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PubMed1996

Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications.

Hepatocellular carcinoma (HCC) is a heterogeneous disease. HCC derived from different stages of cellular differentiation may have different clinical and pathobiological behavior. To test the hypothesis that HCC can be classified into two types based on its phenotypic markers (hepatocellular and biliary differentiation), liver tissues from 290 Chinese patients with HCC were studied. Expression of hepatocytic differentiation marker (HEP-PAR-reactive antigen), biliary differentiation markers (AE1-AE3, cytokeratin-19), proliferation markers (Ki-67, proliferating cell nuclear antigen), alpha-fetoprotein, p53, and transforming growth factor-alpha in the tumor tissue were assessed by immunohistochemistry. Hepatocytic differentiation marker was detected in 99.7% and biliary differentiation markers were detected in 29.3% of these tumors. Clinically, no patient with HCC with biliary markers survived for more than 27 weeks compared with a 22.6% survival rate in patients with HCC negative for biliary markers. HCCs positive for the biliary differentiation markers showed features of more aggressive disease in terms of poorer cellular differentiation (P < 0.001) and high-level expression of proliferation markers (Ki-67, P < 0.001; proliferating cell nuclear antigen, P = 0.0114) compared with HCCs without biliary markers. HCCs with biliary markers also had a higher level of expression of alpha-fetoprotein (P < 0.001) and p53 (P = 0.0077). Classification of HCCs based on its phenotypic (differentiation) markers has both clinical and pathobiological implications.

Adult↗

PubMed2005

Matrix "blues": clue to a cranial thoracic mass in a dog.

A 5-year-old, intact male Italian Spinone dog was presented for progressive, severe dyspnea and coughing. Thoracic radiographs revealed a large mass in the right cranial thorax. Fine needle aspiration of the mass yielded a highly cellular sample containing dense clumps of oval to spindle-shaped mesenchymal cells with distinct intracytoplasmic vacuolation, consistent with lipoblasts and lipocytes. Cell clusters were associated with abundant eosinophilic matrix, which was identified as mucin, based on Alcian blue staining. At exploratory thoracotomy, the mass was found to be nonresectable, and the dog was euthanized. Histologic sections of the multilobular mass had discrete regions of variable cellular differentiation, including highly cellular areas of pleomorphic cells, areas of spindle cells and lipoblasts in a myxoid background, and areas of well-differentiated lipogenic cells. The histologic diagnosis was myxoid liposarcoma. The thoracic cavity is a rare site for liposarcoma in the dog. The cytologic features of lipoblasts together with a mucopolysaccharide matrix were useful for distinguishing the myxoid variant of liposarcoma from other forms of liposarcoma and myxoid sarcomas.

Animals↗

PubMed2003

Loss of protein phosphatase 2A expression correlates with phosphorylation of DP-1 and reversal of dysplasia through differentiation in a conditional mouse model of cancer progression.

A conditional mouse model of time-dependent dysplasia reversal demonstrated that reversal and differentiation of dysplastic salivary gland tissue at the 4-month reversible stage was characterized by the appearance of a phosphorylated slower mobility form of Differentiation Related Transcription Factor 1-polypeptide-1 that was correlated with cellular differentiation. The phosphorylated form of DP-1 was not found at the 7-month irreversible stage or in adenocarcinomas. At the 4-month reversible stage, protein phosphatase 2A expression was down-regulated coincident with loss of oncogene expression, whereas PP2A expression persisted at the 7-month irreversible stage. Results are consistent with the hypothesis that persistent PP2A expression prevented the appearance of the phosphorylated form of DP-1 required for cellular differentiation and reversal of dysplasia after loss of oncogene expression.

Adenocarcinoma↗

PubMed1980

Rhabdomyosarcoma in children: ultrastructural study of 31 cases.

Thirty-one cases of rhabdomyosarcoma in children were studied by electron microscopy. All of the tumors examined fit into a continuum of progressive cellular differentiation mimicking that of normal myogenesis, with increasingly differentiated examples being decreasingly common. We conclude that all childhood forms of rhabdomyosarcoma are essentially embryonal tumors, with many not being sufficiently differentiated at the cellular level to allow positive ultrastructural diagnosis.

Child↗

PubMed2000

Physiological and cell biological aspects of perfusion culture technique employed to generate differentiated tissues for long term biomaterial testing and tissue engineering.

Optimal results in biomaterial testing and tissue engineering under in vitro conditions can only be expected when the tissue generated resembles the original tissue as closely as possible. However, most of the presently used stagnant cell culture models do not produce the necessary degree of cellular differentiation, since important morphological, physiological, and biochemical characteristics disappear, while atypical features arise. To reach a high degree of cellular differentiation and to optimize the cellular environment, an advanced culture technology allowing the regulation of differentiation on different cellular levels was developed. By the use of tissue carriers, a variety of biomaterials or individually selected scaffolds could be tested for optimal tissue development. The tissue carriers are to be placed in perfusion culture containers, which are constantly supplied with fresh medium to avoid an accumulation of harmful metabolic products. The perfusion of medium creates a constant microenvironment with serum-containing or serum-free media. By this technique, tissues could be used for biomaterial or scaffold testing either in a proliferative or in a postmitotic phase, as is observed during natural development. The present paper summarizes technical developments, physiological parameters, cell biological reactions, and theoretical considerations for an optimal tissue development in the field of perfusion culture.

Animals↗

PubMed2001

Sphingolipids in mammalian cell signalling.

Sphingolipids and their metabolites, ceramide, sphingosine and sphingosine-1-phosphate, are involved in a variety of cellular processes including differentiation, cellular senescence, apoptosis and proliferation. Ceramide is the main second messenger, and is produced by sphingomyelinase-induced hydrolysis of sphingomyelin and by de novo synthesis. Many stimuli, e. g. growth factors, cytokines, G protein-coupled receptor agonists and stress (UV irradiation) increase cellular ceramide levels. Sphingomyelin in the plasma membrane is located primarily in the outer (extracellular) leaflet of the bilayer, whilst sphingomyelinases are found at the inner (cytosolic) face and within lysosomes/endosomes. Such cellular compartmentalisation restricts the site of ceramide production and subsequent interaction with target proteins. Glycosphingolipids and sphingomyelin together with cholesterol are major components of specialised membrane microdomains known as lipid rafts, which are involved in receptor aggregation and immune responses. Many signalling molecules, for example Src family tyrosine kinases and glycosylinositolphosphate-anchored proteins, are associated with rafts, and disruption of these domains affects cellular responses such as apoptosis. Sphingosine and sphingosine-1-phosphate derived from ceramide are also signalling molecules. In particular, sphingosine-1-phosphate is involved in proliferation, differentiation and apoptosis. Sphingosine-1-phosphate can act both extracellularly through endothelial-differentiating gene (EDG) family G protein-coupled receptors and intracellularly through direct interactions with target proteins. The importance of sphingolipid signalling in cardiovascular development has been reinforced by recent reports implicating EDG receptors in the regulation of embryonic cardiac and vascular morphogenesis.

Animals↗

PubMed2005

Effects of the differentiated keratinocyte phenotype on expression levels of CYP1-4 family genes in human skin cells.

Epoxyeicosatrienoic acids produced by mouse CYP2B19 have been implicated in mechanisms regulating epidermal cornification (Ladd, P.A., Du, L., Capdevila, J.H., Mernaugh, R., Keeney, D.S., 2003. Epoxyeicosatrienoic acids activate transglutaminases in situ and induce cornification of epidermal keratinocytes. J. Biol. Chem. 278, 35184-35192). In this study, we aimed to identify CYPs that are up-regulated during keratinocyte differentiation and potentially responsible for epoxyeicosatrienoic acid formation in human skin. The cellular differentiation state of human epidermal cell cultures was manipulated to resemble the basal, spinous, and granular cell phenotypes in vivo. Changes in CYP mRNA levels were measured as a function of differentiation state for a panel of 15 CYPs that included known and putative arachidonate monooxygenases. Quantitative real-time PCR analyses showed that all of the CYPs were expressed in differentiating epidermal cell cultures and in human epidermis, with the exception of CYP2B6, which was poorly expressed in vitro. Six CYPs were strongly up-regulated at Day 6 and Day 8 of in vitro differentiation (CYP4B1, 2W1, 2C18, 3A4, 2C19, 2C9); the increase in mRNA levels ranged from 27- to 356-fold. Only CYP2U1 mRNA levels decreased (6-fold change) during cellular differentiation. Six CYPs showed little variation (<2-fold change) in mRNA levels during in vitro differentiation (CYP2S1, 2J2, 1B1, 1A1, 2E1, 2D6). No single CYP was identifiable as being a functional counterpart to CYP2B19 in mouse skin since none qualified as being mainly responsible for epidermal epoxyeicosatrienoic acid formation. Rather, the data suggest that epoxyeicosatrienoic acids in human skin are formed by several CYPs expressed in different cell layers of the epidermis. This would predict that CYP-derived eicosanoids have different functions in different epidermal cell layers.

Cell Culture Techniques↗

PubMed1980

Regulation of development in Dictyostelium discoideum. IV. Effects of ions on the rate of differentiation and cellular response to cyclic AMP.

The effects of ionic environment on both the intrinsic rate of differentiation and the response to exogenous cyclic AMP in Dictyostelium discoideum have been examined. K+ specifically inhibits the rate of early development when present at concentrations > 15 mM. Na+ does not inhibit at concentrations up to 25 mM, and can partially overcome K+ inhibition. The maximum rate of development also depends upon the presence of adequate levels of extracellular Ca++. The effect of exogenous cyclic AMP on the rate of development is inhibited by the absence of Ca++, and/or the presence of high concentrations of K+. Under optimal ionic conditions, the only effect of exogenous cyclic AMP on early developments of K+. Under optimal ionic conditions, the only effect of exogenous cyclic AMP on early development is a specific inhibition. The implications of these results for current models of early developmental regulation are discussed.

Buffers↗

PubMed1989

Anti-c-myc DNA increases differentiation and decreases colony formation by HL-60 cells.

The proto-oncogene c-myc, whose gene product has a role in replication, is overexpressed in the human promyelocytic leukemia HL-60 cell line. Treatment of HL-60 cells with an antisense oligodeoxyribonucleotide complementary to the start codon and the next four codons of c-myc mRNA has previously been observed to inhibit c-myc protein expression and cell proliferation in a sequence-specific, dose-dependent manner. Comparable effects are seen upon treatment of HL-60 cells with dimethylsulfoxide (Me2SO), which is also known to induce granulocytic differentiation of HL-60 cells. Hence, the effects of antisense oligomers on cellular differentiation were examined and compared with Me2SO. Differentiation of HL-60 cells into forms with granulocytic characteristics was found to be enhanced in a sequence-specific manner by the anti-c-myc oligomer. No synergism was observed between the anti-c-myc oligomer and Me2SO in stimulating cellular differentiation. In contrast, synergism did appear in the inhibition of cell proliferation. Finally, the anti-c-myc oligomer uniformly inhibited colony formation in semisolid medium. It is possible that further reduction in the level of c-myc expression by antisense oligomer inhibition may be sufficient to allow terminal granulocytic differentiation and reverse transformation.

Cell Differentiation↗

PubMed1999

Butyrate-induced G2/M block in Caco-2 colon cancer cells is associated with decreased p34cdc2 activity.

Butyrate, a short-chain fatty acid, has been reported to inhibit proliferation and stimulate differentiation in multiple cancer cell lines. Whereas the effects of butyrate on cellular differentiation are well documented, the relationship between butyrate-induced differentiation and its effect on cell cycle traverse is less well understood. The purpose of this study was to investigate the effects of butyrate on the regulatory proteins of the G2/M traverse in the Caco-2 colon cancer cell model. We demonstrated that the inhibition of proliferation and increased cellular differentiation after treatment of Caco-2 cells with butyrate were associated with a significant G2/M cell cycle block. Although protein levels of the major G2/M regulatory protein, p34cdc2, were unchanged, a decrease in p34cdc2 activity was noted. Despite this decrease in activity, the inhibitory tyrosine phosphorylation of p34cdc2 was decreased, suggesting that other factors are responsible for the decreased kinase activity. The reduced activity of p34cdc2 provides a possible mechanism for the accumulation of Caco-2 cells in the G2/M cell cycle compartment following exposure to butyrate. This cell system provides a new model for studies of G2/M cell cycle perturbations.

Alkaline Phosphatase↗

PubMed1980

The effects of steel mutation on testicular germ cell differentiation.

The effects of artificial cryptorchidism and its surgical reversal on spermatogenesis were examined in germ cell mutant, S1/+ and wild type, +/+, mice. In cryptorchid testes no difference was found between S1/+ and +/+ mice in the number of undifferentiated type A spermatogonia. The activity of type A spermatogonia in mutant mice appeared normal as judged by its mitotic cell number and DNA synthesis. The surgical reversal of cryptorchidism resulted in regenerative differentiation of mature germ cells in both types of mice, but the pattern of cellular differentiation in the mutant testes was completely different from that of the wild type testes. At two steps of cellular differentiation, intermediate or type B spermatogonia and spermatid, the numbers of cells were much smaller in the S1/+ testes than those in the +/+ testes. The steel gene was therefore suggested to exert its effects on the differentiation of type A spermatogonia to intermediate or type B spermatogonia, on meiotic division and/or the survival rate of these cells, but not on the undifferentiated type A spermatogonia or stem cells.

Animals↗

PubMed1978

Comparison of the effector cells in human spontaneous cellular cytotoxicity and antibody-dependent cellular cytotoxicity: differential sensitivity of effector cells to in vivo and in vitro corticosteroids.

The effector cells mediating antibody dependent cellular cytotoxicity (ADCC) and spontaneous cellular cytotoxicity (SCC) in humans have been reported to possess similar characteristics. Multiple cell separation techniques were employed in an attempt to physically separate and distinguish the effector cells in these two types of cellular cytotoxicity. Subpopulations of mononuclear cells obtained by a variety of fractionation procedures which either enriched or depleted monocytes, lymphocytes bearing a receptor for sheep erythrocytes (SRBC), a receptor for complement (CRL) or an Fc receptor for IgG always had similar effects on both ADCC and SCC. Aggregated gamma globulin blockade of Fc receptors produced similar dose-dependent depressions of ADCC and SCC. Despite our inability to physically separate the effector cells of ADCC and SCC, administration of in vivo dexamethasone caused a relative increase in ADCC but a profound decrease in SCC. Furthermore, in vitro dexamethasone in pharmacologic and suprapharmacologic concentrations caused no change in ADCC but significantly decreased SCC. This study demonstrates that although the effector cells cannot be physically separated, ADCC and SCC are differentially sensitive to corticosteroids and are hence functionally distinct either on the basis of different subsets of effector cells with similar surface markers or different mechanisms of cytotoxicity by the same effector cell.

Adrenal Cortex Hormones↗

PubMed2005

Development of a sodium/iodide symporter (NIS)-transgenic mouse for imaging of cardiomyocyte-specific reporter gene expression.

UNLABELLED: Development of a small animal imaging system for differentiated cell-specific reporter gene expression will enable us to image cellular differentiation in vivo. In this study, we developed a sodium/iodide symporter (NIS)-transgenic mouse in which NIS is constitutively expressed as an imaging reporter gene only in cardiomyocytes. METHODS: To express NIS gene in cardiomyocytes, alpha-myosin heavy chain (alpha-MHC)-NIS was constructed and used for the production of NIS-transgenic mice. Twelve lines of positive founder were obtained. The adequacy of the transgenic mouse model was tested by in vivo scintigraphy, microPET, and a biodistribution study. RESULTS: The myocardium of transgenic mice showed rapid and intense uptake of 131I, which was much higher than that of the thyroid, and also showed long retention by gamma-camera pinhole imaging. The relative uptake ratio of the heart of transgenic mice was 4.6 +/- 1.5, which was 3.8 +/- 1.2 times higher than that of control wild-type mice. The uptake of the heart was completely blocked by oral administration of KClO4, an NIS inhibitor. The heart of transgenic mouse was also clearly and intensely visualized on microPET using 124I. Biodistribution data of these mice showed the uptake of 40-160 %ID/g (percentage injected dose per gram of tissue) of (99m)Tc-pertechnetate in the heart compared with 40-60 %ID/g in the stomach, respectively. NIS expression in the myocardium was confirmed by immunohistochemistry using a NIS-specific antibody. CONCLUSION: We developed a transgenic mouse model to image cardiomyocytes with a gamma-camera and microPET using an alpha-MHC promoter and NIS. The transgenic mouse can be used as an imaging model for cardiomyocyte-specific reporter gene expression and cellular differentiation into cardiomyocytes after cardiac stem or progenitor cell transplantation.

Animals↗

PubMed1989

Condensation of hypertrophic chondrocytes at the chondro-osseous junction of growth plate cartilage in Yucatan swine: relationship to long bone growth.

Chondrocytes of the cartilaginous growth plate are found in a spatial gradient of cellular differentiation beginning with cellular proliferation and ending with cellular hypertrophy. Although it is recognized that both proliferation and hypertrophy contribute significantly to overall bone growth, mechanisms acting on the chondrocyte to control the timing, the rate, and the extent of hypertrophy are poorly understood. Similarly, mechanisms acting on the terminal chondrocyte to cause its death at the chondro-osseous junction have not been investigated. In this study we examine the condensation of terminal hypertrophic chondrocytes in proximal and distal radial growth plates of Yucatan swine at 4 weeks of age. The animals were raised in a controlled environment where activity and feeding patterns were synchronized to a given time in the light/dark cycle. We analyzed cellular condensation both as a function of circadian rhythms in a 24-hr time period, and as a function of overall rate of growth. The data suggest that the magnitude of circadian influences on long bone growth is significantly damped at the level of the hypertrophic chondrocyte compared to that seen by previous investigators studying circadian influences on chondrocytic proliferation. Secondly, the condensation of hypertrophic chondrocytes at the chondro-osseous junction varies inversely with rate of growth in length of the bone. At any time period, a higher percentage of terminal chondrocytes in the condensed form was found in the slower-growing of the two growth plates. We relate these findings to current hypotheses concerning controls of chondrocytic hypertrophy and possible controls over the timing of hypertrophic cell death.

Animals↗

PubMed2004

Alcohol dehydrogenase 3 transcription associates with proliferation of human oral keratinocytes.

Gene expression underlying cellular growth and differentiation is only partly understood. This study analyzed transcript levels of the formaldehyde-metabolizing enzyme alcohol dehydrogenase 3 (ADH3) and various growth and differentiation-related genes in human oral keratinocytes. Culture of confluent cells both with and without fetal bovine serum inhibited colony-forming efficiency and induced a squamous morphology. Confluency alone decreased the transcript levels of ADH3, the proliferation markers cell division cycle 2 (CDC2) and proliferating cell nuclear antigen (PCNA), and the basal cell marker cytokeratin 5 (K5), but increased transcripts for the suprabasal differentiation markers involucrin (INV) and small proline-rich protein 1B (SPR1). These changes were variably influenced by serum, i.e., loss of CDC2 and PCNA was inhibited, loss of K5 promoted, increase of SPR1 transcripts inhibited, and increase of INV promoted. The extent and onset of the effects implied that ADH3 transcription serves as a proliferation marker and that confluency with or without serum exposure can serve to selectively analyze proliferative and differentiated cellular states.

Aldehyde Oxidoreductases↗

PubMed1992

Spatial rearrangement and enhanced clustering of kinetochores in interphase nuclei of dorsal root ganglion neurons in vitro: association with nucleolar fusion.

Interphase nuclei of several cell types display distinct, nonrandom arrangements of specific chromatin domains. It has been suggested that this arrangement is associated with the functional commitment of the cell and results from compartmentalization of specific DNA sequences to transcriptionally competent sites. In a test of the hypothesis that such topological organization is established during cellular differentiation, the spatial distribution of centromeres was determined, in dorsal root ganglion neurons in vitro, using immunocytochemistry in conjunction with fluorescence microscopy, confocal laser microscopy, and ultrastructural immunogold techniques. Kinetochores occurred as clusters, in association with nucleoli and with the nuclear envelope. Neurons at different stages of differentiation, as determined by nucleolar distribution, exhibited a distinct, stage-specific, spatial organization of kinetochores. Morphometric analyses, together with serial reconstruction, indicated that progressive clustering of kinetochores accompanies differentiation and that such clustering occurs in association with nucleolar fusion. The data presented indicate that the chromatin organization observed in the fully differentiated state may be the result of controlled rearrangements of specific chromatin domains during differentiation and that the mechanism governing such rearrangement and the process of cellular differentiation may be linked.

Animals↗

PubMed2006

Transcriptional network dynamics in macrophage activation.

Transcriptional regulatory networks govern cell differentiation and the cellular response to external stimuli. However, mammalian model systems have not yet been accessible for network analysis. Here, we present a genome-wide network analysis of the transcriptional regulation underlying the mouse macrophage response to bacterial lipopolysaccharide (LPS). Key to uncovering the network structure is our combination of time-series cap analysis of gene expression with in silico prediction of transcription factor binding sites. By integrating microarray and qPCR time-series expression data with a promoter analysis, we find dynamic subnetworks that describe how signaling pathways change dynamically during the progress of the macrophage LPS response, thus defining regulatory modules characteristic of the inflammatory response. In particular, our integrative analysis enabled us to suggest novel roles for the transcription factors ATF-3 and NRF-2 during the inflammatory response. We believe that our system approach presented here is applicable to understanding cellular differentiation in higher eukaryotes.

Algorithms↗

PubMed2001

How and where to build a root hair.

The root hair of Arabidopsis has become a model system for investigations of the patterning and morphogenesis of cells in plants. A cascade of transcriptional regulators controls the pattern of cellular differentiation. Recently, one of the genes that plays a specific role in cellular differentiation in roots, WEREWOLF, has been shown to be functionally equivalent to GLABRA1, which functions only in the shoot. The cloning of genes defined by mutants with defective root-hair growth has provided insights into the roles of the cell wall, ion transport and the cytoskeleton during hair growth. Genetic analyses continue to identify mutants that will be instructive in furthering our understanding of the growth and development of root-hair cells.

Cell Differentiation↗