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PubMed1995

Effects of activin A/erythroid differentiation factor on erythroid and megakaryocytic differentiations of mouse erythroleukemia (Friend) cells: evidence for two distinct modes of cell response.

To further characterize activin A/erythroid differentiation factor (EDF) action on hematopoietic cell differentiation, we examined the effects of activin A/EDF on megakaryocytic and erythroid differentiation by determining acetylcholinesterase (AchE) activity and hemoglobin production in the mouse erythroleukemia (MEL) cell line F55. Activin A/EDF induced AchE activity of F55 cells in a dose-dependent manner. Erythroid differentiation of F55 cells, which was characterized by an increase in dianisidine-positive cells, was also induced by activin A/EDF. The effect of activin A/EDF on hemoglobin synthesis appeared more slowly compared with the effect on AchE activity. Erythroid differentiation induced by activin A/EDF was affected by the initial cell density, but AchE activity was not. Sodium orthovanadate, a tyrosine phosphatase inhibitor, markedly inhibited activin A/EDF-induced erythroid differentiation but not activin A/EDF-induced AchE activity. Other erythroid differentiation inducers, sodium butyrate and butyrylcholine chloride, mildly increased AchE activity in F55 cells, but N,N'-hexamethylene-bis-acetamide (HMBA), dimethyl sulfoxide (DMSO), and genistein did not. Dexamethasone inhibited HMBA-induced erythroid differentiation but did not affect activin A/EDF or sodium butyrate action. These results suggest that F55 cells potentially can differentiate into cells of a megakaryocytic lineage in addition to an erythroid lineage, and that activin A/EDF further potentiates the cell differentiation of this cell line. In addition, our results suggest that the mode of activin A/EDF effects on megakaryocytic differentiation is distinct from that on erythroid differentiation.

Acetylcholinesterase↗
PubMed1987

Poorly differentiated human gastric carcinoma is more sensitive to antitumor drugs than is well differentiated carcinoma.

The chemosensitivities of 41 poorly differentiated gastric cancer tissues were compared with that of 16 well differentiated tissues, using the in vitro succinate dehydrogenase inhibition test. These human tissues obtained at the time of surgery were exposed to six different antitumor drugs: carboquone (CQ), adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP) and 5-fluorouracil (5-FU). The chemosensitivity was determined as positive when the succinate dehydrogenase (SD) activity of the drug exposed cells was decreased to below 50% of that of control cells, on day 3 of exposure. Decrease in SD activity was remarkable in the poorly differentiated tissues, compared to the well differentiated tissues, exposed to ADM, MMC, DDP and 5-FU. The sensitive rates were higher in the poorly differentiated tissues than in the well differentiated tissues, against all six antitumor drugs. Sixty-three per cent of the poorly differentiated tissues were sensitive to more than three antitumor drugs, in an identical tissue, but the rate was only 19% in the well differentiated tissues. The resistant rates to all drugs tested were 20% in the poorly differentiated and 31% in the well differentiated tissues. This would indicate that patients with a poorly differentiated gastric cancer will probably show a better response to antitumor drugs, compared to those with a well differentiated type.

Aclarubicin↗
PubMed1998

Identification by differential display of transcripts regulated during hematopoietic differentiation.

The polymerase chain reaction-based differential display method (DDRT-PCR) was used to identify mRNAs differentially expressed during the maturation of human CD34+ progenitor cells stimulated to differentiate in vitro towards granulomonocytic or erythroid lineages with a mixture of hemopoietins (kit ligand + interleukin 3 + GM-CSF in the absence or presence of erythropoietin, respectively). Three cDNA transcripts (B32, B41, and B56) display differential expression during cytokine-induced maturation of CD34+ cells. These clones have no homology with already-described sequences. Primer extension cofirmed the presence of the corresponding mRNA. The levels of mRNA corresponding to B32 are enhanced in the later phases of the granulomonocytic as well as in the erythroid differentiation of CD34+ cells. The mRNA identified by B41 was induced by a late stage in only granulomonocytic differentiation of CD34+ cells. The mRNA corresponding to B56 was instead present in nonstimulated CD34+ cells, declined in the early stages of differentiation, and reappeared at later stages in cells treated with both combinations of cytokines. Expression of these genes was detected in a number of acute myelogenous leukemias, as well as in some leukemic cell lines. B32 and B41 were downregulated in KG-1 cells induced to differentiate towards the monocytic lineage, whereas the levels of B56 were unchanged. In K562 cells, clones B41 and B56 were downregulated only in the late phases of PMA-induced megakaryocytic differentiation and during erythroid differentiation. B32 was rapidly downregulated when K562 cells were induced to differentiate towards either megakaryocytic or erythroid phenotypes. These transcripts represent novel hematopoietic cDNAs that should prove of value for the study of human blood cells and their disorders.

Antigens, CD34↗
PubMed2000

Differential expressions of protein kinase C isozymes during proliferation and differentiation of human skeletal muscle cells in vitro.

The mechanism of skeletal muscle regeneration in vivo can be well modeled in vitro by culturing skeletal muscle cells. In these cultures mononuclear satellite cells fuse to form polynuclear myotubes by proliferation and differentiation. The aim of this study was to determine how the different protein kinase C (PKC) isozymes were expressed during differentiation of human skeletal muscle in vitro. The expressions of desmin, used as a muscle-specific intermediate filament protein marker of differentiation, and of different PKC isozymes were detected by single and double immunohistochemical labeling, and by Western blot analysis. In skeletal muscle cells we could identify five PKC isozymes (PKC alpha, -gamma, -etha, -theta and -zeta). The expressions of PKC alpha and -zeta did not change significantly during differentiation; their levels of expression were high in the early immature cells and remained unchanged in later phases. In contrast, the expression levels of PKC gamma and -etha increased with differentiation. Furthermore, the cellular localization of PKC gamma markedly altered during differentiation, with a perinuclear-nuclear to cytoplasmic translocation. The change in the level of expression of PKC theta during differentiation showed different pattern; its expression was high during the early phases, but a decreased immunostaining was detected in the matured, well-differentiated myotubes. We conclude, therefore, that cultured human skeletal muscle cells possess a characteristic PKC isozyme pattern, and that the different phases of differentiation are accompanied by different expression patterns of the various isozymes. These data suggest the possible functional and differential roles of PKC isozymes in human skeletal muscle differentiation.

Cell Differentiation↗
PubMed1989

Human B cell differentiation by Fc fragment. III. Effect of IL-1 and IL-2 on differentiation of human B lymphocytes induced by Fc fragments of human IgG.

The human Fc fragment of IgG, when added to blood mononuclear cells in vitro, induces B cell differentiation after 6 days of culture. This activity requires the presence of T cells and monocytes. This work explores the roles of interleukin 1 (IL-1) and interleukin 2 (IL-2) in B cell differentiation induced by Fc fragments. Peripheral blood mononuclear cells (PBMC) from normal donors were examined for plasma cell differentiation following stimulation with Fc fragment (15 and 30 micrograms/ml) with or without IL-1 (6 U/ml) or IL-2 (2 U/ml). Results indicate that both IL-1 and IL-2 accelerated B cell differentiation by the Fc fragment to 3 days of culture, compared to 6 days required with the Fc fragment alone. The time required for differentiation was not further shortened when both IL-1 and IL-2 were present in culture; both IL-1 and IL-2 were able to partially induce B differentiation alone at 6 days of culture. The importance of IL-2 in B cell differentiation was further supported by the finding that antibodies specific for the IL-2 receptor blocked B cell differentiation induced by Fc fragments, with or without additional IL-1 or IL-2. The depletion of monocytes also blocked B cell differentiation and the requirement for monocytes could not be replaced by exogenous IL-1; however, Fc fragments were shown to induce monocytes to secrete IL-1 beta after 24 hr in culture. These results suggest that accelerated differentiation of B cells into plasma cells requires a double signal provided by Fc fragments and IL-1 or IL-2. Monocytes are necessary for Fc fragment-induced differentiation and cannot be replaced by either IL-1 or IL-2.

Adult↗
PubMed1983

Control of cell differentiation during proliferation. I. Monocytic differentiation of HL-60 promyelocytes.

The cell proliferation relating an uncommitted precursor cell to a differentiated terminal cell has been quantitated. HL-60 promyelocytes, a bipotent precursor cell capable of differentiating along either the myeloid or monocytic pathway, were induced by a human lymphocyte-conditioned medium (CM) to differentiate into macrophage-like cells. The promyelocytes had a generation time of approx. 42 h. Most promyelocytes which differentiated became macrophage-like cells after only one cell division. Some, a minority, underwent more than one division. The time between induction of differentiation and expression of differentiated characteristics could thus be very short. Labelled S-phase promyelocytes could differentiate after traversing S. G2 and undergoing mitosis. Some, approx. 21%, required a subsequent complete cell cycle before differentiating. The data suggest a model in which cells must undergo a S-phase-specific differentiation control event in the presence of CM in order to differentiate in the subsequent G1 phase. This model proposes that a discrete time in S phase exists when cells are susceptible to exogenous regulation directing them to yield differentiated daughter cells.

Cell Differentiation↗
PubMed1985

Control of HL-60 myeloid differentiation. Evidence of uncoupled growth and differentiation control, S-phase specificity, and two-step regulation.

Myeloid differentiation of HL-60 human promyelocytic leukemia cells was studied during DMSO-induced differentiation. G 1/0-specific growth arrest could occur without the usual associated subsequent phenotypic differentiation into mature myeloid cells, suggesting that growth arrest and phenotypic differentiation are separately regulated. In the course of differentiating, the cells achieved a semi-stable intermediate state where they had a labile, pre-commitment memory of exposure to inducer, but were not yet committed to differentiation. This state was associated with a nuclear structural change previously found to be associated with the precommitment memory state. The process of differentiation could thus be resolved into two steps, early events up through development of pre-commitment memory and late events subsequents to pre-commitment memory. The kinetics of terminal cell differentiation indicated that the cellular regulatory event initiating a program of differentiation in response to inducer was S phase-specific. A comparison of the present results for DSMO to previous results for retinoic acid (RA)-induced HL-60 myeloid differentiation showed that the two inducers effect different cellular pathways for differentiation of HL-60 cells to mature myeloid cells, but with certain common features including the above S-phase specificity and pre-commitment memory.

Cell Cycle↗
PubMed1998

Differentiation of LA-N-5 neuroblastoma cells into cholinergic neurons: methods for differentiation, immunohistochemistry and reporter gene introduction.

The use of model systems derived from cell lines has been a valuable tool in understanding the molecules and cellular processes that govern differentiation processes (T.R. Breitman, S.E. Selonick, S.J. Collins, Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid, Proc. Natl. Acad. Sci. USA 77 (1980) 2936-2940 [2]; N. Gomez, S. Traverse, P. Cohen, Identification of a MAP kinase in phaeochromocytoma (PC12) cells, FEBS Lett. 314 (1992) 461-465 [4]). The use of such systems provides an inexpensive, quick and simple way to identify and test molecules that can be further studied in more complex in vivo experiments. Some cell lines such as embryonic stem cells can be induced to differentiate in vitro, however, the differentiation is difficult to control and most often leads to the generation of a wide variety of cell types. Cell lines derived from sources committed to a restricted cell fate provide an opportunity to examine cell growth and differentiation within a specific cell type (G.M. Keller, In vitro differentiation of embryonic stem cells, Curr. Opin. Cell Biol. 7 (1995) 862-869 [10]). In this article we describe a simple system for the differentiation of the human neuroblastoma cell line LA-N-5 into cholinergic neurons using all-trans retinoic acid (G. Han, B. Chang, M.J. Connor, N. Sidell, Enhanced potency of 9-cis versus all-trans retinoic acid to induce the differentiation of human neuroblastoma cells, Differentiation, 59 (1995) 61-69 [5]; D.P. Hill, K.R. Robertson, Characterization of the cholinergic neuronal differentiation of the human neuroblastoma cell line LA-N-5 after treatment with retinoic acid, Dev. Brain Res. 102 (1997) 53-67 [6]; J.A. Robson, N. Sidell, Ultrastructural features of a human neuroblastoma cell line treated with retinoic acid, Neuroscience 14 (1985) 1149-1162 [12]; N. Sidell, C.A. Lucas, G.W. Kreutzberg, Regulation of acetylcholinesterase activity by retinoic acid in a human neuroblastoma cell line, Exp. Cell Res. 155 (1984) 305-309 [14]). These cells provide a setting for the study of cholinergic neuronal differentiation and of the factors that influence that process. We also discuss procedures that can be used to study gene expression in LA-N-5 cells by immunohistochemistry and reporter gene analysis.

Cell Differentiation↗
PubMed1990

Adenovirus infection of differentiated F9 cells results in a global shut-off of differentiation-induced gene expression.

Previous experiments have demonstrated a link between transcriptional regulatory mechanisms acting during F9 cell differentiation and transcription control by the adenovirus E1A gene. We have isolated a number of differentiation-specific genes by cDNA cloning to determine if E1A exerts a coordinated control over differentiation specific gene expression. The mRNAs encoded by these cDNAs were undetectable or only barely detectable in undifferentiated cells but then rose in concentration upon differentiation. Analysis of transcription rates in isolated nuclei revealed that all but one of the genes was transcriptionally regulated during differentiation. Interestingly, alpha 2-type IV collagen expression was activated by a post-transcriptional mechanism since the gene was transcribed in both undifferentiated and differentiated cells whereas the cytoplasmic mRNA was undetectable in undifferentiated cells but rose in abundance in parallel with other regulated transcripts. Adenovirus infection of differentiated F9 cells reduced the cytoplasmic mRNA levels of each of the differentiation specific genes to near that found in the undifferentiated cell. Of those genes that were transcriptionally activated by differentiation, adenovirus infection specifically inhibited transcription. In contrast, although the alpha 2 collagen mRNA levels were reduced by adenovirus infection similar to the other mRNAs, the control was post-transcriptional since transcription of the gene was unaffected. Thus, the mechanism for loss of gene expression mediated by E1A reflects the mechanism by which the gene was activated during differentiation. Based on these results we suggest that E1A controls the expression of the F9 cell phenotype by targeting a regulatory activity acting early in the differentiation program.

Adenoviruses, Human↗
PubMed1992

Paracrine regulation of adipose differentiation by arachidonate metabolites: prostaglandin F2 alpha inhibits early and late markers of differentiation in the adipogenic cell line 1246.

The effect of arachidonate metabolites on the differentiation of the adipogenic cell line 1246 was investigated. Among the metabolites examined, only prostaglandin F2 alpha (PGF2 alpha) inhibited differentiation in a dose-dependent fashion with an ED50 of 3 x 10(-9) M. PGF2 alpha inhibited the mRNA expression of lipoprotein lipase, clone 154, and fatty acid-binding protein, which are early markers of differentiation, as well as glycerol-3-phosphate dehydrogenase specific activity and triglyceride accumulation, which are late markers of differentiation. Chronic exposure of 1246 cells to PGF2 alpha before and during differentiation indicated that the cells that have just initiated their differentiation program were the most susceptible to the inhibitory effect of PGF2 alpha. Since 1246 cells produce PGs, we determined whether the PG produced by the cells influenced adipose differentiation. Cyclooxygenase inhibitors added to the culture medium stimulated differentiation of 1246 cells up to 18-fold depending on the type and concentration of inhibitor used. In contrast, lipoxygenase inhibitors had no effect. Treatment of 1246 cells with arachidonic acid resulted in a dose-dependent inhibition of cell differentiation. Oleate or linoleate had no effect. These data indicate that PGF2 alpha inhibits early and late events of adipose differentiation and that the endogenous production of PGs (particularly PGF2 alpha) plays an important role as a negative paracrine or autocrine regulatory pathway of adipose differentiation.

Adipose Tissue↗
PubMed1989

Multistep process of squamous differentiation in tracheobronchial epithelial cells in vitro: analogy with epidermal differentiation.

The lung, in particular the bronchial epithelium, is a major site for tumor formation in humans. Environmental factors, such as cigarette smoke, in conjunction with genetic factors are important determinants in this disease. Malignant cells exhibit alterations in their control of proliferation and differentiation. It is believed that the acquisition of defects in the regulation of these processes is important in the process of carcinogenesis. A clear insight into the basic mechanisms of the regulation of proliferation and differentiation is required to understand the molecular mechanisms involved in tumor development and in other pathological conditions. Studies using in vitro cell culture systems of tracheobronchial epithelial cells provide useful models in which to study the regulation of differentiation and proliferation. The clonogenic cells derived from the treacheobronchial epithelium are pluripotent: They have self-renewal capacity and can differentiate along either a normal, mucosecretory, or a squamous cell pathway. Squamous differentiation in tracheobronchial epithelial cells has many morphological, biochemical, and regulatory properties in common with epidermal differentiation. This pathway of differentiation is a multistep process consisting of at least three stages. In the initial stage, cells become committed to terminal cell division. This is followed by the expression of the squamous differentiated phenotype and finally cornification. Various factors, such as several growth factors, retinoids, calcium ions, and phorbol esters, regulate the program of differentiation at different stages. Studies have indicated that the controls of proliferation and differentiation are interrelated. Cell lines established from tracheobronchial epithelial cells expressing SV 40 large T-antigen, as well as carcinoma cell lines, exhibit altered responses to growth and differentiation regulatory factors. Alterations in the commitment to terminal cell division must be a crucial step in the transition of a normal to a malignant cell.

Animals↗
PubMed1992

Evidence that a novel human differentiation-inhibiting protein blocks the dimethyl sulfoxide-induced differentiation of erythroleukemia cells by inhibiting the activation of membrane protein kinase C.

We have previously reported (J. P. Durkin et al., Blood, 79: 1161-1171, 1992) the isolation of a human differentiation-inhibiting protein (DIP) which selectively inhibits and blocks the differentiation of erythroid burst-forming unit progenitor cells in bone marrow colony assay, and the dimethyl sulfoxide (DMSO)-induced differentiation of cultured murine erythroleukemia (MEL) cells. DIP blocks MEL cell differentiation directly, without affecting the ability of the cells to proliferate. In the present study, DIP (at < 1 ng/ml) inhibited MEL cell differentiation only when added to the culture medium within 1 h after DMSO induction, indicating that it blocked an early, critical step in erythroleukemia cell differentiation. The protein kinase C (PKC) inhibitor H-7 also maximally inhibited the differentiation of MEL cells during this same period following induction, suggesting that DIP may have blocked an early PKC-dependent process. Indeed, DIP was found to abolish a transient increase in membrane PKC activity which was triggered in MEL cells within 10-30 min after DMSO addition. This increase in membrane PKC activity resulted from the activation of an inactive pool of PKC residing on membranes, and not from the translocation of cytosolic PKC to membranes. DMSO also stimulated membrane PKC activity and differentiation in human erythroleukemia cells and HL-60 myeloid leukemia cells. As was the case with MEL cells, DIP prevented the early activation of PKC and the differentiation of human erythroleukemia cells. However, it did not inhibit the early increase in PKC activity in HL-60 cells or the subsequent differentiation of these cells. These results suggest that DIP blocks erythroleukemia cell differentiation by inhibiting an early and critical activation of inactive membrane PKC.

Amino Acid Sequence↗
PubMedDate not supplied

Bcl-2 expression in neuroblastoma is differentially regulated by differentiation inducers.

Neuroblastoma is characterized by differentiation in vivo and in vitro, and the process is known to be associated with changes in various gene expressions, among which is the bcl-2 gene whose major function may be potentially involved in the resistance to anticancer chemotherapy. We investigated the changing patterns of bcl-2 expression in neuroblastoma cell lines according to differentiation to assess whether the expression patterns can be differentially modulated by different types of differentiation inducers. Differentiation was induced in two neuroblastoma cell lines [SK-N-SH, SK-N-BE(2)] using all-trans-retinoic acid, gamma-interferon and EHS laminin, respectively. The levels of expression of bcl-2 were analysed before and after differentiation using immunoblotting and subsequent densitometry. The expression patterns of bcl-2 differed according to the type of differentiation inducers. Its expression increased when treated with retinoic acid and EHS laminin along with neuronal differentiation, while differentiation with gamma-interferon treatment was associated with decreased bcl-2 expression. Decreased expression of bcl-2 despite neuronal differentiation induced by gamma-interferon was thought to be important in that a certain differentiation pathway without increased drug resistance-related factor expression exists, which in turn has implications for the clinical application of gamma-interferon, combined with chemotherapy.

Apoptosis↗
PubMed1997

Contribution of quantitative lectin histochemistry to characterizing well-differentiated, dedifferentiated and poorly differentiated liposarcomas.

OBJECTIVE: To find new diagnostic markers in the group of lipomatous tumors. STUDY DESIGN: The histochemical lectin staining pattern was characterized in a series of 45 lipomatous lesions, including 10 typical lipomas, 6 atypical lipomas, 8 well-differentiated, 6 myxoid, 5 dedifferentiated and 10 pleomorphic liposarcomas. Three lectins were used-peanut (Arachis hypogaea) agglutinin, which binds to terminal Gal(beta 1,3)GalNAc residues; wheat germ (Triticum vulgare) agglutinin (s-WGA, the succinylated form of WGA), which binds to ((1-4)-D-GlcNAc)n and Neu5NAc residues; and jack bean (Concanavalia ensiformis) agglutinin which binds to alpha-D-Man and alpha-D-Glc residues. Histochemical staining was quantitatively measured by means of a cell image processor. RESULTS: In the case of certain carbohydrate residues, typical lipomas closely resemble atypical lipomas, which in turn closely resemble well-differentiated liposarcomas; typical lipomas differ significantly from well-differentiated liposarcomas. This indicates that atypical lipomas, or at least some of them, could represent a biologic link between typical lipomas and well-differentiated liposarcomas. While well-differentiated and pleomorphic liposarcomas differed significantly from each other, the poorly differentiated component of dedifferentiated liposarcomas included histochemical lectin properties, which were common to both well-differentiated and pleomorphic liposarcomas. CONCLUSION: Some atypical lipomas exhibit glycohistochemical characteristics that are common to those of well-differentiated liposarcoma. The poorly differentiated component of dedifferentiated liposarcomas remains more differentiated in terms of glycohistochemical markers than do poorly differentiated pleomorphic liposarcomas.

Adult↗
PubMed2001

Theileria annulata: identification, by differential mRNA display, of modulated host and parasite gene expression in cell lines that are competent or attenuated for differentiation to the merozoite.

To identify both host and parasite genes that show altered expression during differentiation of Theileria annulata from the macroschizont to the merozoite stage of the life cycle, the RNA profiles of two T. annulata-infected clonal cell lines (D7 and D7B12) with the same genetic background have been compared by RNA display. In the cloned cell line D7, T. annulata differentiates from the macroschizont to the merozoite at 41 degrees C, whereas in the cell line D7B12, which was derived by recloning D7, the parasite does not differentiate. Therefore, genes that show altered expression levels in either clone could be modulated by the differentiation event and are possible candidates for regulators of this process. Differential display was carried out initially on RNA extracted from D7 and D7B12 macroschizont-infected cells cultured at 37 degrees C and secondly on RNA extracted from the two cell lines incubated at 41 degrees C to induce differentiation to the merozoite. The first procedure identified 29 cDNA fragments that displayed altered levels between D7 and D7B12, 9 of which were confirmed to be differentially expressed by Northern blot analysis. Of these 9 gene fragments, 8 were found to be of host origin, while 1 was parasite derived. The second RNA display analysis identified 14 transcripts that showed altered levels during a differentiation time course, of which 6 were confirmed to be differentially expressed between D7B12 cells and differentiating D7 cells by Northern blot analysis. Of these 6 gene fragments, 1 was of host and 5 were of parasite origin. The parasite genes either showed levels of RNA consistent with constitutive gene expression or, in one case, a genuine upregulation of mRNA associated with the differentiation process.

Animals↗
PubMed1988

Differentiation of Ia-reactive CD8+ murine T cells does not require Ia engagement. Implications for the role of CD4 and CD8 accessory molecules in T cell differentiation.

The present study was undertaken to assess the Ia differentiation requirements of CD8+ class II-allospecific CTL, whose CD8+ phenotype is apparently "discordant" with their MHC class II reactivity. To do so, we compared the effect of in vivo anti-Ia blockade on the differentiation of Ia-reactive CD8+ CTL with its effect on the differentiation of CD4+ T cells. We found that anti-Ia blockade did not detectably interfere with the differentiation of CD8+ Ia-reactive CTL, even though it arrested the differentiation of CD4+ T cells. Thus, the differentiation of CD4+ T cells is strictly dependent upon Ia engagement, whereas the differentiation of CD8+ T cells, even those with reactivity against MHC class II alloantigens, does not require Ia engagement. These results support the concept that Ia-reactive CD8+ T cells are conventional CD8+ CTL, probably selected by self-class I MHC molecules during differentiation, whose receptors fortuitously crossreact on MHC class II alloantigens. Taken together, the present data indicate an intimate relationship between CD4/CD8 expression with MHC class specificity during T cell differentiation and selection. We suggest that an active triggering role for CD4 and CD8 accessory molecules in T cell differentiation is best able to explain these observations.

Animals↗
PubMed1982

Autoinduction of differentiation in myeloid leukemic cells: restoration of normal coupling between growth and differentiation in leukemic cells that constitutively produce their own growth-inducing protein.

Growth and differentiation of normal myeloid haematopoietic cells are regulated by a family of macrophage- and granulocyte-inducing (MGI) proteins. Some of these proteins (MGI-1) induce cell growth and others (MGI-2) induce cell differentiation. Addition of MGI-1 to normal myeloid cells induces growth and also induces the endogenous production of MGI-2. This induction of differentiation-inducing protein by growth-inducing protein then ensures the coupling between growth and differentiation found in normal cells. There are myeloid leukemic cells that constitutively produce their own MGI-1, but the cells do not differentiate in culture medium containing horse or calf serum. By removing serum from the medium, or in medium with mouse or rat serum, these leukemic cells are induced to differentiate to mature cells, which like normal mature cells, then no longer multiply. Leukemic cells with constitutive production of MGI-1 continuously cultured in serum-free medium with transferrin were also induced to differentiate by removing transferrin. This induction of differentiation was in all these cases associated with the endogenous production of MGI-2 by the cells. The results indicate that changes in specific constituents of the culture medium can result in autoinduction of differentiation in these leukemic cells due to restoration of the induction of MGI-2 by MGI-1, which then restores the normal coupling of growth and differentiation.

Animals↗
PubMed1994

Proliferation and differentiation of rat adipose precursor cells in chemically defined medium: differential action of anti-adipogenic agents.

Primary rat adipose precursor cells, maintained in the minimal chemically defined medium (ITT medium) able to promote differentiation, have been used to investigate the ability of several agents to modulate their proliferation and their differentiation. Fetuin and fibroblast growth factor (FGF), which exhibited a strong and a weak mitogenic activity, respectively, do not significantly affect the proportion of differentiated cells as indicated by glycerol-3-phosphate dehydrogenase (GPDH) activity values. In contrast, carbaprostacyclin (cPGI2), a stable analogue of prostacyclin, behaves as a true adipogenic factor leading to a 4 to 5-fold increase in GPDH-specific activities with no significant effect on cell growth. Submaxillary gland kallikrein (SMGK), transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) behave as growth-promoting agents but at the same time elicit a dose-dependent inhibition of differentiation. Epidermal growth factor (EGF) and prostaglandin F2 alpha (PGF2 alpha) do not show any effect on cell proliferation at concentrations which exert a maximal inhibitory action on differentiation. Upon removal of EGF from the culture medium, complete resumption of differentiation occurs, whereas upon removal of PGF2 alpha or SMGK, complete resumption only takes place when differentiation is triggered by cPGI2. Upon removal of TNF-alpha, a partial resumption of differentiation is observed, whereas no subsequent differentiation is observed upon TGF-beta removal. These results emphasize the adipogenic, nonmitogenic role of cPGI2 and also allow the distinction between the various adipogenic/mitogenic factors which affect adipose cell differentiation.

Adipocytes↗