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PubMed1987

Simultaneous enrichment of HL-60 cells in G1 and separation from differentiating cells by centrifugal elutriation for studies on differentiation induction.

Cultures of the promyelocytic leukemia cell line HL-60 usually contain considerable numbers of spontaneously differentiating cells and are asynchronous in terms of cell-cycle phases. Counterflow centrifugal elutriation studies have been conducted to obtain a homogeneous cell population with regard to cell-cycle phases and stage of differentiation. Despite their small volume and probably because of their high buoyant density, differentiated cells are elutriated predominantly at higher flow rates. Accordingly, G1 cells elutriated at low flow rates are substantially free from spontaneously differentiating cells. By optimizing the technique, a population with approx. 90% G1 cells and less than 1% spontaneously differentiating cells was obtained. The yield in the fractions chosen was 5.1% of all cells recovered from elutriation. In culture, a cell population of this purity maintains a synchronous cell cycle for more than 2 days. This allows an exact determination of the time after induction when the first signs of differentiation occur. The presence of 1 microM retinoic acid (RA) causes the first significant increase of NBT-positive cells between the 24th and 27th h of culture.

Cell Cycle↗
PubMed1983

Differentiation, ageing, and terminal differentiation: a semantic analysis.

The largely unsolved problems in the theoretical analysis of differentiation and ageing involve a substantial component of linguistic (semantic) difficulties. Some of these are simple traps of ambiguity, resulting from metaphorical or analogical employment of established terms--for example, "terminal differentiation" (loss of division potential in vitro) as a borrowing from "differentiation" as used by developmental biologists, or "commitment" by analogy with "determination". Some difficulties represent a failure to adopt (at least provisionally) an operational (empirical) view--for example, failure to ask what is the nature of the evidence for the view that a fertilized ovum is totipotential, or to scrutinize the evidence for the view that cells "terminally differentiated" in vitro in a conventional medium are in fact moribund under all conditions, or to examine more closely the view that the differentiated state and the cycling state are mutually exclusive. With respect to the problem of ageing, we review some of the critical experiments on "terminal differentiation" or "clonal senescence". We then proceed to consider some of the models that have been proposed, including a molecular model proposed by the author which appears to overcome some of the objections to other models. Some of the models exemplify the results of what are ultimately semantic vices. The problems with which these remarks began should indeed yield to the immense and novel resources of molecular biology. But the development of complete analyses demands not only good luck and delicate technique but also critical semantic clarity and severity. Given the best tools, we shall solve major theoretical problems only if we understand quite fully what problem it is that we are trying to solve--and the history of science illustrates that this is not as elementary a matter as it sounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗
PubMed1985

Synergistic interaction between differentiation inducers and DNA synthesis inhibitors: a new approach to differentiation induction in myelodysplasia and acute myeloid leukaemia.

Numerous agents induce differentiation and maturation of neoplastic and dysplastic myeloid cells in vitro and some of these agents have been used with limited success in the treatment of patients with myelodysplastic syndromes (MDS) and myeloid leukaemias. We recently proposed that physiological and pharmacological agents which enhance differentiation and maturation in vitro act by two fundamentally different routes: (1) by hastening the progression through various differentiation/maturation steps; (2) by slowing proliferation (usually by inhibition of DNA synthesis). In order to test this thesis we looked for synergistic effects on differentiation using pairs of agents from the two groups in cultures of cells from myelodysplastic and acute myeloid leukaemia (AML) patients and from normal marrow donors. The results with three MDS, two AML and three normal samples show that combinations of differentiation inducing agents (retinoic acid, N-methylformamide) with DNA synthesis inhibitors (6-mercaptopurine, cytosine arabinoside and aphidicolin) produce a differentiation inducing effect equivalent to that of 10-100, or even 1000 fold higher concentrations of single agents. Myelotoxic effects in vitro were not synergistic. The use of these synergistic combinations should greatly enhance the usefulness of differentiation inducers in the therapy of MDS and myeloid leukaemia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Induction of differentiation in HL-60 cells by retinoic acid and lymphocyte-derived differentiation-inducing factor but not by recombinant G-CSF and GM-CSF.

Various concentrations of retinoic acid (RA, 10(-9) to 10(-7) M), lymphocyte-derived differentiation-inducing factor (DIF, 10-30%), and recombinant human G-CSF (100-4000 U/ml) and GM-CSF (100-4000 U/ml) were used to induce the differentiation of the HL-60 promyelocytic leukemia cells. Retinoic acid at a concentration of 10(-7) M could significantly inhibit the growth of HL-60 cells both in suspension and in soft agar cultures, and induced these cells to differentiate into mature granulocytes capable of reducing nitro-blue tetrazolium and ingesting latex beads. Thirty per cent (v/v) DIF was also an effective inducer of HL-60 cell differentiation, but it triggered the cells to mature into monocytes rather than granulocytes. In contrast, rG-CSF and rGM-CSF had no growth inhibitory effect on HL-60 cells either in suspension or in agar cultures at all concentrations tested, nor could these factors induce HL-60 cells to acquire the more mature granulocytic or monocytic phenotypes. Furthermore, rG-CSF/rGM-CSF had no differentiation-enhancing effect when added to RA-containing HL-60 cultures. These results argue against the efficacy of using CSFs for the treatment of myelocytic leukemia based on the principle of differentiation induction.

Cell Differentiation↗
PubMed1991

Inhibition by vitamin D3 of erythroid differentiation of human leukemia line cells induced by transforming growth factor beta or erythroid differentiation factor (activin A).

Erythroid differentiation of human leukemic cell lines (HEL, KU812F and K562) was induced by their treatment with transforming growth factor beta (TGF-beta) or erythroid differentiation factor (EDF/Activin A). Their erythroid differentiation was markedly inhibited by vitamin D3, dexamethasone or 12-O-tetradecanoyl-phorbol-13-acetate, which are known to induce monocytic differentiation of leukemic cells. These results suggest that inducers of monocytic differentiation may switch off cellular regulatory mechanisms for induction by TGF-beta and EDF of erythroid differentiation of leukemia cells.

Activins↗
PubMed1984

Studies of the differentiation of promyelocytic cells by phorbol ester. I. Induction of discrete membrane proteins characteristic of monocytes and expression of motility functions in HL-60 cells following differentiation by phorbol ester.

Cells of the promyelocytic leukemia line, HL-60, differentiate into macrophage-like cells in response to phorbol ester. We report that this effect is associated with induction of spontaneous motility and a modest expression of chemotactic responsiveness to a formylated peptide. Using two-dimensional gel electrophoresis we demonstrate that the differentiation of HL-60 cells is associated with a differential effect on membrane vs. cytosol proteins. Changes in the cytosol characteristically involved reduction of synthesis of specific proteins. Changes in the membrane were mainly associated with either enhancement or de novo synthesis of discrete proteins. The hallmark of HL-60 cell differentiation appeared to be distinctive induction of a membrane-bound group of six proteins (pI approximately equal to 5, 45-70 kDa) and the de novo induction of a membrane protein indicated as m10 (pI approximately equal to 7, 28 kDa). These discrete membrane proteins were found to be very prominently synthesized by human cultured monocytes, but virtually absent in lymphocytes. It is proposed that our ability to detect synthesis of proteins characteristic of different states of cellular differentiation will permit detailed studies of the biochemical changes which constitute this process. Definition of the role of these proteins and the mechanism regulating their synthesis will help to elucidate the biochemical basis of monocyte differentiation.

Cell Differentiation↗
PubMed1984

Studies of the differentiation of promyelocytic cells by phorbol ester. II. A methylation inhibitor, 3-deazaadenosine, inhibits the induction of specific differentiation proteins. Lack of effect on early and late phosphorylation events.

Cells of the promyelocytic leukemic line, HL-60, differentiate into macrophage-like cells in response to phorbol-12-myristate-13-acetate (phorbol ester). We have shown that this process is associated with expression of motility functions and induction of specific changes in the synthesis of discrete proteins. In the present study we show that a methylation inhibitor, 3-deazaadenosine, inhibits the phorbol ester induction of the differentiation functions, adherence and motility. These effects were associated with interference in the expression of membrane proteins indicative of the acquisition of macrophage-like characteristics by HL-60 cells. Of particular importance was the observation that the methylation inhibitor preferentially arrested the induction of one differentiation, protein m10 (pI approximately equal to 7, 28 kDa). The selective effect of 3-deazaadenosine is further supported by observations in this study which show that the methylation inhibitor did not affect other cellular and biochemical effects of phorbol ester in these cells. Most significantly, 3-deazaadenosine did not inhibit the induction of phosphorylation in pp17 and pp27, which was previously shown to be a rapid event associated with initiation of differentiation in HL-60 cells by phorbol ester (Feuerstein, N. and Cooper, H. (1983) J. Biol. Chem. 258, 10786-10793). Furthermore, later elevated phosphorylation of other proteins as well as the arrest of cell growth induced by phorbol ester were also unimpeded by the methylation inhibitor. These results indicate that the methylation inhibitor did not interfere with the transduction of the phorbol ester signal at an early step so as to block all the subsequent events in this sequence, but rather its effect was selectively associated with interference in later events in the sequence of differentiation. It is proposed that transmethylation events might be specifically involved in the induction and expression of discrete proteins during the differentiation of these leukemic cells but not in the initial propagation of the signal produced by phorbol ester binding.

Cell Adhesion↗
PubMed1983

Preferential synthesis of differentiation related cytoplasmic proteins in low-serum adapted differentiated glioma cells.

Rat glioma (C6) cells can be induced to morphological and biochemical differentiation by culturing in serum-deprived conditions. The induced differentiated cells were found to preferentially synthesize some distinct cytoplasmic proteins, and the rate of synthesis quantitatively correlated well with the degree of morphological differentiation, whereas the total mRNA synthesis was decreased in the differentiated cells. These findings suggest that reduced total mRNA syntheses and preferential translation of differentiation-related mRNAs are parts of the biochemical events during the differentiation process of neuroglia.

Animals↗
PubMed1995

Retinoic acid and cAMP differentially regulate human chromogranin A promoter activity during differentiation of neuroblastoma cells.

We report the first evidence that differential transcriptional regulation of human chromogranin A (CHGA) gene expression occurs during in vitro treatment of tumorigenic neuroblastoma (NB) cells with retinoic acid (5 microM) and/or dibutyryl-cAMP (1 mM). The CHGA gene encodes a tissue specific protein restricted to cells of the diffuse neuroendocrine system, but also widely expressed among NB tumours. We previously reported that CHGA as well as other neuroendocrine markers are modulated during NB differentiation in vitro. To investigate, at the molecular level, the mechanisms leading to NB tumour cell differentiation during the treatment with biologically active compounds, we sequenced and functionally characterised 2169 bp of a genomic DNA clone encompassing the 5' flanking region of the human CHGA gene. Computer-assisted analysis of the sequence revealed the presence of a cAMP responsive element at positions -56 to -49, and Sp1 binding sites at positions -181 to -176 and -216 to -210. Two novel 9 bp motifs, located at position -462 to -454 and -91 to -83 of the CHGA promoter were identified in the regulatory regions of two other neuroendocrine genes encoding for tyrosine hydroxylase and neuropeptide Y. In addition, in the first 1000 bp of the untranslated 5' region, we found the presence of several putative DNA binding sites of bHLH molecules, a protein family regulating tissue specific differentiation. Transient transfection experiments of chloramphenicol acetyltransferase (CAT) deletion constructs, showed the presence of an active promoter within the first 455 bp upstream from the start site. This region conferred tissue specific expression to a CAT reporter gene. In addition, the transcriptional activity of this fragment was modulated during the induction of differentiation of NB cells treated by retinoic acid and/or dibutyryl-cAMP. These observations provide preliminary data regarding CHGA transcriptional regulation in NB cells, and indicate that retinoic acid and cAMP activate distinct, apparently competitive, transcriptional pathways during NB cell differentiation. The molecular characterisation of the mechanisms regulating CHGA expression in tumour and normal neuroendocrine tissue could lead to the identification of novel molecules potentially relevant for future gene therapy of NB tumours.

Base Sequence↗
PubMed2003

Regulation and differential expression of the c-maf gene in differentiating cultured cells.

The Maf transcription factors are involved in a variety of developmental and cellular differentiation processes, but their role in the differentiation of mesenchymal cells has not been described. Here, we have analyzed c-maf expression during the differentiation of adipocytes and muscle cells in cultured systems. The expression of c-maf mRNA was down-regulated during adipogenesis and up-regulated during myogenesis. In adipogenesis, the c-maf mRNA was down-regulated 58h after switching to the differentiation medium and just after PPARgamma2 mRNA was induced. A transient transfection analysis of a reporter gene containing the 5(')-flanking region of the c-maf gene showed that PPARgamma2 represses c-maf gene expression. We previously found that c-Maf, c-Jun, and Pax6 bind to and stimulate the c-maf gene. The PPARgamma2 repression of c-maf expression seems to be due, at least in part, to inhibition of the transactivation functions of c-Maf, c-Jun, and Pax6. The repression of c-maf was partly reversed by CBP, suggesting that these transcription factors compete for CBP or related transcription co-factors. In myogenesis, there was a differentiation-dependent stimulation of c-maf mRNA expression. The increased expression correlated with myoD expression. A transient transfection analysis showed that myoD stimulated a c-maf reporter gene through binding to two typical E-box elements located between 160 and 180 nucleotides upstream of the cap site. Binding of MyoD to the E-boxes was confirmed by a gel mobility shift assay and DNaseI footprinting analysis. Combined, these results suggest that the c-maf gene plays an important role during the differentiation of adipocyte and muscle cells from mesenchymal fibroblast cells.

Adipocytes↗
PubMed2004

Primary murine limb bud mesenchymal cells in long-term culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation.

In vitro models of endochondral bone formation using both primary and immortalized cells have provided insight regarding factors and signaling pathways involved in chondrocyte maturation and endochondral bone formation. However, primary murine cell culture models of chondrocyte differentiation have not been established but have enormous potential due to the possible use of cells from transgenic and knockout animals. Here, we show that stage E11.5 embryonic murine limb bud mesenchymal stem cells in micromass cell culture progress through the stages of chondrogenesis, chondrocyte hypertrophy, terminal differentiation, and matrix calcification. This cell culture system recapitulated the sequential expression of genes that characterize chondrocyte differentiation, including Sox9, col2, colX, MMP13, VEGF, and osteocalcin. TGF-beta treatment for up to 21 days markedly delayed the rate of chondrocyte maturation and inhibited matrix calcification and its related gene expression. In TGF-beta-treated cultures, the hypertrophic and terminal differentiation markers colX, VEGF, MMP13, and osteocalcin were reduced or absent. PGE2 had minimal effects on chondrocyte hypertrophy but delayed terminal differentiation and matrix calcification. Thus, primary murine mesenchymal cells sequentially differentiate through the various stages of chondrocyte maturation and establish a model whereby the role of specific signaling molecules can be examined in cells derived from transgenic or knockout mice.

Animals↗
PubMed2005

Differential effects of SOCS2 on neuronal differentiation and morphology.

Neuronal differentiation of neural progenitor cells is regulated by a variety of growth and transcription factors, that not only regulate cell fate of the progenitor cells but that can also regulate neuronal morphology. Suppressor of cytokine signaling-2 (SOCS2) is an intracellular regulator of Growth Hormone (GH) signaling that is expressed in neural stem cells and neurons during development and is required to overcome the inhibitory effects of GH on neuronal differentiation. SOCS2 also promotes neurite outgrowth, however, whether the mechanism by which SOCS2 regulates neuronal differentiation and neurite outgrowth is the same is not clear. Furthermore, whether the over-expression of SOCS2 has physiological in addition to morphological effects is unknown. To address these questions, we differentiated adult neural progenitor cells derived from wildtype C57BL/6 or SOCS2 over-expressing transgenic mice (SOCS2Tg) in the presence or absence of GH and determined effects on neuronal differentiation and morphology. Compared to wildtype cells, differentiation of SOCS2Tg neurospheres resulted in increased neurogenesis, which was not inhibited by GH. The neurons derived from these cells appeared more complex, with increased neurite outgrowth and number. GH did not, however, have any effect on neurite outgrowth of wildtype or SOCS2Tg neurons. Furthermore, basic electrophysiological analysis of wildtype and SOCS2Tg neurons derived from the neurospheres showed that they were both of an immature electrophysiological neuronal phenotype, indicating that although SOCS2 expression can regulate neuronal morphology, it appears to have little effect on neuronal ion channel expression.

Animals↗
PubMed1998

Collagen type IV promotes the differentiation of neuronal progenitors and inhibits astroglial differentiation in cortical cell cultures.

In an effort to elucidate the interactions between cells in the developing cortex and their microenvironment, we have employed dissociated cell cultures and immunocytochemistry to analyze the effect of collagen type IV (COL) on the proliferation and differentiation of rat cortical progenitor cells during the period of corticogenesis. COL, present in the proliferative zones throughout the period of neurogenesis, belongs to a group of macromolecular proteins that make up a considerable portion of the extracellular matrix (ECM). We have shown that this ECM molecule inhibits cell proliferation and glial cell differentiation while promoting neuronal differentiation. We have also demonstrated that COL, when applied to the cultures with basic fibroblast growth factor (bFGF), induces glial cell differentiation while continuing to promote neuronal differentiation. These results indicate that cortical progenitor cells respond differentially to local environmental signals, and that components of the ECM are involved in the regulation of corticogenesis.

Animals↗
PubMed2001

Wnts differentially regulate colony growth and differentiation of chondrogenic rat calvaria cells.

The wingless- and int-related proteins (Wnts) have an important role during embryonic development and limb patterning. To investigate their function during chondrocyte differentiation, we used NIH3T3 cells producing seven members of the Wnt family and secreted frizzled-related protein (sFRP-2) for co-culture experiments with the rat chondrogenic cell line pColl(II)-EGFP-5. Pilot experiments showed a negative effect of Wnt-7a on the proliferation of three rodent chondrogenic cell lines, RCJ3.1(C5.18), CFK-2, and C1. To establish a reporter system for chondrogenic differentiation we then produced a stably transfected chondrogenic cell line based on RCJ3.1(C5.18) for further experiments, which expresses green fluorescence protein (EGFP) under the collagen type II promoter (pColl(II)-EGFP-5). This cell line permits convenient observation of green fluorescence as a marker for differentiation in life cultures. The colony size of this cell line in agarose suspension cultures was reduced to 20-40% of control, when exposed to Wnt-1, 3a, 4, 7a, and 7b for 14 days. Similarly, reporter gene expression and the synthesis of cartilage-specific proteoglycans were inhibited by this group of Wnts. In contrast, pColl(II)-EGFP-5 cells exposed to Wnt-5a and Wnt-11 reached 140% of control, and reporter gene expression and proteoglycan synthesis were stimulated. The effects of Wnt-7a and Wnt-5a were additive in pColl(II)-EGFP-5 cells and some but not all Wnt effects were antagonized by the inhibition of proteoglycan sulfation with chlorate, by sFRP-2, which may modulate Wnt receptor binding, or by inhibitors of protein kinase C. These results suggest two functional Wnt subclasses that differentially regulate proliferation and chondrogenic differentiation in vitro which may have implications for cartilage differentiation in vivo. Since some, but not all Wnt effects were sensitive to inhibitors of proteoglycan synthesis or protein kinase C, multiple modes of signal transduction may be involved.

3T3 Cells↗
PubMed2003

Differential expression of versican isoforms is a component of the human melanoma cell differentiation process.

Versican is a large chondroitin sulfate proteoglycan produced by human melanoma cell lines and malignant melanocytic lesions. In the present work, we have analyzed the expression of versican spliced variants V0, V1, V2 and V3 in human melanoma cell lines at several differentiation degrees. The isoform expression pattern depends on the degree of cell differentiation. Differentiated cell lines do not produce any of the versican isoforms as analyzed by Western blot, Northern blot and RT-PCR. All cell lines with an early or intermediate degree of differentiation (AX3, SK-mel-37, Rider, SK-mel-1.36-1-5 and SK-mel-3.44) expressed V0 and V1 transcripts, whereas V2 and V3 expression was shown only by the undifferentiated cell lines SK-mel-1.36-1-5 and Rider. Furthermore, we have analyzed the expression of versican isoforms in SK-mel-3.44 and SK-mel-1.36-1-5 cells induced to differentiate by TPA treatment. The expression of the large V0, V1 and V2 isoforms practically disappears in differentiated cells, whereas V3 remains detectable by RT-PCR analysis.

Biomarkers, Tumor↗
PubMed2002

The catalytic DNA topoisomerase II inhibitor ICRF-193 and all-trans retinoic acid cooperatively induce granulocytic differentiation of acute promyelocytic leukemia cells: candidate drugs for chemo-differentiation therapy against acute promyelocytic leukemia.

OBJECTIVE: Although all-trans retinoic acid (ATRA) can bring about complete remission of acute promyelocytic leukemia (APL), the incidence of early recurrence is considerably high. Thus, chemotherapeutic agents, such as anthracycline agents or cytosine arabinoside (AraC), are generally co-administered with ATRA. The therapeutic outcome of APL patients has significantly improved by chemo-differentiation therapy. Late-phase toxicities, such as cardiotoxicity and secondary carcinogenesis, are becoming clinically important. Therefore, we must identify the most suitable chemotherapeutic agents for the treatment of APL. METHODS: We examined the effects of ICRF-193 and several other anticancer drugs on the growth and differentiation of APL cell lines (NB4 and HT-93) and other myeloid leukemia cell lines (HL-60 and U937). RESULTS: If anticancer agents were available that not only inhibited the proliferation of APL cells but also induced their differentiation, they would be very useful for the treatment of APL. DNR slightly induced the differentiation of APL cells. On the other hand, other DNA topoisomerase II inhibitors, such as ICRF-154 and ICRF-193, significantly induced the differentiation of APL cell lines and leukemia cells freshly isolated from APL patients. These drugs effectively cooperated with ATRA in inhibiting the growth and inducing the differentiation of APL cells, whereas DNR did not. The incidence of cardiotoxicity and secondary carcinogenesis associated with ICRF-193 are much lower than that with DNR. CONCLUSION: These results suggest that ICRF-193 may be useful in the treatment of patients with APL.

Antineoplastic Agents↗
PubMed1998

Differential effects of mucosal pH on human (Caco-2) intestinal epithelial cell motility, proliferation, and differentiation.

Mucosal pH abnormalities are associated with anastomotic dehiscence, ischemia, and malignancy. We postulated that intraluminal pH influences intestinal epithelial motility, proliferation, and differentiation and studied extracellular pHo (7.0-8.5) effects on human (Caco-2) intestinal epithelial motility, proliferation, and differentiation. Mucosal healing was modeled by sheet migration and differentiation by alkaline phosphatase and dipeptidyl dipeptidase specific activity. In parallel differentiation and motility studies, we inhibited proliferation with mitomycin to dissociate indirect mitogenic effects. Intracellular pHi was quantitated using BCECF/AM at varying extracellular pHo and in migrating cells. Motility was maximal at pHo 7.6 and proliferation at 7.2. Each decreased with acidity and alkalinity. By contrast, brush border enzyme activity was lowest at pHo 7.0 and highest at pHo 8.5. pHi was highest at pHo 8.5. Migrating cell pHi was higher than static cell pHi. Thus, extracellular pHo deviations perturb Caco-2 pHi homeostasis and motility. Alkalinity promotes differentiation while acidity induces proliferation and limits differentiation.

Caco-2 Cells↗
PubMed2002

BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells.

The p53-transcriptional target, BTG2(TIS21/PC3), was previously identified as an antiproliferative gene. However, the precise biological functions of the protein product remain to be elucidated. BTG2(TIS21/PC3) expression is induced in vivo during neurogenesis, and the gene is transiently expressed in vitro in rat pheochromocytoma PC12 cells after induction of neuronal differentiation by addition of nerve growth factor (NGF). These observations suggest that BTG2(TIS21/PC3) is functionally significant during the neuronal differentiation process. To test this hypothesis, a vector that expressed BTG2(TIS21/PC3) under the control of an inducible promoter was introduced into PC12 cells. Growth arrest and differentiation in response to NGF were greatly enhanced by BTG2(TIS21/PC3) overexpression. Furthermore, an antisense oligonucleotide complementary to BTG2(TIS21/PC3) mRNA, which was able to inhibit endogenous BTG2(TIS21/PC3) expression, triggered programmed cell death in differentiated PC12 cells. These observations confirm that BTG2(TIS21/PC3) expression promotes neuronal differentiation and that it is required for survival of terminally differentiated cells.

Animals↗