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At least 451 records · Page 25Linked to original sources
PubMed2004

Exploring interactions between rat hepatocytes and nonparenchymal cells using gene expression profiling.

Cocultivation of primary hepatocytes with a plethora of nonparenchymal cells (from within and outside the liver) has been shown to support hepatic functions in vitro. Despite significant investigation into this phenomenon, the molecular mechanism underlying epithelial-nonparenchymal interactions in hepatocyte cocultures remains poorly understood. In this study, we present a functional genomic approach utilizing gene expression profiling to isolate molecular mediators potentially involved in induction of liver-specific functions by nonparenchymal cells. Specifically, primary rat hepatocytes were cocultivated with closely related murine fibroblast cell types (3T3-J2, NIH-3T3, mouse embryonic fibroblasts) to allow their classification as "high," "medium," or "low" inducers of hepatic functions. These functional responses were correlated with fibroblast gene expression profiles obtained using Affymetrix GeneChips. Microarray data analysis provided us with 17 functionally characterized candidate genes in the cell communication category (cell surface, extracellular matrix, secreted factors) that may be involved in induction of hepatic functions. Further analysis using various databases (i.e., PubMed, GenBank) facilitated prioritization of the candidates for functional characterization. We experimentally validated the potential role of two candidates in our coculture model. The cell surface protein, neural cadherin (N-cadherin), was localized to hepatocyte-fibroblast junctions, while adsorbed decorin up-regulated hepatic functions in pure cultures as well as cocultures with low-inducing fibroblasts. In the future, identifying mediators of hepatocyte differentiation may have implications for both fundamental hepatology and cell-based therapies (e.g., bioartificial liver devices). In conclusion, the functional genomic approach presented in this study may be utilized to investigate mechanisms of cell-cell interaction in a variety of tissues and disease states.

Animals↗
PubMed1995

A novel type of cell-cell cooperation between epithelial cells.

Ma104 cells (renal, epithelial) have a peculiar way of resisting ouabain: their Na+,K(+)-pumps bind the drug with high affinity, cellular K+ is lost and cell division arrested, but cells do not detach as most cell types do. Then, if up to 4 days later the drug is removed, Ma104 cells recover K+ and resume proliferation (Contreras et al., 1994). In the present work, we investigate whether Ma104 cells are able to protect ouabain-sensitive MDCK cells in co-culture. The main finding is that they do, but in this case protection is not elicited by the usual mechanism of maintaining the K+ content of neighboring cells through cell-cell communications. Ma104 cells treated with ouabain simply remain attached to the substrate and to their MDCK neighbors, and both cells lose K+. This attachment includes tight junctions, because the transepithelial electrical resistance of the monolayers is not abolished by ouabain. Although the beta-subunit of the Na+,K(+)-ATPase is known to possess molecular characteristics of cell-cell attachment molecules, attachment between Ma104-MDCK cells does not seem to be mediated by this enzyme, as immunofluorescence analysis reveals that Na+,K(+)-ATPase is only inserted in the plasma membrane facing a neighboring cell of the same type.

Animals↗
PubMed1996

Retinal pigment epithelial cell proliferation: potentiation by monocytes and serum.

BACKGROUND: The development of proliferative vitreoretinopathy (PVR) results often from a breakdown of the blood-retina barrier and the intraocular accumulation of serum proteins and leukocytes, particularly monocytes, that then come into contact with retinal pigment epithelial (RPE) cells. To examine the effect of these two factors on RPE proliferation, which is characteristic of PVR, we used a coculture system of blood monocytes and human RPE cells. METHODS: RPE cells were incubated with a variable number of monocytes at different serum concentrations and assayed for proliferation by [3H]-thymidine incorporation and cell counting. To assess cell-cell communication. RPE cells were labeled with 2', 7' -bis(carboxyethyl)-5(and 6) carboxyfluorescein acetoxy-methyl ester, and the dye transfer to monocytes was analyzed using an UV microscope. RESULTS: Monocytes (P < 0.0004) and serum (P < 0.0001), each on its own, significantly stimulated RPE cell growth, and these two variables were interrelated (P < 0.0001), showing a potentiating synergism. In serum-free medium, monocytes increased proliferation to just above control levels, whereas the same number of monocytes in 5% serum increased the [3H]-thymidine incorporation 3.8 times. This effect was greatly reduced by prevention of direct cell contact by means of placement of a well insert, which also lessened the monocyte-induced proliferation in both serum-free and serum-containing medium. Furthermore, the transfer of the intracellular dye from RPE cells to cocultured monocytes indicates that RPE cells transferred parts of their cytoplasm to monocytes. CONCLUSION: These observations underline the importance of protein leakage through a damaged blood-ocular barrier and of direct contact of monocytes/macrophages with RPE cells, as well as their reciprocal potentiating effect on RPE cell proliferation. Thus, early stabilization of the blood-ocular barrier, which would preclude or reduce protein leakage and invasion of inflammatory cells into the eye, could be a target for pharmacologic prevention of PVR.

Blood Physiological Phenomena↗
PubMed2003

Eph signaling: a structural view.

Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, shape and mobility. Both Ephs and ephrins are membrane-bound and their interactions at sites of cell-cell contact initiate unique bidirectional signaling cascades, with information transduced in both the receptor-expressing and the ligand-expressing cells. Recent structural and biophysical studies summarized in this review reveal unique molecular features not previously observed in any other receptor-ligand families and explain many of the biochemical and signaling properties of Ephs and ephrins. Of particular importance is the insight into how approximation of ligand-expressing and receptor-expressing cells could lead to the formation and activation of highly ordered signaling centers at cell-cell interfaces.

Animals↗
PubMed1980

Saccharin may act as a tumour promoter by inhibiting metabolic cooperation between cells.

The possible role of saccharin in the carcinogenic process is, at present, still unclear. Carcinogenesis is a complex process involving, in many test systems, initiation and promotion phases. Current evidence favours the hypothesis that initiation is due to a mutagenic event, while promotion (at least the early portion) is the result of epigenetic changes. Although saccharin has been reported to be a weak mutagen in various in vitro test systems and a weak initiator in mouse skin, there is increasing evidence from in vitro, as well as in vivo, studies that it might act as a tumour promoter, rather than as a mutagen. Recently L.P.Y. et al and J.E.T. et al. developed an in vitro assay to detect tumour promoters, which has been independently reported by Murray and Fitzgerald. The assay is based on the principle that phorbol ester-type tumour promoters block 'metabolic cooperation' or a type of cell-cell communication between cells. We report here a series of experiments demonstrating the elimination of metabolic cooperation in the hypoxanthine guanine phosphoribosyltransferase (HGPRT) system in Chinese hamster V79 cells, indicating that saccharin shares properties similar to those of other known promoters.

Animals↗
PubMed1989

Loss of competence in amphibian induction can take place in single nondividing cells.

The ability of ectodermal tissue to be induced to form mesoderm is lost during gastrula stages in Xenopus embryos. We have examined the extent to which this loss of competence depends on intercellular interactions, cell division, or protein synthesis. We find that ectoderm, when separated from a whole embryo as soon as the early blastula stage, and even when dissociated into its component cells, loses its competence at the normal time. When cell division was arrested by culturing isolated cells in solid medium, the time of competence loss was unaffected. To test whether protein synthesis is required for competence loss, ectoderm was treated with cycloheximide during the normal time that competence is lost; in some cases, this treatment had no effect and in others it prolonged competence, but only slightly. We conclude that the loss of mesodermal competence is a highly autonomous process in ectodermal cells, taking place in the absence of cell communication or cell division.

Animals↗
PubMed1996

[Introduction to the structure and functions of junction communications or gap junctions].

Cell-to-cell communication through gap junctions (GJ) represents a direct route of exchange of informations between neighboring cells within tissues and organs. GJ are formed from the assembly of a large number of channels that differ from the other known channels because they connect the cytoplasm of adjacent cells. The GJ channel is built from two parts: the connexons. A connexon inserted into the plasma membrane of a cell interacts with another connexon belonging to an adjacent cell. Connexons are composed of proteins with four transmembrane domains that are named connexins (Cx). Six Cx form a connexon. Cx belong to a protein family with 13 known members at present. Each Cx is defined by its molecular mass in kDa (ex: Cx32, Cx43...). A given cell type expresses one or several Cx. The cell to cell transfer of molecules through GJ channels exhibit a size selectivity; only molecules with a molecular mass lower than 1000 Da such as ions and second messengers freely pass through GJ. Depending on the Cx they are made of, GJ seem to differ somewhat in their permeability properties. Cell-to-cell communication via GJ is a regulated process. GJ channels can be either open or closed. GJ mediated cell-to-cell communication or junctional coupling can be detected and quantified by visualization of the cell to cell transfer of a fluorescent probe (such as Lucifer Yellow...) previously introduced in a single cell by microinjection. The presence of GJ channels can also be identified by recording the passage of an electric current between contiguous cells. GJ are involved in numerous fundamental biological processes from the embryonic development to the homeostasis in adult tissues and organs. GJ coordinate cell activities and sometimes synchronize cell behaviour. This is the case for the propagation of the excitation wave in the cardiac muscle and smooth muscle. GJ mediate metabolic cooperation between cells; they represent a way of supply of nutrients for tissues that are weakly or not vascularized. GJ take part in the control of cell proliferation. The loss of GJ-mediated cell-to-cell communication is a common feature of transformed cells and the re-establishment of junctional coupling is associated with a decrease of tumoregenicity. Allowing the cell-to-cell transfer of second messengers, GJ participate (and sometimes control) the response of a cell population to signalling molecules. It is known for example that hormones influence the expression of Cx and thus the level of the junctional coupling and that communication via GJ has an effect on the type and extent of action of hormones.

Connexins↗
PubMed1994

Interleukin-1 alpha suppresses gap junction-mediated intercellular communication in human endothelial cells.

Interleukin-1 alpha (IL-1 alpha) is a potent modulator of endothelial cell-surface properties and function as well as an inhibitor of endothelial cell proliferation. The present experiments demonstrate that IL-1 alpha can also suppress gap junction activity as measured by dye-coupling assays on human umbilical vein endothelial cells (HUVEC). The effect of IL-1 alpha is dose- and time-dependent, inhibitable by IL-1 receptor antagonist, independent of changes in intracellular [Ca+2], and distinguishable from the short-term effects of phorbol 12-myristate 13-acetate. Interestingly, IL-1 alpha was not effective in reducing cell communication in senescent HUVEC which exhibit lower coupling than early-passage cells and for which elevated levels of IL-1 alpha transcript and polypeptide had been reported previously. These results suggest a novel role for IL-1 alpha in the regulation of intercellular communication, which may be related to its role as a regulator of endothelial differentiation and senescence.

Alkaloids↗
PubMed1992

Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines.

Subtractive hybridization, selecting for mRNAs expressed in normal human mammary epithelial cells (NMECs) but not in mammary tumor cell lines (TMECs), led to the cloning of the human gap junction gene connexin 26 (Cx26), identified by its sequence similarity to the rat gene. Two Cx26 transcripts derived from a single gene are expressed in NMECs but neither is expressed in a series of TMECs. Northern analysis using rat Cx probes showed that Cx43 mRNA is also expressed in the normal cells, but not in the tumor lines examined. Connexin genes Cx31.1, Cx32, Cx33, Cx37, and Cx40 are not expressed in either normal cells or the tumor lines examined. In cell-cell communication studies, the normal cells transferred Lucifer yellow, while tumor cells failed to show dye transfer. Both Cx26 and Cx43 proteins were immunolocalized to membrane sites in normal cells but were not found in tumor cells. Further analysis demonstrated that Cx26 is a cell-cycle regulated gene expressed at a moderate level during G1 and S, and strongly up-regulated in late S and G2, as shown with lovastatin-synchronized NMECs. Cx43, on the contrary is constitutively expressed at a uniform low level throughout the cell cycle. Treatment of normal and tumor cells with a series of drugs: 5dB-cAMP, retinoic acid, okadaic acid, estradiol, or TGFb had no connexin-inducing effect in tumor cells. However, PMA induced re-expression of the two Cx26 transcripts but not of Cx43 in several TMECs. Thus Cx26 and Cx43 are both downregulated in tumor cells but respond differentially to some signals. Modulation of gap-junctional activity by drug therapy may have useful clinical applications in cancer.

Amino Acid Sequence↗
PubMed1990

Gap-junctional communication of bone marrow stromal cells is resistant to irradiation in vitro.

Bone marrow is one of the most radiosensitive organs. Irradiation causes a marked decrease in the total number of hematopoietic cells in the bone marrow. The reticular meshwork structure of marrow stromal cells, however, is relatively resistant to irradiation. Unimpaired stromal cell structure has been thought to be a prerequisite for the repopulation of hematopoietic cells during recovery from the effects of irradiation. The reticular framework is maintained by cell adhesion apparatuses such as gap junctions. The in vitro radiobiologic survival values of a cloned stromal cell line, H-1/A, were studied (ñ = 1.8, D0 = 138 cGy). Radiation doses of up to 4000 cGy had no detectable effects on the production of colony-stimulating factor 1. H-1/A cells communicate with each other via gap junctions as determined by the sensitive dye-transfer method. Gap-junctional communication between H-1/A cells was resistant to different levels of irradiation (500 to 10,000 cGy), but it was lost during adipocyte differentiation of H-1/A cells. Marrow stromal cells, which are important in the recovery of hematopoiesis, seemed capable of coordination with each other through gap junctions even when exposed to radiation.

Bone Marrow↗
PubMed2000

Atomic force microscopy to study direct neurite-mast cell (RBL) communication in vitro.

Communication between nerves and mast cells is a prototypic demonstration of neuroimmune interaction. We used an in vitro co-culture approach comprising cultured murine superior cervical ganglia (SCG) and rat basophilic leukemia (RBL-2H3) cells. Atomic force microscopy (AFM) showed how neurites attached to a pseudopodium or a cell body of an RBL cell. After stimulation of SCG neurites with bradykinin or scorpion venom, RBL cells attached to neurites spread and flattened, and several discharged granules (0. 5-1.0 microm in diameter) were found on the surface of the RBL cells. A neurokinin (NK)-1 receptor (i.e. substance P receptor) antagonist prevented the RBL degranulation. The results showed that activation of the SCG neurites with bradykinin or scorpion venom was able to elicit degranulation in RBL cells which were attached to neurites.

Animals↗
PubMed2006

v-Src requires Ras signaling for the suppression of gap junctional intercellular communication.

Cell transformation by v-Src causes suppression of gap junctional intercellular communication (GJIC). Although tyrosine phosphorylation of connexin43 (Cx43), a gap junctional component, appears to be necessary for the suppression, involvement of other signaling remains unclear. We investigated the role of Ras signaling in the suppression of GJIC by v-Src. Conditional expression of either S17N Ras or mtGap1m dramatically recovered GJIC in v-Src-transformed cells. Although expression of S17N Ras or mtGap1m substantially decreased the levels of active Ras, tyrosine phosphorylation of cellular proteins including Cx43 remained unchanged. Similarly, treatment of v-Src-transfomed cells with a Ras farnesyltransferase inhibitor, manumycin A, restored GJIC, whereas tyrosine phosphorylation of Cx43 remained unchanged. Thus, these results strongly suggest that, in addition to Cx43 phosphorylation, constitutive activation of Ras signaling is required for the suppression of GJIC by v-Src.

Animals↗