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PubMed2001

Keratinocyte growth factor promotes goblet cell differentiation through regulation of goblet cell silencer inhibitor.

BACKGROUND & AIMS: Keratinocyte growth factor (KGF) is an epithelial cell-specific growth factor. Previous reports demonstrated that KGF induces differentiation of epithelial cells of gastrointestinal tract in vivo, especially goblet cell-specific lineage stimulation. Intestinal trefoil factor (ITF) is selectively expressed in intestinal goblet cells and its expression correlates with intestinal goblet cell differentiation. In this study, we analyzed the mechanism of KGF modulation of goblet cell differentiation through characterization of its effects on ITF gene expression. METHODS: Subclone H2 of the human colonic epithelial cell line HT-29, which can be induced to intestinal goblet cells, was treated with KGF and characterized by Northern and Western blot analyses, transient transfection assays, and electrophoretic mobility shift assays (EMSAs). RESULTS: KGF promoted differentiation of H2 cells to goblet cells as reflected by induced ITF expression. Transient transfection assays revealed that KGF regulates mouse ITF transcription through the goblet cell silencer inhibitor (GCSI) element, which is essential for goblet cell-specific expression of ITF. EMSAs showed that KGF induces GCSI binding protein (GCSI-BP). CONCLUSIONS: KGF promotes goblet cell differentiation through the induction of GCSI-BP, a goblet cell-specific transcription factor. GCSI-BP may play a central role in intestinal goblet cell differentiation.

Cell Differentiation↗
PubMed1987

Characterization of photoreceptor cell differentiation in the rat retinal cell culture.

Photoreceptor cell differentiation in the rat retina was studied in vivo and in vitro, using an immunohistochemical method to demonstrate opsin-like immunoreactivity. Cells in a dissociated monolayer culture expressed some properties characteristic of rat rod cells developing in vivo, including a ciliary structure and opsin-like immunoreactivity. Immunoblot analysis revealed that cultured retinal cells synthesize a polypeptide with the same molecular weight as that synthesized by the intact retina. Although the outer segment (OS) was not present in the culture, immunoreactive cells possessed a ciliary structure. Opsin-like immunoreactivity was found on the plasma membrane, including the cilia. The neuritic extensions were also intensely stained. In mature rod cells of the intact rat retina, opsin was detected only on the OS but, during development, it was found both in the somatic region of the rod cells and on the differentiating OS. During maturation of rod cells opsin immunoreactivity seemed to shift to the OS from other locations. However, some "displaced" photoreceptor cells, found in the inner nuclear layer and extending fibers bipolarly, retained immunoreactivity throughout their structure. The absence of polarized distribution of opsin in these cells is considered to be due to an abnormal environment, which may also be the case with cultured retinal cells. The present culture conditions will offer a useful model system to understand the cellular mechanism of the hereditary retinal dystrophy of rodent animals in which photoreceptor cells selectively degenerate.

Animals↗
PubMed2003

Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1.

The transcription factor X-box binding protein 1 (XBP-1) is essential for the differentiation of plasma cells and the unfolded protein response (UPR). Here we show that UPR-induced splicing of XBP-1 by the transmembrane endonuclease IRE1 is required to restore production of immunoglobulin in XBP-1-/- mouse B cells, providing an integral link between XBP-1, the UPR and plasma cell differentiation. Signals involved in plasma cell differentiation, specifically interleukin-4, control the transcription of XBP-1, whereas its post-transcriptional processing is dependent on synthesis of immunoglobulins during B cell differentiation. We also show that XBP-1 is involved in controlling the production of interleukin-6, a cytokine that is essential for plasma cell survival. Thus, signals upstream and downstream of XBP-1 integrate plasma cell differentiation with the UPR.

Animals↗
PubMed1993

p53 gene is up-regulated during skeletal muscle cell differentiation.

Differentiation of cells in the mouse myogenic cell line C2, or a primary culture of chicken satellite cells was induced by low serum levels in the growth medium. Endogenous wild-type p53 mRNA was substantially expressed after approximately 5 h of incubation. Induction of p53 mRNA expression was also observed in cells treated with 10(-8) M retinoic acid, after 18 h of incubation. In both cases, the increase in p53 mRNA was transient. c-fos mRNA levels decreased rapidly and were barely detectable after 2 h of exposure to retinoic acid. The down-regulation of c-fos confirms its role in muscle cell differentiation, whereas the up-regulation of wild-type p53 suggests its role during this process.

Animals↗
PubMed2006

Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c+CD86+ cells with direct and indirect antigen-presenting function.

Dendritic cells (DCs) derive from CD34+ cells or monocytes and stimulate alloimmune responses in transplantation. We hypothesized that the interaction between CD34+ cells and allogeneic T cells would influence the function of hematopoietic stem cells (HSCs). Cord blood (CB) CD34+ cells proliferated briskly in response to allogeneic, but not autologous, T cells when mixed with irradiated T cells for 6 days in vitro. This proliferation was significantly inhibited by an anti-HLA class II monoclonal antibody (mAb), by an anti-TNFalpha mAb, or by CTLA4-Ig. Allogeneic T cells induced the differentiation of CD34+ progenitors into cells with the morphology of dendritic monocytic precursors and characterized by the expression of HLA-DR, CD86, CD40, CD14, and CD11c, due to an endogenous release of TNFalpha. Cotransplantation of CD34+ cells with allogeneic T cells into nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice resulted in a greater engraftment of myeloid CD1c+ dendritic cells compared with cotransplantation with autologous T cells. In vitro, CD34+ cell-derived antigen-presenting cells (APCs) were functionally capable of both direct and indirect presentation of alloantigens. Based on these findings, we hypothesize that in HSC transplantation the initial cross talk between allogeneic T cells and CD34+ cells may result in the increased generation of APCs that can present host alloantigens and possibly contribute to the development of graft-versus-host disease.

Animals↗
PubMed1991

Increase in beta-1,4-galactosyltransferase activity during PC12 cell differentiation induced by forskolin and 2-chloroadenosine.

Galactosyltransferase (GALTase) activity was measured in differentiating PC12 cells induced by either forskolin or 2-chloroadenosine. The specific activity of GALTase in whole cells and isolated Golgi membranes increased as early as 3 h after initiating treatment with 2-chloroadenosine, and maximal activity was reached at approximately 12 h. In two mutant PC12 cell lines deficient in protein kinase A, both forskolin and 2-chloroadenosine failed to increase GALTase activity. The adenosine A2 receptor antagonist, xanthine amine congener, prevented 2-chloroadenosine stimulation of GALTase, demonstrating that this adenosine derivative was mediating its effect via the A2 receptor. These data suggest that GALTase activity during PC12 cell differentiation is regulated by cyclic AMP (cAMP)- and protein kinase A-dependent processes. In support of the role of cAMP in regulating GALTase activity were studies with murine PC carcinoma cells demonstrating that the greatest stimulation of GALTase activity occurred with cells treated with both retinoic acid and dibutyryl cAMP.

2-Chloroadenosine↗
PubMed2006

The immunogenicity and immunomodulatory function of osteogenic cells differentiated from mesenchymal stem cells.

Multipotent mesenchymal stem cells (MSC) are reported to be immunoprivileged as well as immunosuppressive. Hence, they are ideal candidates for allogeneic transplantation to induce regeneration of diseased tissues and organs. However, it is not known whether MSC would retain their immunoprivileged and immunomodulatory properties after differentiating into the local cell types of the transplantation site. This study sought to investigate this question with a novel New Zealand White rabbit osteogenesis model. Results showed that osteogenic cells differentiated from MSC (DOC) in vitro did not express the MHC class II molecule, were incapable of inducing allogeneic lymphocyte proliferation in mixed lymphocyte culture or generating CTL, were inhibitory in ongoing lymphocyte proliferation, and secreted anti-inflammatory cytokines (IL-10 and TGF-beta). There was a significantly higher secretion of IL-10 by DOC than that by MSC, while there was no significant difference between the TGF-beta secretion of MSC and DOC in vitro. However, after IFN-gamma treatment, TGF-beta secretion by DOC significantly decreased despite the increased production by MSC. Four weeks after local DOC implantation, despite MHC class II expression, second-set allogeneic skin rejection showed similar survival to first-set allogeneic skin rejection and DOC appeared to function as osteoblasts. In conclusion, DOC retained their immunoprivileged and immunomodulatory properties in vitro, but the latter was lost following transplantation.

Animals↗
PubMed2001

Mechanisms that regulate mechanosensory hair cell differentiation.

Hair cells of the vertebrate inner ear are mechanosensors that detect sound, gravity and acceleration. They have a specialized cytoskeleton optimized for the transmission of mechanical force. Hair cell defects are a major cause of deafness. The cloning of disease genes and studies of model organisms have provided insights into the mechanisms that regulate the differentiation of hair cells and their cytoskeleton. The studies have also provided new insights into the function of receptors such as integrins and protocadherins, and cytoplasmic proteins such as Rho-type GTPases and unconventional myosins, in organizing the actin cytoskeleton.

Actins↗
PubMed1995

B cell differentiation factor-induced human B cell maturation: stimulation of intracellular calcium release.

We have recently identified a novel human B cell differentiation factor, 446-BCDF, derived from anti-CD3-stimulated peripheral blood (PB) T cells. This novel cytokine, which may act through a pertussis toxin-sensitive Gi-linked receptor, induces a 5- to 100-fold increase in immunoglobulin (Ig) secretion by SAC (0.001%, v/v)-activated PB B cells. Coculture of B cells with 446-BCDF induces a decrease in intracellular cAMP which is necessary but not sufficient to drive terminal B cell differentiation. A second signal appears to be required. We therefore measured Ca2+ flux in indo-1 AM-loaded PB B cells. Stimulation with 446-BCDF resulted in an immediate rise in intracellular Ca2+ comparable to that seen with the anti-IgM mAb HB57. Ca2+ appeared to be mobilized from internal stores as pretreatment with BAPTA but not EGTA inhibited the response. Ca2+ mobilization was critical for the induction of differentiation as BAPTA pretreatment of PB B cells completely inhibited Ig secretion without affecting cell viability. In contrast, neither SAC, rIL6, IL2, IFN-gamma, nor IL4 could mobilize Ca2+. Pertussis toxin, a Gi and G0 protein inhibitor, was able to inhibit 446-BCDF-induced Ca2+ flux as well as Ig secretion. To determine whether the Ca2+ flux was generated in the course of inositol phosphate turnover, we measured IP3 turnover and the translocation of PKC from cytosol to membrane. An increase in IP3 comparable to that seen with a monoclonal anti-human IgM antibody was noted and was specifically inhibited by the 446-BCDF-specific mAb 929. Interestingly, no membrane PKC was demonstrable in either SAC- or BCDF-stimulated B cells, although PMA (50 ng/ml) could directly activate PKC. To confirm these findings functionally, B cells were stimulated with SAC and 446-BCDF in the presence of two known PKC inhibitors, staurosporin and calphostin. No inhibition of Ig secretion was detected at any concentration tested (0.39-100 nM staurosporin and 0.0625-1 microM calphostin C). These data suggest that induction of B cell differentiation is a Ca(2+)-dependent and PTX-sensitive event.

Alkaloids↗
PubMed2005

Cutaneous CXCL14 targets blood precursors to epidermal niches for Langerhans cell differentiation.

Dendritic cells (DCs) are major constituents of peripheral tissues, where they control immunity to foreign and self-antigens. The process of continuous DC renewal under homeostatic conditions is largely undefined. Here, we demonstrate that CD14+ DC precursors, either derived from CD34+ hematopoietic progenitor cells or isolated from blood, were attracted by the chemokine CXCL14, which is constitutively produced in healthy skin and other epithelial tissues. In a tissue model we show that human epidermal equivalents profoundly affected CD14+ DC precursors, including their suprabasal positioning and survival as well as their differentiation into Langerhans cell-like cells with potent antigen-presentation functions. Our model assigns unprecedented roles to CXCL14 and epidermal tissue as attractant and niche of differentiation, respectively, in the renewal of Langerhans cells under steady-state conditions.

Cell Differentiation↗
PubMed2005

Human umbilical cord blood-derived cells differentiate into hepatocyte-like cells in the Fas-mediated liver injury model.

Human umbilical cord blood (HUCB) contains stem/progenitor cells, which can differentiate into a variety of cell types. In this study, we investigated whether HUCB cells differentiate into hepatocytes in vitro and in vivo. We also examined whether CD34 could be the selection marker of stem cells for hepatocytes. HUCB cells were obtained from normal full-term deliveries, and CD34(+/-) cells were further separated. For in vitro study, HUCB cells were cultured for 4 wk, and expressions of liver-specific genes were examined. For the in vivo study, nonobese diabetic/severe combined immunodeficient mice were subjected to liver injury by a Fas ligand-carried adenoviral vector or only radiated. Mice were treated simultaneously with or without cell transplantation of HUCB, CD34(+), or CD34(-) cells. After 4 wk, human-specific gene/protein expression was examined. In the in vitro study, human liver-specific genes were positive after 7 days of culture. The immunofluorescent study showed positive staining of alpha-fetoprotein, cytokeratin 19, and albumin in round-shaped cells. In the in vivo study, immunohistochemical analysis showed human albumin-positive, hepatocyte-specific antigen-positive cells in mouse livers of the Fas ligand/transplantation group. Fluorescence in situ hybridization analysis using the human Y chromosome also showed positive signals. However, no difference between transplanted cell types was detected. In contrast, immunopositive cells were not detected in the irradiated/transplantation group. The RT-PCR result also showed human hepatocyte-specific gene expressions only in the Fas ligand/transplantation group. HUCB cells differentiated into hepatocyte-like cells in the mouse liver, and liver injury was essential during this process. The differences between CD34(+) and CD34(-) cells were not observed in human hepatocyte-specific expression.

Animals↗
PubMed2005

2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, enhances the adhesion of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes.

2-Arachidonoylglycerol (2-AG), an endogenous cannabionoid receptor (CB1 and CB2) ligand, enhanced the adhesion of HL-60 cells differentiated into macrophage-like cells to fibronectin and the vascular cell adhesion molecule-1. The CB2 receptor, Gi/Go, intracellular free Ca(2+) and phosphatidylinositol 3-kinase were shown to be involved in 2-AG-induced augmented cell adhesion. 2-AG also enhanced the adhesion of human monocytic leukemia U937 cells and peripheral blood monocytes. These results strongly suggest that 2-AG plays some essential role in inflammatory reactions and immune responses by inducing robust adhesion to extracellular matrix proteins and adhesion molecules in several types of inflammatory cells and immune-competent cells.

Arachidonic Acids↗
PubMed1997

Activin is a local regulator of human cytotrophoblast cell differentiation.

Cytotrophoblast cells of the first trimester placenta are highly invasive when removed from villi and cultured in vitro. In vivo, however, only selected cytotrophoblast cells break through the overlying syncytiotrophoblast to form cytotrophoblast columns and ultimately invade the endometrium. To explore the role of paracrine growth factors in regulating cytotrophoblast development, we cultured explants of first trimester chorionic villi in vitro. Both activin and inhibin, as well as the activin binding protein follistatin, are produced by various trophoblast cells throughout pregnancy. We found that addition of activin-A, but not inhibin-A, stimulated the outgrowth of cytotrophoblast cells into the surrounding matrix. This outgrowth was characteristic of that observed in extravillous cytotrophoblast cells in vivo; it was accompanied by cell division within the proximal region of the cytotrophoblast outgrowth, synthesis of fibronectin, as well as the expression of markers characteristic of invasive cytotrophoblast cells, human leukocyte antigen-G and matrix metalloproteinase (MMP)-9. Activin also specifically induced the early expression of MMP-2 within villous cytotrophoblast cells. Addition of the activin binding protein, follistatin, blocked all of the effects of exogenous activin. The morphological and biochemical effects of activin were similar to those observed when signaling of endogenous transforming growth factor-beta was blocked. Interestingly, the latter effects were also reversed by the addition of follistatin. These data suggest that activin plays a local role in promoting cytotrophoblast column formation, likely by regulating the differentiation of villous cytotrophoblast into extravillous cytotrophoblast cells.

Activins↗
PubMed2003

Cell-cycle-regulatory elements and the control of cell differentiation in the budding yeast.

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult to study at a mechanistic level. We consider the relatively well-understood mechanisms by which mating-type switching and the pheromone-induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse.

Cell Cycle↗
PubMed2000

The B cell receptor, but not the pre-B cell receptor, mediates arrest of B cell differentiation.

B cell development in organ cultures of fetal liver from mice at day 14 of gestation resembles in kinetics and cell numbers generated the one observed in vivo. This development in vitro can be blocked by an IL-7 receptor-specific monoclonal antibody. Monoclonal antibodies specific for the pre-B cell receptor, i. e. for VpreB, lambda5, or muH chains, do not perturb B cell development in these organ cultures up to and including the CD25+ small pre-BII cell stage. However, muH chain-specific antibodies inhibit the appearance of the subsequent surface IgM+ immature B cells. In organ cultures of muH chain allotype heterozygous (muHa x muHb)F1 fetal livers a dose-dependent inhibition by allotype-specific monoclonal antibodies of sIgM+ immature B cells expressing the corresponding, but not the other, allotype was observed. By combining cell sorting with limiting dilution analysis of lipopolysaccharide-reactive cells, the probable target cell of this muH chain-specific inhibition was identified as an IgM+, CD23-immature B cell. Hence, engagement of the pre-B cell receptor by specific antibodies does not influence B cell development, while engagement of the B cell receptor on immature B cells does.

Animals↗
PubMed2000

KPL1, which encodes a novel PH domain-containing protein, is induced during ciliated cell differentiation of rat tracheal epithelial cells.

Using differential display, we have identified a novel gene, KPL1, induced in rat tracheal epithelial (RTE) cells grown under conditions which stimulate ciliogenesis. The KPL1 protein is predicted to contain a pleckstrin homology (PH) domain, which has been found in numerous signal transduction and cytoskeletal proteins. These domains are thought to function by recruiting proteins to cellular membranes, and they have been shown to bind phosphoinositols and the beta/gamma subunit of G proteins. We have cloned rat and human KPL1; the predicted protein translations are 94% identical. Alternate transcripts exist in rat and human tracheal cells that predict a protein which contains a 35-amino acid insert. KPL1 was upregulated in RTE cultures undergoing mucociliary but not squamous differentiation; and in cultures undergoing mucociliary differentiation, KPL1 expression most closely paralleled that of a marker of ciliated cell differentiation (axonemal dynein heavy chain) and not a marker of mucous cell differentiation (mucin 5AC). As a new member of the family of PH domain-containing proteins, KPL1 may have a unique role in ciliated cell differentiation or function.

Amino Acid Sequence↗
PubMed2002

Morphometric analysis of photoreceptive, neuronal and endocrinal cell differentiation of avian pineal cells: an in vitro immunohistochemical study on the developmental transition from neuronal to photo-endocrinal property.

Little is known about the developmental origin, determination and differentiation of different pineal immunoreactive cells in the avian group, and an experimental establishment is then required to explain the differentiation of cell types (i.e. photosensory, neural and secretory types). The present in vitro study suggests that the avian pineal organ is made up of multiple types of cells with different immunoreactivity at the ontogenic state (from embryonic day 9 to day 14), before it acquires the final photoendocrinal nature of the mature state. The morphometric analysis suggests that the developmental changes in the morphology of the quail pinealocytes appear to represent a condensed expression of the phylogenic development in the ontogeny. Several types of immunoreactive cells from a neuronal line were suppressed with maturation of developing pineal glands, while other cell types such as photoreceptive and endocrinal lines became more prominent. The melatonin level in the culture medium presented a high value up to 72 hr of culture, followed by a decrease as well as dampening of the level at the end of the culture possibly because the cultures were maintained in dark. The results of the present study, a combined analysis of morphometry and RIA, open a new line for research into the pineal development and cell differentiation.

Animals↗
PubMed2006

Cytotoxic T-lymphocyte antigen-4 inhibits GATA-3 but not T-bet mRNA expression during T helper cell differentiation.

Naive CD4+ T-cell differentiation to T helper 1 (Th1) and Th2 cells is dependent on T-bet and GATA-3 factors, respectively. T-bet and GATA-3, indeed, through chromatin remodelling allow transcriptional activation of Ifngamma and Th2 cytokine (Il4, Il5, Il13) genes, respectively. We investigated the effects of the negative costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) on GATA-3 and T-bet mRNA expression and Th cell differentiation in mouse naive CD4+ T cells. Our results show that CTLA-4 inhibits GATA-3 mRNA expression and Th2 cell differentiation. At variance, CTLA-4 does not affect T-bet mRNA expression and Th1 cell differentiation. GATA-3 mRNA expression is inhibited when CD4+ cells are stimulated under both neutral (i.e. absence of cytokines) and Th2-polarizing (i.e. presence of interleukin (IL)-4) conditions, the effect being larger under the latter condition. Hence CTLA-4 might affect the IL-4/signal transducer and activator of transcription-6 (STAT6) pathway leading to GATA-3 mRNA up-regulation. We found, indeed, that CTLA-4 engagement inhibits STAT6 activation leaving unaffected the STAT6 protein level. Moreover, CTLA-4 engagement drastically inhibits IL-4Ralpha mRNA and protein up-regulation under Th2-polarizing conditions. Thus, CTLA-4 exerts a tight control on Th2 cell differentiation by negatively regulating both the CD3/CD28 and the IL-4/STAT6 pathways.

Animals↗