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PubMed1988

A transient increase in histone H2A ubiquitination is coincident with the onset of erythroleukemic cell differentiation.

Murine erythroleukemia cells are useful for studying the regulation of erythroid differentiation since these malignant pronormoblasts differentiate to orthochromatic normoblasts when treated with a variety of inducing agents. Changes in chromatin proteins have been described following inducer exposure. The significance of these changes, which are greatest in terminally differentiated cells remains unknown. Ubiquitin is a highly conserved 8.5 kilodalton peptide that is covalently linked to up to 10% of histone H2A. We demonstrate that following exposure of MEL cells to inducers of differentiation, a transient increase in ubiquitination of H2A occurs. This change is coincident with the onset of differentiation. This result suggests that ubiquitination of H2A may have a role in the nuclear changes necessary for erythroleukemic cell differentiation.

Animals↗
PubMed1997

[The relationship between insulin-like growth factor-binding proteins and cell differentiation of osteoblastic clone MC3T3-E1 cells].

Insulin-like growth factors, which are important local factors in bone, are associated with specific binding proteins (IGFBPs). In this study, the relationship between IGFBPs and cell differentiation of MC3T3-E1 cells (E1 cells), a clonal osteoblast-like mouse calvarial cell line, was investigated. IGFBP-3 had no effect on alkaline phosphatase (ALP) activity of E1 cells, but in the presence of IGF-II at an ineffective concentration stimulated ALP activity. ALP activity of E1 cells cultured in alpha-MEM supplemented with 10% fetal calf serum (FCS) gradually increased after confluency, which demonstrated that E1 cells differentiate. In this experiment, 39 kd IGFBP-3 of FCS origin was decreased in the conditioned medium after 48 hours of culture of the cells obtained on day 0 after confluency, but not of those obtained on day 21, which suggests that the use of IGFBP-3 of FCS origin is diminished related with cell differentiation and E1 cells secrete themselves. E1 cells secreted three IGFBP, Mr 23, 26, and 31kd. Secretion of 31kd IGFBP gradually increased, and this increase correlated with ALP activity of E1 cells. These findings suggest that secretion of 31kd IGFBP is related with osteogenic differentiation of E1 cells.

3T3 Cells↗
PubMed1995

Inhibition of vitamin D3-induced cell differentiation by interferon-gamma in HL-60 cells determined by a nitroblue tetrazolium reduction test.

The combined effects of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] and interferon-gamma (IFN-gamma) or tumor necrosis factor alpha (TNF-alpha) on cell differentiation in HL-60 human promyelocytic leukemia cells were examined by a nitroblue tetrazolium (NBT) reduction test. 1,25(OH)2D3 at the concentrations of 7-70 nM induced NBT-positive cells, which was used as a criterion of cell differentiation. IFN-gamma itself showed little effect on induction of NBT-positive cells or on cell growth at a concentration up to 1000 U/ml. However, in a combination of 1,25(OH)2D3 with IFN-gamma (100 and 300 U/ml), cell differentiation was strongly inhibited and was accompanied by growth inhibition. Treatment with a combination of 1,25(OH)2D3 and TNF-alpha or IFN-gamma and TNF-alpha showed an additive effect on cell differentiation. IFN-gamma seems to act as a specific inhibitor for 1,25(OH)2D3-induced cell differentiation. To elucidate the cause of the inhibition of cell differentiation by IFN-gamma, the ability of the cells to produce superoxide (O2-) was examined after culture for 5 days in the presence of 1,25(OH)2D3 and IFN-gamma. The results indicated that the inhibition of IFN-gamma was caused by a reduction in the ability of the cells to produce O2- in response to stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA).

Calcitriol↗
PubMed1986

Ganglioside GM3: an acidic membrane component that increases during macrophage-like cell differentiation can induce monocytic differentiation of human myeloid and monocytoid leukemic cell lines HL-60 and U937.

When human myeloid and monocytoid leukemic cell lines HL-60 and U937, respectively, were treated with an exogenous sialoglycosphingolipid, ganglioside GM3, in serum-free medium, cell growth was markedly inhibited, and their morphological maturation along a monocytic lineage was observed. In addition to a significant increase in phagocytic and nonspecific esterase activities, marked increase of monocyte-specific surface antigens detectable with monoclonal antibodies such as OKM1 and OKM5 was observed in GM3-fed cells. Other sialoglycosphingolipids with the carbohydrate structure belonging to ganglio-series oligosaccharide, ganglioside GM1 and a brain ganglioside mixture, had no effect on the cell differentiation, showing instead stimulatory actions on the growth of these cell lines. We recently demonstrated that the ganglio-series ganglioside GM3 characteristically increased during macrophage-like cell differentiation of these cell lines. The present results indicate that ganglioside molecular species that specifically increase during monocytic cell differentiation of human myeloid and monocytoid leukemic cell lines may play, in turn, an important role in the differentiation-induction of these cell lines along a monocytic cell lineage.

Animals↗
PubMed1998

Helper T cell differentiation is controlled by the cell cycle.

Helper T (Th) cell differentiation is highly regulated by cytokines but initiated by mitogens. By examining gene expression in discrete generations of dividing cells, we have delineated the relationship between proliferation and differentiation. Initial expression of IL-2 is cell cycle-independent, whereas effector cytokine expression is cell cycle-dependent. IFNgamma expression increases in frequency with successive cell cycles, while IL-4 expression requires three cell divisions. Cell cycle progression and cytokine signaling act in concert to relieve epigenetic repression and can be supplanted by agents that hyperacetylate histones and demethylate DNA. Terminally differentiated cells exhibit stable epigenetic modification and cell cycle-independent gene expression. These data reveal a novel mechanism governing Th cell fate that initially integrates proliferative and differentiative signals and subsequently maintains stability of the differentiated state.

Animals↗
PubMed1995

Regulation of ciliated cell differentiation in cultures of rat tracheal epithelial cells.

The cellular pathway of ciliated cell differentiation and its regulation is poorly defined. To begin to understand the process of ciliated cell differentiation, we sought to identify factors regulating ciliated cell development in vitro. Rat tracheal epithelial (RTE) cells were cultured on collagen gel-coated membranes at an air-liquid interface in hormone- and growth factor-supplemented medium (complete medium [CM]). Under these conditions, RTE cells first proliferate and then differentiate into a pseudostratified mucociliary epithelium. Ciliated cell differentiation was measured using a monoclonal antibody, RTE3, which was shown to specifically react with the plasma membrane of ciliated cells. Cultures were immunostained in situ, and the percentage of the culture surface covered with ciliated cells was estimated using videomicroscopy and an image analysis program. If an air-liquid interface was not created and the cells were maintained in the submerged state, ciliated cell differentiation was suppressed 25-fold. Culture in the absence of mitogenic components present in CM, including epidermal growth factor (EGF), cholera toxin (CT), or bovine pituitary extract, resulted in 2- to 4-fold increases in the percentage of ciliated cells. When both EGF and CT were removed from the media, DNA synthesis and total cell number was reduced, while ciliated cell differentiation increased as much as 5-fold. These results demonstrate that submersion inhibits, while withdrawal of mitogenic compounds promotes, ciliated cell differentiation in vitro.

Animals↗
PubMed2004

Plasticity and reprogramming of differentiated cells in amphibian regeneration: partial purification of a serum factor that triggers cell cycle re-entry in differentiated muscle cells.

The reversal of cellular differentiation to form proliferating progenitor cells is a critical aspect of regenerative ability in the urodele amphibians. This process has been studied using skeletal muscle during limb or tail regeneration, or dorsal iris epithelium during lens regeneration. An unknown activity in serum triggers cell cycle re-entry from the differentiated state. Here we describe the biochemical properties and fractionation of this serum factor. The factor is a glycoprotein that associates with large molecular weight complexes. The purification and molecular identification of the serum factor represents an important avenue in understanding regenerative ability and dedifferentiation capacity on a molecular basis.

Animals↗
PubMed1995

p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells.

Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21Cip1 is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner. Although the muscle-specific transcription factor MyoD is sufficient to activate p21 expression in 10T1/2 cells, p21 was expressed in myogenic cells of mice lacking the genes encoding MyoD and myogenin, demonstrating that p21 expression does not require these transcription factors. The p21 protein may function during development as an inducible growth inhibitor that contributes to cell cycle exit and differentiation.

Animals↗
PubMed1982

Human b-cell differentiation. I. Analysis of immunoglobulin heavy chain switching using monoclonal anti-immunoglobulin M, G, and A antibodies and pokeweed mitogen-induced plasma cell differentiation.

Monoclonal antibodies were used to examine the immunoglobulin isotypes expressed by B lymphocyte precursors of IgM, IgG, IgA, and IgA2 plasma cells. Plasma-cell differentiation was induced by the addition of pokeweed mitogen to cultures of blood mononuclear cells. Anti-mu, -gamma, -alpha, and -alpha 1 antibodies were used in some experiments to inhibit differentiation of B lymphocytes bearing these heavy chain isotypes, and for selective removal of B lymphocyte precursors before culture with pokeweed mitogen in other experiments. Three major subpopulations of B lymphocyte precursors were identified: (a) a subpopulation of surface (s) IgM+ precursors of IgM plasma cells that did not express IgG or IgA isotypes, (b) a subpopulation of sIgG+ precursors of IgG plasma cells of which approximately one-half bore some IgM and none had detectable IgA receptors, and (c) a subpopulation of sIgA+ precursors of IgA plasma cells; one half of these precursors could be shown to express functional IgM receptors but none were found to express IgG receptors. The sIgA subpopulation could be further subdivided into sIgA1+ precursors of IgA1 plasma cells and IgA1-negative precursors of IgA2 plasma cells. These results suggest that normal human B cells can switch from mu directly to each of the other heavy chain isotypes, and that these represent the main switch pathways.

Animals↗
PubMed2004

The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation.

Pancreatic beta cells play a central role in maintaining glucose homeostasis because they secrete insulin in response to increased level of blood glucose; failure of this capacity constitutes a major component of the pathogenesis of diabetes. The identification of key regulators of pancreatic beta-cell differentiation is relevant for the overall understanding of this process and for future experiments aimed at regenerating insulin-producing beta cells from pancreatic or embryonic stem cells. Several studies using transgenic or knockout mice have established that the development and function of pancreatic beta cells are controlled by several genes encoding specific transcription factors. By inactivating the homeobox gene Pax4, we previously demonstrated that its function is required for the formation of mature insulin-producing cells. Here, we show that during pancreas ontogeny, Pax4 is expressed in differentiating endocrine cells, including beta cells. Pax4 activity appears essential for appropriate initiation of beta-cell differentiation because loss of Pax4 prevents the expression of Pdx1, HB9 and insulin in beta-cell precursors. This role of Pax4 appears to be accomplished via its genetic interaction with another homeobox gene, Nkx2.2.

Animals↗
PubMed2004

Runx3-/- gastric epithelial cells differentiate into intestinal type cells.

We have previously reported that Runx3, a runt domain transcription factor, is a major growth regulator of gastric epithelial cells, that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer, and that expression of RUNX3 is greatly reduced in intestinal metaplasias in human stomachs. Here we examined the differentiation of Runx3-/- mouse gastric epithelial cells and found that some cells differentiated into intestinal type cells, which expressed Cdx2, a transcription factor that has been shown to induce intestinal metaplasia in transgenic mice. Differentiation of intestinal type cells was not found in culture of Runx3+/+ gastric epithelial cells. These results suggest that gastric epithelial cells can differentiate into intestinal type cells, probably due to expression of Cdx2 in them when the function of Runx3 is impaired. The relationship between loss of function of Runx3, formation of intestinal metaplasia, and gastric cancer was discussed.

Animals↗
PubMed1989

Effects of 3-deazaadenosine, an inducer of HL-60 cell differentiation, on human blood cells in vitro.

The adenosine analogue 3-deazaadenosine (c3 Ado) induces differentiation of human promyelocytic leukemia HL-60 cells in vitro. c3 Ado affects in vitro viability and growth of cells involved indirectly (cytokine-producing cells) and directly (transformed myeloid cells) in leukemic cell differentiation. Growth inhibition of proliferating cells is achieved at c3 Ado concentrations between 10-100 microM. Concentrations higher than 100 microM affect viability of proliferating and nonproliferating cells.

Cell Differentiation↗
PubMed2006

Variable expression of Epstein-Barr virus-induced gene 3 during normal B-cell differentiation and among B-cell lymphomas.

Epstein-Barr virus (EBV)-induced gene 3 (EBI3) is expressed by tumour cells in several EBV-associated malignancies. EBI3 was recently found to associate with a novel peptide, p28, to form a new heterodimeric cytokine, called interleukin-27. In this study, we investigated EBI3 and p28 expression in normal human B lymphocytes and in non-EBV-associated B-cell lymphomas. Low levels of EBI3 were detected in purified tonsillar B cells and expression was upregulated upon anti-CD40 or anti-micro stimulation via NF-kappaB activation. In non-neoplastic tissues, EBI3 expression by lymphocytes was largely restricted to a subset of germinal centre (GC) B cells located at the margin of the light zone, in close contact with CD3+ T lymphocytes. Over 50% of EBI3+ GC B cells were engaged in cell proliferation as assessed by Ki67 expression, and 10-30% expressed MUM1, an early marker of plasma cell differentiation expressed by late centrocytes. Many EBI3+ GC B cells had downregulated bcl-6 expression, which further suggests that these cells correspond to late CD40-activated centrocytes. Immunohistochemical analysis of 64 B-cell lymphomas showed that the highest EBI3 levels were detected in follicular lymphomas and in diffuse large B-cell lymphomas of both GC B-cell-like or non-GC B-cell-like types. No or rare p28 expression was detected in normal or tumour B cells. This constitutive expression of EBI3 by neoplastic B cells may be involved in lymphomagenesis, and may be a useful marker for lymphoma diagnosis.

B-Lymphocytes↗
PubMed1999

Ventrally emigrating neural tube cells differentiate into vascular smooth muscle cells.

A multipotential cell population originating in the ventral part of the hindbrain neural tube, the ventrally emigrating neural tube cells (VENT cells), has recently been shown to migrate into the craniofacial mesenchyme. Because vascular smooth muscle cells develop from this mesenchyme, we sought to determine if the VENT cells contributed to their differentiation. VENT cells were tagged with replication-deficient retroviral vector with LacZ by microinjection into the lumen of the rostral hindbrain of chick embryos on day 2. Embryos were processed for the detection of LacZ positive cells on day 7. LacZ-positive cells were present in the wall of craniofacial arteries and veins. Immunostaining with the smooth muscle alpha-actin confirmed the labeled cells to be smooth muscle cells. It is concluded that some vascular smooth muscle cells differentiate from neural tube cells. the developmental and functional significance of which remains to be established.

Actins↗
PubMed2005

The influence of technical factors on differential cell count in milk.

Differential cell count of milk is a traditional parameter for the evaluation of udder health. The literature shows great variation in differential cell counts of the milk of healthy mammary glands: macrophages range from 0% to 80%, lymphocytes from 1.5% to 79.5%, polymorphonuclear neutrophils from 3% to 95%, and epithelial cells from 1% to 19%. We conducted three studies to seek explanations for such variation. In the first, we evaluated the impact of polyethylene and glass sampling bottles. The aim of the second study was to compare the results of differential cell counts performed by three different technicians. The third study evaluated two methods of smear preparation. When polyethylene plastic bottles were used, the macrophage population was minimized but lymphocytes remained unaffected. This was shown by an exemplary flow cytometric analysis using four monoclonal antibodies against three lymphocyte surface structures. There were significant differences in the differential cell counts of 40 smears made by three technicians despite identical operating procedures. For the sediment smear, milk was centrifuged once and the sediment spread by eye on a glass slide. For the "coffee grinder" smear method, the sample was subjected to four centrifugations and then placed on a cover glass in order to spread the sediment using centrifugal force. The coffee grinder procedure led to a reduction of lymphocytes and an enrichment of polymorphonuclear neutrophils without affecting the macrophage population. Both methods made it possible to distinguish different udder health classes. It can be concluded that differential cell counts are a useful tool for comparing and monitoring udder health only if: samples are taken in a glass bottle; smears are prepared with the identical technique; and the differential cell counts are performed by a single person.

Animals↗
PubMed1993

DNA regions flanking the mouse Ig 3' alpha enhancer are differentially methylated and DNAase I hypersensitive during B cell differentiation.

Two B cell-specific enhancer elements are associated with the IgH gene cluster. One enhancer is located within the J-C mu intron (E mu), whereas a second enhancer (3' alpha E) is approximately 12.5 kb 3' of the C alpha membrane exon. In an attempt to understand the function of 3' alpha E, we have characterized its surrounding structural milieu during various stages of B cell differentiation through analysis of methylation patterns and the identification of DNAse I-hypersensitive sites. We observed a correlation between the chromatin structure of this region and the differentiation state of the cell. Compared to liver and brain, the region 3' of alpha was hypermethylated in pre-B and T cell lines and became progressively demethylated as B cell differentiation continued. A DNAse I-hypersensitive site was present in pre-B cell lines about 17 kb 3' of 3' alpha E. In fully differentiated myeloma cell lines, a second cluster of DNAse I-hypersensitive sites was present immediately 5' of 3' alpha E. Our data indicate that the 3' alpha enhancer is relatively sequestered during early stages of B cell differentiation and becomes increasingly accessible at later stages.

Animals↗
PubMed2006

Non-snRNP U1A levels decrease during mammalian B-cell differentiation and release the IgM secretory poly(A) site from repression.

A regulated shift from the production of membrane to secretory forms of Immunoglobulin M (IgM) mRNA occurs during B cell differentiation due to the activation of an upstream secretory poly(A) site. U1A plays a key role in inhibiting the expression of the secretory poly(A) site by inhibiting both cleavage at the poly(A) site and subsequent poly(A) tail addition. However, how the inhibitory effect of U1A is alleviated in differentiated cells, which express the secretory poly(A) site, is not known. Using B cell lines representing different stages of B cell differentiation, we show that the amount of U1A available to inhibit the secretory poly(A) site is reduced in differentiated cells. Undifferentiated B cells have more total U1A than differentiated cells and a greater proportion of this is not associated with the U1snRNP. We show that this is available to inhibit poly(A) addition at the secretory poly(A) site using cold competitor RNA oligos to de-repress poly(A) addition in nuclear extracts from the respective cell lines. In addition, endogenous non-snRNP associated U1A-immunopurified from the different cell lines-inhibits poly(A) polymerase activity proportional to U1A recovered, suggesting that available U1A level alone is responsible for changes in its inhibitory effect at the secretory IgM poly (A) site.

Animals↗