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Results for “Cellular differentiation”

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At least 145 records · Page 8Linked to original sources

PubMed1997

Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation.

Phosphatidylinositol 3-kinase (PI3K) has been shown to be an important mediator of intracellular signal transduction in mammalian cells. We show here, for the first time, that the blockade of PI3K activity in human fetal undifferentiated cells induced morphological and functional endocrine differentiation. This was associated with an increase in mRNA levels of insulin, glucagon, and somatostatin, as well as an increase in the insulin protein content and secretion in response to secretagogues. Blockade of PI3K also increased the proportion of pluripotent precursor cells coexpressing multiple hormones and the total number of terminally differentiated cells originating from these precursor cells. We examined whether any of the recently described modulators of endocrine differentiation could participate in regulating PI3K activity in fetal islet cells. The activity of PI3K was inversely correlated with the hepatocyte growth factor/scatter factor-induced downregulation or nicotinamideinduced upregulation of islet-specific gene expression, giving support to the role of PI3K, as a negative regulator of endocrine differentiation. In conclusion, our results provide a mechanism for the regulation of hormone-specific gene expression during human fetal neogenesis. They also suggest a novel function for PI3K, as a negative regulator of cellular differentiation.

Androstadienes↗

PubMed1999

The antioxidant N-acetylcysteine induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.

Prolonged culture of mesangial cells produces multifocal nodular structures, i.e., "hillocks," consisting of cells and extracellular matrix. Hillock formation is associated with induction of a differentiated phenotype of mesangial cells, with suppressed mitogenesis and downregulation of alpha-smooth muscle actin (alpha-SMA). Currently, little is understood regarding physiologically relevant factors that facilitate this cytodifferentiation. This study explores whether and how the cellular redox state modulates hillock formation. Exposure of confluent rat mesangial cells to the antioxidant N-acetylcysteine (NAC), an inducer of glutathione, dramatically facilitated hillock formation. This effect was mimicked by external addition of the reduced form of glutathione ethyl ester. In contrast, the oxidizing agents diamide and menadione inhibited the development of hillocks triggered by either NAC, glutathione, or prolonged culture. The induction of hillocks by NAC was correlated with downregulation of alpha-SMA as well as attenuated activity of the CArG box element (the cis-element relevant to the expression of the alpha-SMA gene and growth-associated genes). These results indicate that, by a redox-sensitive mechanism, NAC induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.

Acetylcysteine↗

PubMed1989

Root graviresponsiveness and cellular differentiation in wild-type and a starchless mutant of Arabidopsis thaliana.

Primary roots of a starchless mutant of Arabidopsis thaliana L. are strongly graviresponsive despite lacking amyloplasts in their columella cells. The ultrastructures of calyptrogen and peripheral cells in wild-type as compared to mutant seedlings are not significantly different. The largest difference in cellular differentiation in caps of mutant and wild-type roots is the relative volume of plastids in columella cells. Plastids occupy 12.3% of the volume of columella cells in wild-type seedlings, but only 3.69% of columella cells in mutant seedlings. These results indicate that: (1) amyloplasts and starch are not necessary for root graviresponsiveness; (2) the increase in relative volume of plastids that usually accompanies differentiation of columella cells is not necessary for root graviresponsiveness; and (3) the absence of starch and amyloplasts does not affect the structure of calyptrogen (i.e. meristematic) and secretory (i.e. peripheral) cells in root caps. These results are discussed relative to proposed models for root gravitropism.

Arabidopsis↗

PubMed1986

Assessment of interlobar variation of bronchoalveolar lavage cellular differentials in interstitial lung diseases.

Alveolitis is thought to precede permanent lung derangement in a variety of interstitial lung diseases (ILD). Bronchoalveolar lavage (BAL) cell differentials can be used to evaluate the intensity of alveolitis, whereas clinical, roentgenographic, and functional studies are insensitive monitors of lung inflammation. As ILD is generally diffuse, unilobar lavage is widely used and presumed to gauge overall lung inflammation. Consistency of lobe to lobe cell differential findings has not been systematically addressed. We analyzed 53 bilateral lobar lavages (right middle lobe and lingula) in 34 patients with sarcoidosis, idiopathic pulmonary fibrosis-collagen vascular disease (IPF-CV) and a group of mixed interstitial diseases. Cellular differentials from each lobe were independently assessed and compared. The sarcoid group, with predominantly T-lymphocytes in BAL, showed excellent interlobar correlation (r = 0.92, p less than 0.001), with only 17% showing a discrepancy of greater than 10% in percentage of T-lymphocytes. In contrast, the IPF-CV group, with predominantly neutrophils in BAL, showed good interlobar correlation (r = 0.79; p less than 0.01), but 35% had a greater than 10% discrepancy in percentage of neutrophils. Finally, the mixed group, with lymphocytes as the predominant cell in BAL, showed poor interlobar correlation (r = 0.58; p greater than 0.10), with 42% showing a greater than 10% discrepancy in percentage of lymphocytes. These results were not explicable on the basis of differences in volume of lavage fluid or total cells recovered, these parameters being remarkably consistent between lobes in the 3 patient groups and in a control group of 8 subjects without ILD. The chest roentgenogram was markedly insensitive to lavage interlobar variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗

PubMed1990

Stability of anticancer activity induced by cellular differentiation.

Human and murine cells can express anticancer activity which we define as any biologic process that can prevent or inhibit the expression of the transformed phenotype. The existence of anticancer activities has been demonstrated by many systems, including the fusion of normal cells with tumorigenic cells and the implantation of cancer cells into specific embryonic sites. Furthermore, cellular differentiation has recently been shown to regulate the expression of anticancer activity without limiting a cell's proliferative potential. Those results show that reversible nonterminal differentiation (NTD) induces 3T3T mesenchymal stem cells to become resistant to transformation by physical or chemical carcinogens or oncogene products and NTD induces spontaneously transformed 3T3T cells to revert to a benign state and to become resistant to retransformation. In addition, NTD induces SV40 T-antigen transformed 3T3T cells to revert to a nontransformed state that prevents growth in soft agarose. Data are now presented that define the relative stability of these differentiation-induced anticancer activities. Anticancer activity induced by NTD in 3T3T cells is shown to have a mean stability of 55 population doublings (PD) and a maximum stability of 88 PD. Anticancer activity induced by NTD in spontaneously transformed 3T3T cells shows a similar stability with a mean of 55 PD and a maximum of 95 PD. Finally, in SV40-3T3T cells, the induction of NTD suppresses soft agarose growth for a maximum of 20-30 PD. These results demonstrate that three forms of differentiation-induced anticancer activity are stable for an extended number of population doublings.

Animals↗

PubMedDate not supplied

The potential roles of nm23 in cancer metastasis and cellular differentiation.

The majority of cancer patients succumb to the consequences of metastatic disease. A correlation of increased nm23 expression to low metastatic potential has been established in several malignancies, based on published prognostic studies with tumour cohorts and transfection studies. Transfection of highly metastatic MDA-MB-435 human breast carcinoma cells with nm23-H1 cDNA resulted in a significant reduction in the metastatic potential in vivo. These transfections also showed inhibition of colonisation and motility, as well as morphological and biosynthetic differentiation in vitro. The biochemical mechanism of Nm23-H1 action, as well as the identity of proteins involved in its functional biochemical pathway, are still unknown. We summarise published and recent research concerning the role of the nm23 gene in metastasis and normal cellular differentiation.

Animals↗

PubMed1991

13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-1 lymphoma.

A 35-year-old man with refractory cutaneous Ki-1 lymphoma was salvaged successfully with oral 13-cis-retinoic acid (1 mg/kg/day). He had a complete remission lasting for 20 months before a single nodule recurred on his skin. Excisional biopsy of the recurrent tumor revealed a distinct morphologic change, suggesting cellular differentiation toward a more benign phenotype. No significant side effects were noted except mild xerostomia, bone pain, and hyperlipidemia. The authors believe that 13-cis-retinoic acid should be considered in the treatment of cutaneous Ki-1 lymphoma.

Adult↗

PubMed1985

A morphometric analysis of cellular differentiation in caps of primary and lateral roots of Helianthus annuus.

In order to determine if patterns of cell differentiation are similar in primary and lateral roots, I performed a morphometric analysis of the ultrastructure of calyptrogen, columella, and peripheral cells in primary and lateral roots of Helianthus annuus. Each cell type is characterized by a unique ultrastructure, and the ultrastructural changes characteristic of cellular differentiation in root caps are organelle specific. No major structural differences exist in the structures of the composite cell types, or in patterns of cell differentiation in caps of primary vs. lateral roots.

Cell Differentiation↗

PubMed1999

Growth, cellular differentiation and virulence factor expression by Proteus mirabilis in vitro and in vivo.

A uropathogenic strain of Proteus mirabilis was grown in vitro in human and mouse urine and brain-heart infusion broth (BHIB) and in vivo in subcutaneous open chambers (SOC) in mice, intraperitoneal diffusion chambers (IPC) in rats and by ascending urinary tract infection in mice in order to compare growth pattern, cellular differentiation and expression of virulence factors. Although the growth rate was slower in vivo than in vitro, the extent of growth was similar after 24 h. PR mirabilis differentiated into filamentous swarmer cells in all in-vitro culture conditions, but no filamentous cells were observed in either of the in-vivo chamber models. Transurethrally infected mice showed a rapid release or loss of filamentous cells and these could not be seen in kidney or bladder homogenates 7 days after infection. Bacteria showed increasing haemagglutination titres for fresh and tanned red blood cells after subculturing in BHIB, but bacteria grown in vivo did not show haemagglutination. An increasing resistance to normal serum was found when bacteria were grown in vivo. Significant haemolytic activity was detected with bacteria grown in BHIB and IPC, but almost no activity was found when bacteria had grown in urine. These findings improve the understanding of the role of P. mirabilis uropathogenic virulence factors in vivo.

Animals↗

PubMed2002

The jing Zn-finger transcription factor is a mediator of cellular differentiation in the Drosophila CNS midline and trachea.

We establish that the jing zinc-finger transcription factor plays an essential role in controlling CNS midline and tracheal cell differentiation. jing transcripts and protein accumulate from stage 9 in the CNS midline, trachea and in segmental ectodermal stripes. JING protein localizes to the nuclei of CNS midline and tracheal cells implying a regulatory role during their development. Loss of jing-lacZ expression in homozygous sim mutants and induction of jing-lacZ by ectopic sim expression establish that jing is part of the CNS midline lineage. We have isolated embryonic recessive lethal jing mutations that display genetic interactions in the embryonic CNS midline and trachea, with mutations in the bHLH-PAS genes single-minded and trachealess, and their downstream target genes (slit and breathless). Loss- and gain-of-function jing is associated with defects in CNS axon and tracheal tubule patterning. In jing homozygous mutant embryos, reductions in marker gene expression and inappropriate apoptosis in the CNS midline and trachea establish that jing is essential for the proper differentiation and survival of these lineages. These results establish that jing is a key component of CNS midline and tracheal cell development. Given the similarities between JING and the vertebrate CCAAT-binding protein AEBP2, we propose that jing regulates transcriptional mechanisms in Drosophila embryos and promotes cellular differentiation in ectodermal derivatives.

Animals↗

PubMed2003

Planar and vertical signals control cellular differentiation and patterning in the mammalian cochlea.

The sensory epithelium of the mammalian cochlea is composed of a regular mosaic of sensory hair cells and nonsensory supporting cells. During development, differentiation occurs in a gradient that progresses along the axis of the cochlea from base to apex. To begin to identify some of the factors that regulate this developmental process, the potential roles of planar and vertical signals were examined during early stages of cochlear development. We demonstrate roles for both underlying mesenchymal cells and adjacent epithelial cells in the differentiation and patterning of the sensory epithelium, and in particular in the development of mechanosensory hair cells. As development proceeds, the requirements for both planar and vertical signals decrease, and development of the sensory epithelium becomes essentially independent from these cues. Finally, we demonstrate that the temporal gradient of cellular differentiation is not dependent on planar signals within the developing sensory epithelium.

Animals↗

PubMed2002

Effects of estrogen on collagen synthesis by cultured human osteoblasts depend on the rate of cellular differentiation.

Estrogen is known to act on osteoblasts according to their stage of differentiation and estrogen receptor (ER) isoform expression. The aim of this study was to determine when type I collagen (COL1) synthesis by cultured low-passage, human bone-derived osteoblasts (hOBs) is upregulated in response to estrogen. Cell lines from female donors aged 1 and 66 years were cultured for 11 days on collagen in growth medium supplemented with human serum, hydrocortisone, and beta-glycerophosphate. Young-donor hOBs grew more quickly than old-donor hOBs and did not mineralize. Old-donor hOBs formed mineralized nodules 5 days after reaching confluence. Changes in mRNA levels with time for ERs, type I collagen, and alkaline phosphatase reflected the faster differentiation of the old-donor cells. The ERbeta/ERalpha ratio fell threefold in young-donor hOBs but rose 300-fold in old-donor hOBs. Increased ERbeta/ERalpha ratios prevented ligand-dependent downregulation of ERalpha transcription, resulting in reduced proliferation in old-donor hOBs. Upregulation of COL1 mRNA expression in response to estrogen was confined to intermediate stages of differentiation, resulting in significant increases in COL1 mRNA by estradiol only in young-donor cells. Since the young and old-donor hOBs were cultured under identical conditions, our results indicate that the response of hOBs to estrogen is largely dependent on intracellular mechanisms that control the timing of cellular differentiation.

Adolescent↗

PubMed1992

Expression of SV-40 T antigen in the small intestinal epithelium of transgenic mice results in proliferative changes in the crypt and reentry of villus-associated enterocytes into the cell cycle but has no apparent effect on cellular differentiation programs and does not cause neoplastic transformation.

The mouse intestinal epithelium represents a unique mammalian system for examining the relationship between cell division, commitment, and differentiation. Proliferation and differentiation are rapid, perpetual, and spatially well-organized processes that occur along the crypt-to-villus axis and involve clearly defined cell lineages derived from a common multipotent stem cell located near the base of each crypt. Nucleotides -1178 to +28 of the rat intestinal fatty acid binding protein gene were used to establish three pedigrees of transgenic mice that expressed SV-40 large T antigen (TAg) in epithelial cells situated in the uppermost portion of small intestinal crypts and in already committed, differentiating enterocytes as they exited these crypts and migrated up the villus. T antigen production was associated with increases in crypt cell proliferation but had no apparent effect on commitment to differentiate along enterocytic, enteroendocrine, or Paneth cell lineages. Single- and multilabel-immunocytochemical studies plus RNA blot hybridization analyses suggested that the differentiation programs of these lineages were similar in transgenic mice and their normal littermates. This included enterocytes which, based on the pattern of [3H]thymidine and 5-bromo-2'-deoxyuridine labeling and proliferating nuclear antigen expression, had reentered the cell cycle during their migration up the villus. The state of cellular differentiation and/or TAg production appeared to affect the nature of the cell cycle; analysis of the ratio of S-phase to M-phase cells (collected by metaphase arrest with vincristine) and of the intensities of labeling of nuclei by [3H]thymidine indicated that the duration of S phase was longer in differentiating, villus-associated enterocytes than in the less well-differentiated crypt epithelial cell population and that there may be a block at the G2/M boundary. Sustained increases in crypt and villus epithelial cell proliferation over a 9-mo period were not associated with the development of gut neoplasms--suggesting that tumorigenesis in the intestine may require that the initiated cell have many of the properties of the gut stem cell including functional anchorage.

Animals↗

PubMed1995

Retinoid activation of retinoic acid receptors but not of retinoid X receptors promotes cellular differentiation and replication of human cytomegalovirus in embryonal cells.

The susceptibility of human embryonal cell line NT-2/D1 to replicate human cytomegalovirus (hCMV) is dependent on retinoic acid (RA) stimulation. Physiological responses to retinoic acid involve two distinct subfamilies of nuclear receptors, the RA receptors (RARs) and retinoid X receptors (RXRs), which function by activating transcription as heterodimeric or RXR homodimeric complexes from cis-acting DNA response elements. At present, it is not clear whether the association between these two classes of receptors can lead to multiple distinct induction pathways by signalling one or both receptor partners. Here we have determined, by selectively activating endogenous receptors with novel synthetic ligands specific for either RARs or RXRs, what ligand interaction is physiological in the retinoid receptor pathways necessary for inducing replication of hCMV in differentiated embryonal cells. We show that ligand binding to RAR alone is sufficient and that exclusive ligand activation of RXR is insufficient for inducing replication of hCMV. We also find that differentiation and inhibition of NT-2/D1 cell growth are promoted by compounds that signal the RAR pathway. These results provide direct evidence that RAR ligand-mediated physiological responses are separable and distinct from RXR ligand activation functions. Moreover, our results provide insight into a hormone response pathway for cellular differentiation that might be coopted by hCMV in the host.

Cell Differentiation↗

PubMed2002

A novel therapeutic approach for hematological malignancies based on cellular differentiation and apoptosis.

Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells.

Animals↗

PubMed1998

Fibroblast growth factor receptor expression reflects cellular differentiation in human oral squamous carcinoma cell lines.

This study examined the expression of fibroblast growth factor receptor 2 (FGFR 2) splice variants, IIIb and IIIc, in normal and malignant human oral keratinocytes and in normal oral fibroblasts by RT-PCR using both exon-specific primers and primers common to both FGFR 2 isoforms. Fibroblasts expressed exclusively FGFR 2/IIIc whilst the normal and malignant keratinocytes co-expressed FGFR 2/IIIb and FGFR 2/IIIc. Well-differentiated keratinocytes expressed proportionally more FGFR 2/IIIb than IIIc whereas the poorly-differentiated cells expressed more FGFR 2/IIIc than IIIb. The normal and malignant keratinocytes, but not fibroblasts, expressed an additional amplification product, which consisted of both IIIb and IIIc of FGFR 2 joined by an extra base pair and with the intronic sequence removed. The results indicate that the expression of FGFR 2 isoforms reflects the degree of cellular differentiation in normal and malignant human oral keratinocytes and that receptor complexes of FGFR 2/IIIb and IIIc may regulate ligand-receptor interactions.

Carcinoma, Squamous Cell↗

PubMed2000

Gastro-intestinal stromal tumours (GISTs): a six year Zimbabwean experience. Cellular differentiation with immunocytochemistry.

OBJECTIVES: To determine the prevalence of GISTs in general, the terminology in use, biological behaviour in terms of benign, borderline and malignant variants and assessment of the different lines of differentiation using immunochemical techniques. DESIGN: A retrospective study. SETTING: Department of Histopathology, University of Zimbabwe Medical School at Parirenyatwa and Harare Central teaching Hospitals. SUBJECTS: Patients with a surgical pathology diagnosis of gastro-intestinal related stromal tumours including leiomyosarcomas, leiomyomas and GISTs over a six year period. MAIN OUTCOME MEASURE: Evaluation for different lines of differentiation and malignant potential using immunocytochemical techniques. RESULTS: A total of 24 cases with a primary diagnosis of GISTs over a period of six years were retrieved from the records and of these 22 had material available for evaluation. Four of these were reported as pure GISTs, two of them benign and the other two malignant. Seven cases were reported as leiomyosarcomas. Six of these had evidence of neural differentiation on immunocytochemistry and therefore were strictly not leiomyosarcomas. Of the 11 cases reported as leiomyomas, four (36.4%) had neural differentiation on immunohistochemistry implying a low malignant potential. CONCLUSION: GISTs are not uncommon in this patient population considering that 24 cases were reported over a six year period in a department that averages 11,000 surgical pathology cases per year. Minimal use of immunostains, in addition to general morphological features, can be utilized to determine the line of cellular differentiation and malignant potential of the seemingly benign tumours.

Adult↗

PubMed1997

Induction of cellular differentiation and apoptosis by signal transduction inhibitors.

We have isolated signal transduction inhibitors of low molecular weight from microorganisms and plants. Since inducers of differentiation and apoptosis may be developed as new anticancer agents, we have studied induction of differentiation and apoptosis in neoplastic cells by our signal transduction inhibitors. Aristeromycin isolated as an Abl function inhibitor induced erythroid differentiation in human CML K562 cells. Aristeromycin may induce differentiation by inhibition of methylating reactions in the cell. We isolated dephostatin from Streptomyces as a tyrosine phosphatase inhibitor, and synthesized its stable analogue, 3,4-dephostatin. The stable analogue, 3,4-dephostatin, potentiated NGF-induced morphological differentiation in rat pheochromocytoma PC12h cells, possibly by inhibition of tyrosine dephosphorylation of MAPK. Erbstatin, a tyrosine kinase inhibitor, induced morphological apoptosis and internucleosomal DNA fragmentation in mouse leukemia L1210 and human SCLC cells. Erbstatin was shown to induce apoptosis by hydrogen peroxide formation. Thus, these signal transduction inhibitors appear to be useful tools for the mechanistic study of cellular differentiation and apoptosis.

Adenosine↗