondary lymphoid tissues is severely disrupted. In particular the germinal centers, which play a key role in the orchestration of the secondary immune response, undergo gross phenotypic alterations, leading to a complete destruction of the germinal center microenvironment. The precise mechanisms responsible for the lymphoid tissue destruction in HIV infection are still unknown. However, the large influx of CD8+ T lymphocytes suggests an important role for T cell-mediated cytotoxicity. To establish whether the infiltrating CD8+ T lymphocytes are killing competent, we investigated the expression of granzyme B, which is known to be present in the cytotoxic granules of NK cells and "activated" CTLs with cytolytic potential. We observed a 20-fold increase in the percentage of granzyme B-expressing CD8+ T cells in both the germinal center and the interfollicular areas in HIV patients relative to HIV-negative controls. This increase was present in patients with early-stage disease (i.e., absolute CD4+ T cell count > 500/microliters) as well as in patients with intermediate and late-stage disease. Thus, from relatively early stages of HIV infection onward large numbers of killing competent T lymphocytes are present in the lymphoid tissues, a finding that supports the notion that CTL act as mediators of destruction of immune function during HIV infection.

Adult↗

PubMed1995

Thymic reticulum of mice. III. The connective compartment (innervation, vascularisation, fibrous tissues and myoid cells).

T lymphocytes interact at various levels of differentiation, with cells of the thymic reticulum, forming a peculiar and complex microenvironment. Following earlier descriptions by electron microscopy of three types of epithelial cells and two types of non-epithelial cells (macrophages and interdigitated cells) forming the thymic microenvironment, we report a study on a third compartment, the connective tissue, whose elements occur throughout the organ. The components of the capsule and trabeculae, the vascularisation and the innervation of the thymus and the presence of a few myoid cells are described. This is very rarely studied in ultrastructure. All these cells are completely imbricated and form a network trapping the lymphocytes, playing an essential role in the differentiation, maturation and selection of T cells.

Animals↗

PubMed2002

Distinct distribution of laminin and its integrin receptors in the pancreas.

Tissue function is regulated by the extracellular microenvironment including cell basement membranes, in which laminins are a major component. Previously, we found that laminin-1 promotes differentiation and survival of pancreatic islet cells. Here we characterize the expression pattern of laminins and their integrin receptors in adult pancreas. Although they are expressed in the basement membrane of acinar cells and duct epithelium, no laminin chains examined were detected extracellularly in the pancreatic islets. In contrast to laminin beta(1)- and gamma(1)-chains, the alpha(1)-chain, unique to laminin-1, was not detected. Laminin-10 (alpha(5)beta(1)gamma(1)) was expressed in acinar tissue, whereas laminins-2 (alpha(2)beta(1)gamma(1)) and -10 were expressed in the blood vessels. The laminin connector molecule, nidogen-1, had a distribution similar to that of laminin beta(1) and gamma(1), whereas fibulin-1 and -2, which compete with nidogen-1, were mostly confined to blood vessels. Integrin subunits alpha(6) and alpha(3) were detected in acinar cells and duct epithelial cells, but alpha(6) was absent in islet cells. Integrin alpha(6)beta(4) was detected only in duct cells, alpha(6)beta(1) in both acinar and ductal cells, and alpha(3)beta(1) in acinar, duct, and islet cells. These findings are a basis for further investigation of the role of extracellular matrix molecules and their receptors in pancreas function.

Animals↗

PubMed1996

Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis.

In patients with rheumatoid arthritis the synovial membrane of the affected joint is infiltrated with lymphoid cells which may be arranged in structures resembling germinal centers. We have directly isolated such infiltrates to determine whether B-cell clones within them are selected and expanded in a process analogous to that which normally takes place in the germinal centers in secondary lymphoid organs. The data suggest that an antigen-driven process leads to the accumulation of B cells in the synovial membrane. The finding of identical sequences in consecutive sections suggests that under conditions of chronic stimulation, memory B cells may enter a stage of differentiation in which they proliferate without further accumulation of somatic mutations. Further we see intraclonal diversity which underlines the germinal center-like character of these infiltrates and demonstrates that a microenvironment is built up in this nonlymphoid tissue which supports antigen-dependent differentiation of B cells. This is the first demonstration, to our knowledge, of a germinal center-like reaction outside lymphoid tissue.

Adult↗

PubMed1995

Effects of astrocyte implantation into the hemisected adult rat spinal cord.

Morphological and biochemical methods were applied to assess the effects of implanting cultured astrocytes into the hemisected adult rat spinal cord. Astrocytes were purified from neonatal rat cortex and introduced into the lesioned spinal cord either in suspension injection or cultured on gelfoam first. The control groups were rats which had hemisection with injection of culture media or with gelfoam grafted alone. At various time points after surgery (two weeks to two months), the spinal cord was removed and processed for routine light microscopy, immunofluorescence, gel electrophoresis and immunoblotting. As early as two weeks after surgery, a significantly smaller volume of scar tissue was consistently found in the experimental groups. This reduced scarring was also confirmed by immunofluorescence staining and immunoblotting for glial fibrillary acidic protein in the specimens two months after hemisection. Compared to the control groups, the experimental groups also had more intense staining for neurofilaments, which was confirmed by immunoblotting. However, labelling of the astrocytes with Phaseolus vulgaris leucoagglutinin conjugated with fluorescein showed that the astrocytes migrated at a rate of 0.6 mm/day from the original implanted site. The results therefore suggested that the cultured astrocytes probably exerted their effects over a short time period (less than two weeks) around the lesion site. They could have altered the microenvironment and as a result less scar tissue was formed. Hence, there was less barrier to the regrowth of nerve fibres.

Animals↗

PubMedDate not supplied

EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair.

Matrix metalloproteinases (MMPs) play a central role in normal tissue remodeling and disease, they regulate tumor microenvironment and their expression is increased in most human cancers. Targeting their activity remains a major challenge. Their production and activation is tightly regulated by complex mechanisms that include cytokines and growth factors, cell-matrix and cell-cell interactions. The observations of increased MMP level at the epithelio-stromal interface led to the identification of EMMPRIN/CD147, a membrane spanning molecule highly expressed in tumor cells, that stimulates MMPs production in neighboring fibroblasts. Later studies have shown that EMMPRIN can also induce MMP in the same population of cells. Elevated EMMPRIN level was detected in numerous malignant tumors and has been correlated with tumor progression in experimental and clinical conditions. The presence and modulation of EMMPRIN in normal tissues associated with increased MMP expression suggests that this EMMPRIN-mediated MMP induction could be a common mechanism in non-tumoral physiological and/or pathological situations. Targeting EMMPRIN in cancer and other pathological conditions such arthritis and ulceration appears a promising future therapeutic strategy, but requires a better understanding of its mode of action and regulation. Potential regulators that influence EMMPRIN level and its MMP inducing activity include growth factors, hormones, glycosylation and membrane shedding. This review will discuss the recent findings concerning these diverse regulatory mechanisms in various physiological and pathological situations.

Animals↗