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PubMed1985

The murine thymic nurse cell: an isolated thymic microenvironment.

The thymic nurse cell (TNC) consists of an epithelial cell enclosing lymphoid elements and is found in enzymic digests of the thymus. Although these structures have been implicated in the normal intrathymic development of T lymphocytes, little is known about the in situ structure of this unusual cell complex. In this study, various dyes were introduced into the intact thymus and their differential permeability was used to demonstrate that the TNC exists as a sealed structure in situ. The lymphocytes within the TNC were shown to be isolated from the general thymic environment. Preliminary studies on these lymphocytes and the physiology of their active release from individual, micromanipulated TNC in microcultures are reported.

Animals↗
PubMed1991

Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment.

In order to assess the possible role of lymphoid cells in the development of thymic epithelium, we compared the organization and maturation of thymic epithelium in scid mice lacking T cell receptor (TcR)-positive cells with that in scid mice containing TcR+ cells. Immunohistologic examination revealed that thymi from TcR- scid mice were deficient in thymic medullary epithelial cells recognized by the monoclonal antibody ER-TR5, and that the few thymic medullary epithelial cells present were not organized into discrete medullary areas. In contrast, thymi from scid mice containing TcR+ cells possessed ER-TR5+ thymic medullary epithelial cells and these cells were organized normally into discrete medullary regions. Thus, normal organization and maturation of thymic medullary epithelial cells did not occur in the absence of TcR+ cells, but did occur upon introduction of TcR+ cells. We conclude that lympho-stromal cell interactions in the thymus are not unidirectional, and that a symbiotic relationship exists between maturing epithelial cells and developing lymphocytes.

Animals↗
PubMed1994

Extracellular matrix components of the mouse thymus microenvironment. IV. Modulation of thymic nurse cells by extracellular matrix ligands and receptors.

Extracellular matrix (ECM) proteins can influence cell migration and differentiation in a variety of cell systems. Within the thymus, these molecules are heterogeneously distributed, and their physiological role is poorly understood. This prompted us to carry out in vitro studies using the thymic nurse cell (TNC) model. We observed that fibronectin and laminin accelerate spontaneous in vitro release of thymocytes from TNC, whereas anti-ECM antibodies exhibited a blocking effect. Similar results were obtained with anti-ECM receptor reagents. Moreover, these antibodies abrogated in vitro reconstitution of TNC complexes and thymocyte adhesion to TNC-derived epithelial cultures. Our results indicate that lymphocyte traffic in TNC (comprising both entrance into and exit from the epithelial structure) is affected by interactions involving extracellular matrix ligands and receptors. In this respect, the dynamic analysis of thymic nurse cell complexes should be regarded as a relevant in vitro tool for functional studies of distinct adhesion molecules in intrathymic lymphocyte traffic.

Animals↗
PubMed1987

Problems of space gastroenterology and microenvironment.

Numerous studies have revealed changes in gastrointestinal secretion, motility, evacuation, and absorption in humans and animals after actual space missions and under hypokinesia of various duration as well. It is found that short-term space missions produce transient changes in the activity of digestive enzymes, instability of bifido- and lactoflora peculiar to stress reaction, and an enhanced evacuation of the stomach. Extended space missions result in more pronounced but transient changes which characterize mainly two states: development of a hypersecretory syndrome of the stomach and decrease in the functional capacity of the pancreas. As a rule, the changes of membranous enzymes are of compensatory-and-adaptive character. Concurrent with this, there occur disbiotic changes of various degree in the intestinal microflora.

Digestion↗
PubMed1993

Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain.

The nature and function of previously described perineuronal nets are still obscure. In the present study their polyanionic components were demonstrated in the rat brain using colloidal iron hydroxide (CIH) staining. In subcortical regions, such as the red nucleus, cerebellar, and vestibular nuclei, most neurons were ensheathed by CIH-binding material. In the cerebral cortex perineuronal nets were seen around numerous nonpyramidal neurons. Biotinylated hyaluronectin revealed that hyaluronan occurs in perineuronal nets. Two plant lectins [Wisteria floribunda agglutinin (WFA) and Vicia villosa agglutinin (VVA)] with affinity for N-acetylgalactosamine visualized perineuronal nets similar to those rich in anionic components. Glutamic acid decarboxylase (GAD)-immunoreactive synaptic boutons were shown to occupy numerous meshes of perineuronal VVA-positive nets. Electron microscopically, VVA binding sites were scattered throughout perisynaptic profiles, but accumulated at membranes and in the extracellular space except not in synaptic clefts. To investigate the spatial relationship between glial cell processes and perineuronal nets, two astrocytic markers (S100-protein and glutamine synthetase) were visualized at the light and electron microscopic level. Two methods to detect microglia by the use of Griffonia simplicifolia agglutinin (GSA I-B4) and the monoclonal antibody, OX-42, were also applied. Labelled structures forming perineuronal nets were observed with both astrocytic, but not with microglial, markers. It is concluded that perineuronal nets are composed of a specialized type of glia-associated extracellular matrix rich in polyanionic groups and N-acetylgalactosamine. The net-like appearance is due to perisynaptic arrangement of the astrocytic processes and these extracellular components. Similar to the ensheathment of nodes of Ranvier, perineuronal nets may provide a special ion buffering capacity required around various, perhaps highly active, types of neurons.

Acetylgalactosamine↗
PubMed2001

Telomerase deregulation in immortalized human epidermal cells: modulation by cellular microenvironment.

Modulation of telomerase activity was investigated in the spontaneously immortalized SIK human epidermal cell line. Although these cells displayed low telomerase activity in early passage, similar to that in normal human epidermal cells, the activity was found to be markedly stimulated by cultivation in the presence of epidermal growth factor (EGF). This stimulation was evident in later passage as well, but the relative increase was not as marked inasmuch as the basal activity increased with passage. Normal human epidermal cells in culture displayed low telomerase activity shortly after inoculation and it decreased further with time, reaching minimum levels several days after cultures became confluent, independently of EGF addition. SIK cultures grown in the absence of EGF behaved similarly. However, addition of EGF to these cultures prevented the telomerase decrease otherwise observed in log-phase growth. In the presence of EGF, telomerase activity was maximal approximately 12 days after inoculation and then decreased considerably at confluence. In the absence of EGF, telomerase activity was increased by UV exposure despite its suppressive effect on keratinocyte growth. In the absence of EGF, the protein tyrosine phosphatase inhibitor vanadate stimulated growth marginally and did not have a pronounced effect on telomerase. In the presence of EGF, however, vanadate antagonized EGF action on cell growth and on telomerase activity, and it stimulated spontaneous envelope formation in a dose-dependent manner. Thus the spontaneously immortalized SIK line provides a useful model for study of telomerase modulation during the neoplastic progression of keratinocytes.

3T3 Cells↗
PubMed1986

A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment.

The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance.

Cell Cycle↗
PubMed2003

How to build an adapted and bioactive cell microenvironment? A chemical interaction study of the structure of Ca-alginate matrices and their repercussion on confined cells.

Alginates are increasingly being used as medical materials (matrices for tissue regeneration, surgical sponges, hemostatic bandages, microbial and cell encapsulation, artificial bacterial biofilms, etc.). The constitution of alginate gel networks is a complex phenomenon. A great number of different kinds of polysaccharidic frameworks can come to existence depending on the conditions used for their attainment. For instance, the degree of heterogeneity and porosity of Ca-alginate beads rely on this molecular organization. The formation of structural irregularities (superficial crust, cavities, shafts, dense or light gel frameworks, ordered or chaotic domains, etc.) within the alginate gel beads are inherent to this skeletal design. Several specific staining molecules (e.g. calcon carboxylic acid, murexide, methylene blue) that are negatively or positively charged interact with the gel network. These molecules allowed us to reveal a great variety of chemical interactions shown by the pattern coloration of the internal structure of the gel. The results observed are very different for the several matrices analyzed, which could explain to a great extent the singular behavior that cells confined in these kind of matrices exhibit.

Alginates↗
PubMed1984

In vitro hemopoiesis within a microenvironment created by MC3T3-G2/PA6 preadipocytes.

The clonal preadipose cell line, MC3T3-G2/PA6, has the capacity to differentiate into adipocytes in response to glucocorticoids and to support in vitro growth of hemopoietic stem cells (CFU-S). To study the relationship between these capacities, we precultured the MC3T3-G2/PA6 cells for varying days in the presence or absence of dexamethasone and then cocultured them with mouse bone marrow cells. Logarithmically growing cultures contained no detectable adipocytes and showed the highest growth-supporting activity for CFU-S, whereas cultures containing the largest number of adipocytes showed the lowest activity. When bone marrow cells were seeded onto 3-day-old MC3T3-G2/PA6 preadipocyte layers at 1 X 10(5) cells/35-mm dish, day 12 CFU-S grew with a population doubling time of about 37 hr, and at least 75% of them were associated with the cell layer between days 2 and 7. In the absence of the preadipocytes, CFU-S were not detected in the adherent cell fraction and decreased with a half-life of about 18 hr. More than 80% of CFU-C were also found to be associated with the preadipocyte layer, and they increased about 24-fold in number during 7 days in culture. Morphologically, hemopoietic cells developing into mature granulocytes and macrophages were distributed between the layers of preadipocytes. Dendritic processes of preadipocytes were frequently in close alignment with the hemopoietic cells. However, adipocytes failed to show such an intimate association with hemopoietic cells. These results indicate that MC3T3-G2/PA6 cells in the preadipocyte stage, but not in the adipocyte stage, have the capacity to support CFU-S growth, and that hemopoiesis in our cocultivation system proceed within the microenvironmental milieu provided by MC3T3-G2/PA6 preadipocytes.

Adipose Tissue↗
PubMed1992

Importance of tyrosine phosphatases in the effects of cell-cell contact and microenvironments on EGF-stimulated tyrosine phosphorylation.

We have compared the EGF responses of A431 cells when grown as monolayers at a variety of cell densities or as multicellular spheroids in order to investigate the effects of cell contact and 3-dimensional structure on signal transduction. Proliferation of the A431 squamous carcinoma cell line grown in our laboratory was unaffected by EGF when grown in monolayer culture. As 3-dimensional, multicellular spheroids, however, growth was stimulated by EGF. The maximum volume attainable in the presence of EGF was more than 30 times that in its absence. EGF-dependent tyrosine phosphorylation was compared under these conditions by immunohistochemistry and Western blotting. In initial experiments using published procedures, tyrosine phosphorylation was density-dependent in monolayers and undetectable in spheroids. However, the density-dependence was abolished by the addition of high concentrations of protein tyrosine phosphatase inhibitors (1 mM Zn++ and VO4(3)-). The density dependence of EGF-stimulated tyrosine phosphorylation in monolayers was, therefore, largely the result of changes in phosphatase activity rather than kinase. Using high concentrations of phosphatase inhibitors, phosphotyrosine was clearly visible by immunohistochemistry in the outermost cells of spheroids, but it was still not visible in the spheroid center. The lack of response within the spheroid was not related to the presence of EGF receptor nor diffusion of EGF. In companion experiments, we showed that staining for EGF receptor was present homogeneously throughout the spheroid and that EGF penetrated to its center under the conditions of the experiment. Thus, although an increase in tyrosine phosphatase activity was a major factor affecting tyrosine phosphorylation in the outer cells, other factors were important in the inner cells. We concluded that an increase of tyrosine phosphatase activity was the most important component of the adaptation of the EGF signal transduction system to high cell density in monolayer cultures. In spheroids, tyrosine phosphatases are also enhanced, but other factors, such as autocrine synthesis of TGF-alpha and possibly the cellular distribution of EGF receptors and cell shape, play a role.

Blotting, Western↗
PubMed2004

Adenosine stimulation of proliferation of breast carcinoma cell lines: evaluation of the [3H]thymidine assay system and modulatory effects of the cellular microenvironment in vitro.

The purine nucleoside adenosine is produced at increased levels in the tissues of solid cancers as a result of local hypoxia. Adenosine inhibits the cell-mediated anti-tumor immune response, promotes tumor cell migration and angiogenesis, and stimulates the proliferation of tumor cells. We examined the stimulatory effect of adenosine on DNA synthesis, cell cycle progression, and cell proliferation in MCF7 and T-47D breast carcinoma cell lines in culture, and identified factors that modulate the growth response. The ability of adenosine to stimulate DNA synthesis, as measured by the incorporation of [(3)H]thymidine, was independent of the total radioactivity of the [(3)H]thymidine up to 10 microCi/ml, total thymidine concentrations up to 100 microM, and the labeling interval. It was also not affected by the presence of low-molecular-weight compounds (such as thymidine and adenosine) in the serum used to supplement the medium. Adenosine stimulated DNA synthesis and cell proliferation with an EC(50) of 4-6 microM and a maximum response at 30-100 microM, when given as a single addition. The stimulatory effect of adenosine involved progression through the cell cycle and a genuine increase in cell number, in the absence of significant apoptotic or necrotic cell death. The mitogenic effect of adenosine was dependent upon the culture cell density, with an optimum adenosine response at around 50% of confluent density. The response was also highly dependent upon the form of the serum addition to the growth medium, with the best response elicited in the presence of low concentrations of nonfetal bovine serum, although adenosine was mitogenic under standard culture conditions. The effects of serum supplementation and cell density were not due to differences in the rate of adenosine metabolism by either serum or cellular enzymes, but appeared to result from changes in the sensitivity to adenosine of the cell population in response to environmental cues. We, therefore, find that adenosine is consistently mitogenic for human breast carcinoma cells, and that the [(3)H]thymidine incorporation assay is a valid measure of this response. The data are consistent with the stimulatory effect of adenosine on cell proliferation being modulated by the local cellular environment.

Adenosine↗
PubMed2006

Healing of articular cartilage defects. An experimental study of vascular and minimal vascular microenvironment.

The repair potential in a chondral defect with (treatment A) or without access to bone marrow elements (treatment B) at the basis of the defect sealed by a rim-sutured periosteal flap was studied using adult New Zealand rabbits (22 weeks) as an experimental model. At sacrifice, macroscopical changes, synovial fluid contents, degree of filling, thickness of the cartilage rim, and the subchondral bone were evaluated. Histomorphometric measurements of extent of filling (mainly fibrous tissue) of the defect at 36 weeks postoperatively, showed 50% filling in treatment A compared with 33% in treatment B (p = 0.011). A difference in height of the cartilage rim between the experimental groups and sham-control was measured ( p = 0.005). Cartilage degeneration was observed at the cartilage rim of the original defect, and included loss of chondrocytes and disruption of surface continuity in both experimental groups. In addition, treatment A resulted in a significantly increased thickness of the subchondral bone in the defect in comparison to treatment B at 2 weeks and at 36 weeks (p = 0.021). The increased thickness of the subchondral bone may be of concern for the bone marrow stimulation techniques regarding the long-term outcome.

Animals↗
PubMed1981

Cell interactions in the bone marrow microenvironment: role of endogenous colony-stimulating activity.

Adherent stromal cells from mouse bone marrow inhibited the formation of granulocyte/monocyte (G/M) colonies induced in vitro by colony-stimulating factor (CSF). This inhibition occurred both when crude conditioned media obtained from various sources were used to induce colony formation or when a pure CSF preparation from mouse lung origin was tested. The inhibition did not appear to be toxic in nature since despite the lack of colony formation, progenitor CFU-C proliferated in the presence of stromal cells. Medium conditioned by adherent stromal cells was devoid of inhibitory activity when incorporated into the culture medium used for G/M colony formation, indicating that the inhibitory activity may not be present in a soluble form. Inhibitors of prostaglandins did not affect G/M colony formation. In contrast, D-glucose and a number of other free monosaccharides but not pyruvate lactate or glycerol induced formation of myeloid colonies in the presence of stromal cells. This did not require addition of exogenous CSF. Released factors concentrated from serum-free medium conditioned by stromal cells exhibited colony-stimulating activity provided that the medium contained a high glucose concentration during incubation. It is proposed that stromal cells produce a resident CSF that, in contrast to exogenous CSF species, is capable of inducing myelopoiesis within the bone and marrow stroma.

Animals↗
PubMed1994

Modulation of gamete and embryonic microenvironments by oviduct glycoproteins.

Studies on protein molecules in oviduct luminal fluid are viewed historically, and then in terms of more recent studies on a possible involvement of unique glycoproteins in embryonic development. As a caution, however, it is noted that incorporation of such molecules into the vitellus may be nonspecific. The question is raised as to whether oviduct glycoproteins could be acting primarily in a physical sense to stabilize differing chemical environments along the oviduct. Equally or more importantly, glycoproteins might be acting as carrier molecules to present cations and metabolic substrates at appropriate concentrations to the vitelline membrane. This latter possibility is examined in some detail and could be tested by manipulating the composition of the perivitelline fluid. Glycoproteins may also be critically involved in regulating the physiological competence of spermatozoa in the pre- and peri-ovulatory oviduct, in maintaining a coordinated pattern of cilial beat, and in immunosuppressive functions within the oviduct, not least in those associated with the masking of paternal antigens on both spermatozoa and embryos.

Animals↗