The role of progenitor cells in cellular differentiation, cellular senescence and neoplastic transformation.
Explore the source record for details and available documents.
Adipose Tissue↗
SEARCH · Search PubMed
Results for “cellular differentiation”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Biogenesis of mitochondrial membranes in Neurospora crassa during cellular differentiation: ultrastructural changes accompanying differentiation.
The ultrastructural characteristics of Neurospora cells during dedifferentiation and redifferentiation of conidiospores into vegetative cells have been determined. This germination process occurs between 2 and 5 h after inoculation; by 3-5 h, approximately 50% of the cells have germinated. The cells enter the exponential phase of dry-weight gain between 4 and 5 h after inoculation. Several unusual structures are observed in Neurospora cells during germination. Whorled structures are frequently seen in the cytoplasm during germination, and occasionally at other times. They appear to be derived from the cytoplasmic membrane. Whorled structures of different appearance were observed in the mitochondria between 2 and 4 h after inoculation. Their number was related to the level of metabolizable carbohydrate, and was higher in 15% glucose-than in 2% sucrose-supplemented medium, and very low in medium containing 15% mannitol, or 2% sucrose+13% 2-deoxyglucose, or no added carbohydrate. The mitochondrial inclusions were osmiophilic and could be removed by treatment with 90% aqueous acetone in the cold, indicating that they were composed at least in part of lipid. The strong dependence of the number of mitochondrial inclusions on time and on carbohydrate supplementation, suggests that there is a physiological basis for these structures and that they reflect changes occurring in the mitochondria at times significant to cellular differentiation.
Carbohydrate Metabolism↗
Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases.
Mononuclear phagocytes have the capacity to directly participate in extracellular matrix turnover via secretion of neutral proteinases. We have studied the effects of in vivo and in vitro differentiation upon cellular content or secretion of a spectrum of neutral proteinases, along with a counter-regulatory metalloproteinase inhibitor (TIMP). We found 1) matrix-degradative serine proteinases (leukocyte elastase and cathepsin G) were lost during cellular maturation and/or differentiation; 2) the 92-kDa type IV/type V collagenase and TIMP were secreted earliest in mononuclear phagocyte differentiation, whereas stromelysin secretion was observed only by LPS-stimulated alveolar macrophages; 3) exposure of alveolar macrophages, but not monocytes, to phorbol esters and LPS resulted in markedly augmented secretion of all studied metalloproteinases and TIMP; 4) monocyte-derived macrophages partially (but not completely) mimicked the metalloproteinase secretory phenotype of alveolar macrophages; and 5) the secretory phenotype of alveolar macrophages for interstitial collagenase (but not TIMP) was largely lost during in vitro culture. These results underscore the complexity of the process of differentiation in human mononuclear phagocytes, and provide insights into the variable capacity of mononuclear phagocytes to degrade extracellular matrix components. Moreover, we anticipate that human mononuclear phagocytes at various stages of differentiation will provide a useful model system for study of the variable regulation of secretion of human matrix-degrading metalloproteinases.
Cell Differentiation↗
Oxygen free radicals play a role in cellular differentiation: an hypothesis.
Evidence from a variety of sources supports the view that oxygen free radicals play a role in cellular differentiation. It is postulated that cellular differentiation is accompanied by changes in the redox state of cells. Differentiated cells have a relatively more prooxidizing or less reducing intracellular environment than the undifferentiated or dedifferentiated cells. Changes in the redox balance during differentiation appear to be due to an increase in the rate of O2- generation. Differentiated cells, in general, exhibit higher rates of cyanide-resistant respiration, cyanide-insensitive SOD activity, and peroxide concentration and lower levels of GSH as compared to undifferentiated cells. The effects of free radicals on cellular differentiation may be mediated by the consequent changes in ionic composition.
Animals↗
Suppression of tumorigenicity by the cell-cycle-dependent control of cellular differentiation and proliferation.
The experiments described in this report were designed to determine if suppression of tumorigenicity can be mediated by cell-cycle-dependent mechanisms that control cellular differentiation and/or proliferation in mesenchymal stem cells of the 3T3 T type. These cells were employed because they possess distinct, well-characterized cell-cycle-dependent mechanisms to control both cellular differentiation and proliferation. To achieve our goal we developed by non-mutagenic procedures 23 clonal variants of 3T3 T stem cells that expressed one of 4 distinct phenotypes for the regulation of cellular differentiation and proliferation. Six clones expressed combined defects in the control of differentiation and proliferation; 6 expressed intact mechanisms to control proliferation but defects in the control of differentiation; and 3 expressed intact mechanisms to control differentiation but defects in the control of proliferation. Finally, 8 clones expressed no detectable phenotypic defects in the control of either differentiation or proliferation. Once isolated and characterized, each of these clones was assayed for its tumorigenic potential. The results establish that clones which express combined defects in the control of differentiation and proliferation are highly tumorigenic. By contrast, tumorigenicity is markedly suppressed in clones that maintain the ability to control their proliferation or their differentiation. Furthermore, clones that maintained the ability to control both proliferation and differentiation showed no evidence of tumorigenicity. These data are interpreted to suggest that stringently regulated control of cellular differentiation and/or proliferation can act as a cancer suppressor mechanism.
Animals↗
Cellular differentiation regulates expression of Cl- transport and cystic fibrosis transmembrane conductance regulator mRNA in human intestinal cells.
The gene defective in cystic fibrosis has recently been shown to code for a membrane protein designated the "cystic fibrosis transmembrane conductance regulator" (CFTR) protein. While it has been shown that detectable levels of the mRNA for the normal CFTR protein are present in epithelial cells from different tissues, factors which regulate CFTR expression have not been identified. A clonal cell line originating from a human colon adenocarcinoma (HT29-18) differentiates to multiple epithelial cell types when deprived of glucose in the culture medium. In these studies, mRNA isolated from these cells was examined by hybridization to a 1.45-kilobase cDNA probe which encodes transmembrane portions of the CFTR protein between exons 13 and 19. Cellular differentiation of HT29-18 causes a 9-18-fold increase in CFTR mRNA abundance versus the mRNA for the structural proteins actin and tubulin. Cellular differentiation also causes a 5-fold increase in second messenger-regulated Cl- transport which is sensitive to a Cl- channel blocker (diphenylamine 2-carboxylate). Subclones of HT29-18 which are committed to differentiate to either a mucin-secreting (HT29-18-N2) or an "enterocyte-like" (HT29-18-C1) phenotype have also been examined. In both subclones, elevated levels of CFTR mRNA are observed when compared with undifferentiated HT29-18 cells. However, during cellular differentiation, the regulation of CFTR mRNA abundance and membrane enzyme expression by the subclones is different from HT29-18. The results show that elevated CFTR mRNA occurs in multiple differentiated intestinal epithelial cell types, despite a phenotype-specific regulation of membrane protein expression. This suggests that CFTR expression plays a role in the differentiated functions of multiple epithelial phenotypes and that both cellular differentiation and cellular phenotypes are factors which regulate CFTR expression.
Biological Transport↗
Bromodeoxyuridine-immunohistochemistry on cellular differentiation and migration in the fundic gland of Xenopus laevis during development.
Cellular differentiation and migration in the fundic glands of adult and larval Xenopus laevis have been examined using bromodeoxyuridine-immunohistochemistry. In the adult fundic gland, cumulative labeling with bromodeoxyuridine revealed a proliferative cell zone between the surface mucous cells and mucous neck cells, in what is referred to as the neck portion of the gland. The labeling-index of mucous neck cells had rapidly increased by week-5. The labeling-index of oxynticopeptic cells showed a more delayed increase until week-7, coincident with the decrease in the labeling of mucous neck cells. In the immature fundic glands of larvae, the labeled proliferating cells were randomly distributed throughout the developing gastric mucosa. During metamorphosis, the labeling-index of immature epithelial cells was highest at stage 63. Following administration of bromodeoxyuridine at this stage, there was no significant loss of labeled epithelial cells during the metamorphosing period. Furthermore, there was no significant difference in the labeling-indices among the epithelial cells, such as surface mucous cells/generative cells, mucous neck cells, and oxynticopeptic cells, 7 days after administration. Cellular differentiation and migration pathways of epithelial cells in the fundic gland of adult X. laevis and its larvae are discussed.
Animals↗
Secondary metabolites as chemical signals for cellular differentiation.
Several microbial secondary metabolites function as essential chemical signals for induction of cellular differentiation in the producing organisms. The role of A-factor and its analogues such as essential autoregulators in actinomycetes is discussed and a review is given of fungal metabolites with hormonal activities. Divergent secondary metabolites with the capability to induce cellular differentiation in other organisms are also discussed as to their possible involvement in a symbiotic relationship in the ecosystem.
Actinomycetales↗
Apolipoprotein expression and cellular differentiation in Caco-2 intestinal cells.
Caco-2 cells, cultured for 18 days on porous filter supports and conventional plastic culture dishes, were used to study the effects of cellular differentiation on the expression of apolipoprotein (apo) genes. Media of filter-grown cells accumulated more apo B as apo B-48 and contained three times the amount of edited apo B mRNA compared with plastic-grown cells. The accumulation of apo A-I by media of plastic-grown cells was higher than accumulation by filter-grown cells, despite similar concentrations of apo A-I mRNA. The apo A-IV was detectable in the culture media earlier with filter-grown cells compared with plastic-grown cells, despite similar apo A-IV mRNA concentrations. Plastic-grown cells contained more apo E mRNA, and their media accumulated more apo E than filter-grown cells. With the exception of apo A-I, apo gene expression changed with Caco-2 cell differentiation to resemble more closely the patterns seen in adult enterocytes. There were no effects or minimal effects of added retinoic acid, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or thyroid hormone on apo accumulation in media of filter-grown cultures of Caco-2 cells. However, 1,25(OH)2D3 and thyroid hormone increased apo B, apo A-IV, and apo A-I mRNA concentrations, retinoic acid increased apo B mRNA concentrations alone, and all three reduced apo E mRNA concentrations. Ratios of edited to unedited apo B mRNA were unaffected. In conclusion, culture substratum importantly influences Caco-2 cell differentiation. Soluble factors that influence cellular differentiation may affect apo gene expression over and above effects mediated by the culture substratum.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein A-I↗
Metastatic potential of human colon cancer cell lines: relationship to cellular differentiation and carcinoembryonic antigen production.
The relationship between cellular differentiation and carcinoembryonic antigen (CEA) production by human colorectal tumor cells and their ability to form hepatic metastases was studied. Eight human colon cancer cell lines were injected into athymic mice using different routes of administration to characterize their metastatic potential. The four poorly differentiated, non or low CEA producing cell lines were poorly metastatic to the liver after intrasplenic injection. After intraperitoneal implantation the same cell lines were highly tumorigenic, and subsequently metastatic to the liver. In contrast, the four moderate to well-differentiated cell lines that produced moderate to high levels of CEA were highly metastatic to the liver following intrasplenic injection. After intraperitoneal implantation they were less tumorigenic, and metastatic to the liver. We conclude that in this system poorly differentiated non or low CEA producing colorectal cell lines have a lower metastatic capacity compared to the well-differentiated high CEA producing colorectal cell lines. These data correlate directly with the pattern of metastatic spread and clinical course observed in patients with these tumors, suggesting that degree of differentiation and level of CEA production may play a role in development of site-specific metastases.
Animals↗
Cellular differentiation in ovarian sex-cord-stromal and germ-cell tumors studied with antibodies to intermediate-filament proteins.
Seventy ovarian sex-cord-stromal and germ-cell tumors were immunohistochemically studied for the presence of intermediate-filament proteins of different types used as markers for cellular differentiation. Cells of ovarian granulosa-cell tumors constantly expressed vimentin and appeared to lack cytokeratin. Two tumors previously classified as granulosa-cell tumors were reclassified as poorly differentiated "common" epithelial tumors based on their cytokeratin positivity, vimentin negativity, and morphologic features. Dysgerminomas and Leydig-cell tumors showed only vimentin positivity. Tubular structures in androblastomas, which are considered to represent Sertoli-cell differentiation, were cytokeratin positive, and thus differed from the majority of normal Sertoli cells that are known to express vimentin and not cytokeratin. Embryonal carcinomas, choriocarcinomas, and endodermal sinus tumors showed cytokeratin positivity in the neoplastic cells whereas vimentin was observed in the stromal cells. In immature teratomas, epithelial differentiation was demonstrated with cytokeratin antibodies, and neural and glial differentiation was also frequently demonstrated by immunostaining with antibodies to neurofilaments and glial fibrillary acidic protein. The results show that antibodies to intermediate filaments can be used in the differential diagnosis between ovarian epithelial and nonepithelial tumors, and they provide a very accurate additional method to characterize the cellular differentiation of ovarian neoplasms.
Animals↗
The role of diffusible molecules in regulating the cellular differentiation of Dictyostelium discoideum.
A central problem in developmental biology is to understand how morphogenetic fields are created and how they act to direct regionalized cellular differentiation. This goal is being pursued in organisms as diverse as moulds, worms, flies, frogs and mice. Each organism has evolved its own solution to the challenge of multicellularity but there appear to be common underlying principles and, once pattern formation is fully understood in any system, some general truths seem certain to be revealed. As a non-obligate metazoan, Dictyostelium discoideum has proven a particularly tractable system in which to identify and characterize cellular morphogens. Cyclic AMP and ammonia stimulate prespore cell differentiation and ammonia plays an additional role in repressing terminal cellular differentiation. Differentiation Inducing Factor (DIF) acts to direct prestalk cell differentiation and adenosine may play a synergistic role in repressing prespore cell differentiation. This review summarizes the evidence for these interactions and describes a number of models which show how this small repertoire of diffusible molecules, acting in concert, may direct the formation of a differentiated structure.
Cell Differentiation↗
Growth inhibition and induction of cellular differentiation of human myeloid leukemia cells in culture by carbamoyl congeners of ribavirin.
A series of 1,2,3-triazole (2), pyrazole (3 and 5), and pyrrole (4) ribonucleosides with two adjacent carbamoyl groups have been synthesized and evaluated for cell growth inhibition and induction of cellular differentiation of HL-60 cells in culture. Glycosylation of the TMS derivatives of dimethyl 1,2,3-triazole-4,5-dicarboxylate (6) and diethyl pyrazole-3,4-dicarboxylate (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D- ribofuranose (8) in the presence of TMS triflate gave predominantly the beta-nucleosides 9 and 14, respectively. Ammonolysis of 9 and 14 furnished 2-beta-D-ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (2) and 1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide (3), respectively. Stereoselective ring annulation of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-D- ribose (16) with tetracyanoethylene (15) gave 5-amino-1-(2,3-O-isopropylidene-beta-D-ribofuranosyl)pyrazole-3,4- dicarbonitrile (17). Deisopropylidenation of 17, followed by oxidative hydrolysis of the reaction product (18), gave the 5-amino derivative of 3 (5). Stereospecific glycosylation of the sodium salt of preformed diethyl pyrrole-3,4-dicarboxylate (22) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D- ribofuranose (23) was accomplished to furnish blocked nucleoside 24, which on ammonolysis and deisopropylidenation gave 1-beta-D-ribofuranosylpyrrole-3,4-dicarboxamide (4). The structures of 2 and 3 were assigned by single-crystal X-ray diffraction studies, which showed extensive inter- and intramolecular hydrogen bonding. Nucleosides 2-5 are devoid of significant cytotoxic properties against L1210 and WI-L2 leukemia cells in culture. However, these compounds were found to be inducers of cellular differentiation of HL-60 cells in the range of 30-60 microM and were comparable to ribavirin in this regard.
Acetylation↗
Human immunodeficiency virus infection of monoblastoid cells: cellular differentiation determines the pattern of virus replication.
Stringent control of human immunodeficiency virus (HIV) replication was observed in the human monoblastoid cell line U937. A low-multiplicity infection of these cells by the LAV1 strain of HIV was productive for 2.5 days; then virus replication became restricted and no further evidence of virion production was observed. The dramatic decrease in HIV production was due in part of reduced accumulation of cytoplasmic viral RNA and occurred in the absence of evident cytopathic effects. In contrast, infected cells induced to differentiate by phorbol ester, vitamin D3, or lymphokine supernatant did not release markers of HIV despite the accumulation of significant levels of cytoplasmic viral RNA. HIV infection altered the pattern of c-myc RNA accumulation in U937 cells. Expression of this gene changes normally in response to the state of cellular differentiation; in infected cells the level of c-myc expression was correlated to the levels of viral RNA accumulation and not to cellular differentiation. These results suggest that restricted replication of HIV in monocytes might be an important mechanism of virus persistence and demonstrate a relationship between HIV replication and monocyte differentiation.
Cell Differentiation↗
Evidence for differential cellular adhesion as the mechanism of sorting-out of various cellular slime mold species.
Various authors have shown previously that if the amoebae of two species of slime molds are mixed they have the ability to sort themselves out. In the work reported here, the sorting-out of cells of several slime mold species was examined in clumps of cells in suspension. Cells of four species, Dictyostelium discoideum (Dd), D. mucoroides (Dm), D. purpureum (Dp), and Polysphondylium violaceum (Pv), were mixed in pairs in suspension and clumps of cells formed. Dd and Pv cells sorted out completely and formed separate clumps, each of single species. Both Dd and Dm, when mixed separately with Dp, formed clumps containing both species. Sorting-out took place in these clumps such that the cells of Dd and Dm partially enveloped the Dp cells. Finally, in the Dd-Dm mixtures, the Dm cells always sorted out such that they surrounded the Dd cells. When mixed in a 1:2 ratio (Dd:Dm) the Dm cells formed a complete shell around a sphere of Dd cells. Sorting-out of cells in clumps in suspension can occur by either of two possible mechanisms: response of cells to a chemotactic gradient or differences in cell surface strengths of adhesion (Steinberg, 1964). Mixing of two species in a clump of cells and observing the process of sorting-out permits one to distinguish between these two mechanisms (Steinberg, 1964). By such an analysis it was found that the sorting-out observed in mixtures of Dd and Dm is consistent with the mechanism of differential cellular adhesion. The major reasons for this are (1) when the adhesive properties of the cells are known to change the Dd cells began to move inside the clumps, (2) the Dd cells coalesced into islands rather than streaming inward independently, and (3) the Dd cells and cell masses did not lie at the center of the clumps but rather lay randomly within the clumps. The partial envelopment observed in the Dd-Dp and Dm-Dp mixtures and the separate clumps formed by the Dd-Pv mixtures are also consistent with differential cellular adhesion. They represent cases in which the interspecific strengths of adhesion are low (Dd-Dp and Dm-Dp) and near zero (Dv-Pv).
Cell Membrane↗
[Hormonal stimulation and in vitro cellular differentiation in the integument of the desert locust Schistocerca gregaria (author's transl)].
Spontaneous cellular differentiation (glandular units appearance with a well-defined duct) is observed in larval integument of Schistocerca cultured in an hormone free medium. Hormonal stimulations modify the expression of this phenomenon, particularly the frequency of new elaborated duct cells belonging to secretory units. The most effective factor is supplied by the prothoracic glands. Complete secretory units can be observed but the glandular cells are in an undifferentiated and unfunctional state. They appear active if the corpora allata act after the prothoracic glands. Corpora allata alone or synthetic juvenile hormones have an inhibitory effect. The addition of alpha-ecdysone permits only cellular divisions, a preliminary and indispensable condition for ulterior differentiation. Between cuticles deposited with beta-ecdysone, new formed ducts take place in the theorical imaginal exuvia. These observations prove that the elaboration and the activity of imaginal glandular units are conditioned by the larval hormonal context: by contrast, sex dimorphism is only a genetic dependant process.
Animals↗
Loss of intragenomic DNA repair heterogeneity with cellular differentiation.
The influence of terminal differentiation on UV-induced DNA damage and its repair in transcriptionally active and inactive genomic sequences was investigated using the murine 3T3-T proadipocyte cell culture system. Actively cycling 3T3-T cells terminally differentiate into adipocytes after exposure to media containing platelet-depleted human plasma. Suitable DNA fragments were analyzed from four genes: beta-actin, adenosine deaminase, dihydrofolate reductase, and lipoprotein lipase. As a result of 3T3-T cell differentiation, lipoprotein lipase and beta-actin expression was modified, whereas adenosine deaminase and dihydrofolate reductase expression was not affected. A DNA fragment representing the transcriptionally inactive locus 70-38 was also evaluated. UV-induced cyclobutane pyrimidine dimers, detected as UV-specific endonuclease-sensitive sites, in each fragment increased linearly as a function of UV dose (0-20 J/m2) independently of gene expression or differentiation. Sequence-specific repair of dimers was measured in stem and terminally differentiated 3T3-T cells after UV irradiation (10 J/m2). For undifferentiated stem cells, the rate and extent of dimer repair was higher in the actively transcribed adenosine deaminase and dihydrofolate reductase genes than in the inactive lipoprotein lipase or 70-38 fragments, the greater difference being observed in the first 8 h post-UV irradiation. In contrast, similar dimer repair rates were found for each DNA fragment in terminally differentiated 3T3-T cells. These data suggest that cellular differentiation is accompanied by a loss of heterogeneity in intragenomic DNA repair.
3T3 Cells↗
Composition and synthesis of cellular lipids in Neurospora crassa during cellular differentiation.
The synthesis of cellular lipids of Neurospora crassa was measured during growth on low (2% sucrose)- and high (15% glucose)-carbohydrate supplementation. The amount of lipid per dry weight of cells does not change during the germination and early logarithmic growth periods, but the percentage of phospholipid in the lipid does increase, reaching a maximal value of 90% at 4 to 5 h after inoculation, at which time the phospholipid content of the cells is approximately 60 mumol/g (dry weight). The content of the anionic phospholipids, as a percentage of the lipid fraction, is relatively constant during the growth period, but the contents of the zwitterionic phospholipids phosphatidylcholine and phosphatidylethanolamine change in a reciprocal fashion. During the first 8 h of growth, phosphatidylcholine falls from 53% of the phospholipid to 43%, whereas phosphatidylethanolamine rises from 29 to 38%. The total of these two phospholipids is approximately 83% during the growth period studied. The synthesis of cellular phospholipids, measured either by [32P]H3PO4 or [14C]glucose incorporation, reached maximal levels between 3 and 5 h of growth. The effect of the high-carbohydrate supplement on cellular lipids was minimal. Inclusion of 15% glucose decreased the labeling of phospholipid by [32P]H3PO4, but did not affect lipid composition. This observation is in contrast to the effects of high glucose on mitochondrial phospholipid synthesis.
Cell Differentiation↗