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PubMed2006

A conserved organization of transcription during embryonic stem cell differentiation and in cells with high C value.

Although we have detailed information on the alterations occurring in steady-state levels of all cellular mRNAs during differentiation, we still know little about more global changes. Therefore, we investigated the numbers of molecules of RNA polymerase II that are active--and the way those molecules are organized--as two mouse cells (aneuploid F9 teratocarcinoma, and euploid and totipotent embryonic stem cells) differentiate into parietal endoderm. Quantitative immunoblotting shows the number of active molecules roughly halves. Transcription sites (detected by light and electron microscopy after allowing engaged polymerases to extend nascent transcripts in bromouridine-triphosphate) are uniformly distributed throughout the nucleoplasm. The numbers of such sites fall during differentiation as nuclei become smaller, but site density and diameter remain roughly constant. Similar site densities and diameters are found in salamander (amphibian) cells with 11-fold larger genomes, and in aneuploid HeLa cells. We conclude that active polymerases and their nascent transcripts are concentrated in a limited number of discrete nucleoplasmic sites or factories, and we speculate that the organization of transcription is conserved during both differentiation and evolution to a high C value.

Cell Differentiation↗
PubMed1999

[Does the universal "signal transduction pathway of differentiation" exist? Comparison of different cell differentiation experimental models with differentiation of HL-60 cells in response to 1,25-dihydroxyvitamin D3].

The comparison of distinct cell-differentiation models can help to answer the question whether there are common signalling pathways activated in the cells during the differentiation process or not. The differentiation of PC12 pheochromocytoma cells in response to NGF, the differentiation of melanoma B16 cells triggered by alpha-MSH, the formation of myotubes by L6E9 skeletal muscle myoblasts deprived of FCS or differentiation of HL-60 cells in response to steroid hormone 1,25-dihydroxyvitamin D3 share some similarities in the activation of signal transduction pathways. Differentiation-inducing agents stimulate sustained activation and nuclear translocation of MAP kinases (ERK1 and ERK2). Some of differentiation-inducing agents activate PI3-kinase as well, and the inhibition of the PI3K/p70S6K pathway blocks the process of differentiation in the cells.

Animals↗
PubMed2006

Regeneration of the intestinal epithelia: regulation of bone marrow-derived epithelial cell differentiation towards secretory lineage cells.

The intestinal epithelia consists of four lineages of differentiated cells, all of which arise from stem cells residing in the intestinal crypt. For proper regeneration from epithelial damage, both expansion of the epithelial cell number and appropriate regulation of lineage differentiation from the remaining stem cells are thought to be required. In a series of studies, we have shown that bone-marrow derived cells could promote the regeneration of damaged epithelia in the human intestinal tract. Donor-derived epithelial cells substantially repopulated the gastrointestinal tract of bone-marrow transplant recipients during epithelial regeneration after graft-versus-host disease. Furthermore, precise analysis of epithelial cell lineages revealed that during epithelial regeneration, secretory lineage epithelial cells that originated from bone-marrow significantly increased in number. These findings may lead to a novel therapy to repair damaged intestinal epithelia using bone marrow cells, and provide an alternative therapy for refractory inflammatory bowel diseases.

Bone Marrow Cells↗
PubMedDate not supplied

Electron microscopic analysis of the relationship between nuclear matrix stability and cell differentiation.

Two cell lines, the less differentiated CC2/CUHK2 and the more differentiated CC3/CUHKE3, were used to study the difference in nuclear matrix stability against DNase 1 digestion. The nuclear matrix was almost totally extracted when the CC3/CUHK3 cells were digested with 100 micrograms/ml DNase 1, while that of the CC2/CUHK2 cells was still present even when 200 micrograms/ml DNase 1 was used. It is suggested that more differentiated cells have a less stable nuclear matrix while the less differentiated ones have a more stable nuclear matrix. The same phenomenon was also observed in normal human and rat cervical epithelia. The nuclear matrix of the poorly differentiated basal cells was more stable than that of the more differentiated superficial cells. This cell differentiation stage dependent stability of the nuclear matrix is probably related to the nuclear activity and gene expression.

Animals↗
PubMed1999

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling.

Leukocyte-associated Ig-like receptor-1 (LAIR-1) belongs to the growing family of immunoreceptor tyrosine-based inhibitory motif-bearing receptors and is expressed on the majority of peripheral mononuclear cells, including NK cells, T cells, B cells, monocytes, and dendritic cells. In this study, we investigated the distribution and the capacity of LAIR-1 to function as an inhibitory receptor on human B cells. LAIR-1 is expressed from early on during B cell differentiation, but is absent on approximately half of the memory B cells, and all germinal center B cells, plasmablasts, and terminally differentiated plasma cells. In vitro stimulation of naive B cells via the B cell receptor (BCR) or CD40, triggering proliferation and differentiation into Ig-producing plasma cells, is accompanied by loss of LAIR-1 expression. We previously reported that LAIR-1 can function as an inhibitory receptor on NK cells and T cells. Here, we demonstrate that it can also function as a negative regulator of BCR-mediated signaling, since simultaneous cross-linking of LAIR-1 and the BCR reduces the increase of intracellular Ca(2+) evoked by BCR ligation. Taken together, this suggests that the inhibitory mechanism of LAIR-1 is functional in multiple components of the hematopoietic system.

Adult↗
PubMed2004

Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion.

Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit-positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplanted cells in the recipient heart. By this approach, we have demonstrated that BMCs, when properly administrated in the infarcted heart, efficiently differentiate into myocytes and coronary vessels with no detectable differentiation into hemopoietic lineages. However, BMCs have no apparent paracrine effect on the growth behavior of the surviving myocardium. Within the infarct, in 10 days, nearly 4.5 million biochemically and morphologically differentiated myocytes together with coronary arterioles and capillary structures were generated independently of cell fusion. In conclusion, BMCs adopt the cardiac cell lineages and have an important therapeutic impact on ischemic heart failure.

Animals↗
PubMed1999

Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation.

Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.

Animals↗
PubMed1979

Induction of suppressor activity on B-cell differentiation in human T-cell subset without fc(IgG) receptors by levamisole administration.

A single oral dose of 150 mg levamisole was administered to five healthy adults. Circulating Fc(IgG) receptor-bearing T cells (T gamma cells) increased for 5 days after levamisole intake, but total E rosette-forming cells showed no significant alterations. The generation of immunoglobulin-producing cells in the peripheral blood lymphocytes (PBL), which was induced in the in vitro pokeweed mitogen (PWM)-stimulated cultures, was significantly suppressed for 5 days after levamisole administration. Suppressor T-cell activity on B-cell differentiation, which was induced by levamisole intake, was evaluated by co-culturing with allogeneic untreated adult PBL in the PWM system in six other volunteers. A seemingly dose-dependent suppression on B-cell differentiation was exerted by T cells isolated on day 3 of levamisole treatment, but not by T cells differentiation was exerted by T cells isolated on day 3 of levamisole treatment, but not by T cells which were isolated before or on day 14 of the experiment. When T cells were fractionated into two subsets with regard to the presence or absence of Fc(IgG) receptors, suppressor T-cell activity appeared to be generated by levamisole largely in T cells lacking Fc(IgG) receptors, but not in T gamma cells.

Adult↗
PubMed1999

Pluripotent stem cells of the mouse as a potential in vitro model for mammalian germ cells. Sister chromatid exchanges induced by MMC and ENU in undifferentiated cell lines compared to differentiated cell lines.

We tried to develop an in-vitro test system which could serve as a model for mammalian germ cells in vivo. Two pluripotent cell types were used, because they express some germ cell specific immunological and biochemical markers: (1) Embryonal carcinoma cells (ECC) of the line P19 had been isolated from a teratocarcinoma of murine primordial germ cells (PGC). (2) Embryonal stem cells (ESC) are obtained from the inner cell mass of mouse blastocysts. Sister chromatid exchanges (SCE) induced by mitomycin C and ethylnitrosourea (ENU) were analysed in the two undifferentiated cell lines, ECC and ESC, to detect differences in their sensitivity compared with differentiated cell lines of the mouse. Neither of the model cell lines have shown a greater sensibility after exposure to MMC and ENU. In contrary, the carcinoma cell line was able to tolerate higher concentrations of these genotoxicants. Therefore, SCE analysis in the ECC and ESC lines used does not provide a suitable model for genotoxicity testing on mammalian germ cells.

Animals↗
PubMed1994

Interferon-gamma regulation of B lymphocyte differentiation: activation of B cells is a prerequisite for IFN-gamma-mediated inhibition of B cell differentiation.

The Th1 and NK cell-derived cytokine interferon-gamma (IFN-gamma) influences both immune and inflammatory responses, and under some circumstances, IFN-gamma can inhibit B cell differentiation. We found that IFN-gamma inhibited LPS-induced IgM production in B cells by reducing the precursor frequency of IgM-secreting cells. This occurred without a significant decrease in B cell proliferation in response to either LPS or F(ab')2 anti-IgM. We also found that IFN-gamma inhibited IgM secretion, even when added as late as 48 hr after LPS stimulation. Small resting B cells were not affected by a pulse with IFN-gamma. However, a pulse of IFN-gamma inhibited the response of activated B cells to subsequent stimulation with LPS. Also, LPS upregulated expression of the IFN-gamma receptor on B cells. Our studies show that IFN-gamma targets stimulated but not resting B cells and suggest that IFN-gamma plays an important role in the normal homeostatic control of B cell polyclonal responses.

Animals↗
PubMed1992

Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail.

Mature T cells express either CD4 or CD8 on their surface. Most helper T cells express CD4, which binds to class II major histocompatibility complex (MHC) proteins, and most cytotoxic T cells express CD8, which binds to class I MHC proteins. In the thymus, mature CD4+CD8- and CD4-CD8+ T cells expressing alpha beta T-cell antigen receptors (TCR) develop from immature thymocytes through CD4+CD8+ alpha beta TCR+ intermediates. Experiments using mice transgenic for alpha beta TCR suggest that the specificity of the TCR determines the CD4/CD8 phenotype of mature T cells. These results, however, do not indicate how a T cell differentiates into the CD4 or CD8 lineage. Here we show that the CD4 transmembrane region and/or cytoplasmic tail mediates the delivery of a specific signal that directs differentiation of T cells to a CD4 lineage. We generated transgenic mice expressing a hybrid molecule composed of the CD8 alpha extracellular domains linked to the CD4 transmembrane region and cytoplasmic tail. We predicted that this hybrid molecule would bind to class I MHC proteins through the extracellular domains but deliver the intracellular signals characteristic of CD4. By crossing our transgenic mice with mice expressing a transgenic alpha beta TCR specific for a particular antigen plus class I MHC protein, we were able to express the hybrid molecule in developing thymocytes expressing the class I MHC-restricted TCR. Our results show that the signal transduced by the hybrid molecule results in the differentiation of immature thymocytes expressing a class I-restricted TCR into mature T cells expressing CD4.

Animals↗
PubMed1987

T cell receptor-CD3 complex during early T cell differentiation. Analysis of immature T cell acute lymphoblastic leukemias (T-ALL) at DNA, RNA, and cell membrane level.

T cell acute lymphoblastic leukemias (T-ALL) can be regarded as the malignant counterparts of cells in various T cell differentiation stages. To study the expression of the human T cell receptor (TcR)-CD3 complex during the early stages of T cell differentiation, we have analyzed 22 T-ALL at the cell membrane level and the DNA level and 12 of them at the RNA level. According to their immunologic phenotype, the T-ALL could be divided into three main groups: 10 immature T-ALL (CD1-/CD3-), seven common thymocytic T-ALL (CD1+/CD3-or+), and five mature T-ALL (CD1-/CD3+). Among the 10 immature T-ALL three appeared to express the immunologic phenotype of the putative prothymocyte (TdT+/HLA-DR+/CD7+/CD2+/CD5-/CD1-/CD3-), whereas the other seven T-ALL appeared to be immature thymocytic (TdT+/HLA-DR-/CD7+/CD2+/CD5+/CD1-/CD3-). Transcripts of the CD3-delta and CD3-epsilon genes were present in all CD3- and CD3+ T-ALL tested, including prothymocytic T-ALL. However, prothymocytic T-ALL had germline TcR-beta genes and were not rearranged to the characterized TcR-gamma joining regions. The presence of CD3 transcripts and absence of TcR gene rearrangements in prothymocytic T-ALL supports their immature T cell character. Two immature thymocytic T-ALL also had germline TcR-gamma genes and one of them had germline TcR-beta genes. In all other T-ALL the TcR-gamma and TcR-beta genes were rearranged. The presumptive functional 1.3-kilobase TcR-beta transcripts were detected in the majority of T-ALL with rearranged TcR-beta genes. Distinct levels of TcR-gamma transcripts appeared to be present only in some thymocytic T-ALL, i.e., some immature thymocytic T-ALL and common thymocytic T-ALL. TcR-alpha mRNA could only be detected in CD3+ mature T-ALL, but was absent in all CD3+ common thymocytic T-ALL tested. Our data indicate that CD3 gene transcription is one of the earliest events during T cell differentiation and already occurs in prothymocytes. The TcR-gamma and TcR-beta genes rearrange early during thymocytic differentiation and can subsequently be transcribed. High levels of TcR-gamma gene transcription may only occur in a part of the T cells during thymic differentiation, while TcR-beta gene transcription continues during further differentiation. TcR-alpha gene transcription may be the final step in the production of the complete set of TcR and CD3 proteins, resulting in the expression of the TcR alpha beta-CD3 complex at the cell surface of mature T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1988

T helper cell-dependent induction of resting B cell differentiation need not require cognate cell interactions.

We have analyzed the role of cognate interaction with helper T cells (Th) in support of resting B cell differentiation to plaque formation. Co-culture of histoincompatible resting B cells and resting Th cells resulted in the induction of plaque-forming cells when dimeric but not monomeric fragments of anti-T cell receptor (TcR) antibody were added to culture. The efficiency of B cell activation was comparable to that supported by lipopolysaccharide and lectin-mediated Th-B cell conjugate formation. Further, if resting Th cells were preactivated with antigen and histocompatible antigen-presenting cells, the requirement for addition of anti-TcR to mixtures of histoincompatible Th and B cells was obviated. These results demonstrate that TcR-mediated Th recognition of major histoincompatibility complex class II/antigen composites on the resting B cell membrane does not provide obligate signals for B cell differentiation to plaque formation. We are left with two possibilities. Either the entire process of Th cell-dependent induction of resting B cell differentiation is mediated by soluble lymphokines or if Th-B cell contact is mandatory, it is mediated through nonpolymorphic cell surface determinants.

Animals↗
PubMed2001

Dermal-resident CD14+ cells differentiate into Langerhans cells.

Epidermal Langerhans cells (LCs) show extraordinary immunostimulatory capacity and play a key role in the initiation and regulation of immune responses. Studies of LC biology are currently the focus of efforts to engineer immune responses and to better understand the immunopathology of cutaneous diseases. Here we identified and characterized a population of LC precursors that were resident in human skin. These immediate precursors expressed CD14, langerin and functional CCR6. When cultured with transforming growth factor-beta1 alone, they had the potential to differentiate into epidermal LCs; when cultured in the presence of granulocyte macrophage-colony-stimulating factor and interleukin 4 they differentiated into functionally mature dendritic cells. Identification and characterization of these LC precursors provided insight into LC biology and the mechanism(s) through which LCs repopulate the epidermis.

Antigens↗
PubMed2006

Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury.

BACKGROUND: Embryonic stem cells possess the ability to differentiate into endothelium. The ability to produce large volumes of endothelium from embryonic stem cells could provide a potential therapeutic modality for vascular injury. We describe an approach that selects endothelial cells using magnetic beads that may be used therapeutically to treat arterial injury. METHODS AND RESULTS: Large numbers of endothelial cells (ECs) with high purity were produced using Sca-1+ cells isolated with magnetic beads from predifferentiated embryonic stem cells (ESCs) cultured in alpha-MEM containing 10 ng/mL VEGF165 for a minimum of 21 days (esEC). The transcription regulator histone deacetylase (HDAC3) was essential for VEGF-induced EC differentiation. Immunofluorescence or fluorescence-activated cell sorter (FACS) analysis revealed that esECs expressed a full range of EC lineage-specific markers including CD31, CD106, CD144, Flk-1, Flt-1, and von Willebrand factor (vWF). FACS analysis confirmed that 99% of esECs were CD31-positive and 75% vWF-positive. Furthermore, almost all cells were positive for DiI-acLDL uptake. When matrigel containing esECs was subcutaneously implanted into mice, various vessel-like structures were observed indicating their endothelial cell like phenotype. In keeping with this, when esECs infected with adenovirus-LacZ were injected into denuded femoral arteries of mice, they were found to form a neo-endothelium that covered the injured areas (86%+/-13.6%), which resulted in a 73% decrease in neointimal area 2 weeks after injury. CONCLUSIONS: We conclude that Sca-1+ cells can differentiate into functional ECs via activation of HDAC3, accelerating re-endothelialization of injured arteries and reducing neointima formation.

Animals↗
PubMed1984

Characteristic expression of glycosphingolipid profiles in the bipotential cell differentiation of human promyelocytic leukemia cell line HL-60.

Changes of glycosphingolipids (GSLs) in the bipotential cell differentiation of human promyelocytic leukemia cell line HL-60 cells were investigated by high-performance thin-layer chromatography (HPTLC), with special reference to morphological and functional changes, such as phagocytosis and nitroblue tetrazolium (NBT) reduction. Nine molecular species of neutral GSLs and 13 or more species of sialo-GSLs, ie, gangliosides, were detected on the HPTLC chromatograms for untreated HL-60 cells. The major components were ceramide dihexoside (CDH), GM3, and sialo-paragloboside (SPG). When HL-60 cells were induced to differentiate into both myeloid mature cells and macrophage-like cells in vitro, no new molecular species of GSLs specific for one of the cell differentiations was induced, but distinctive quantitative changes in the GSL composition were definitely observed between the two cell differentiations. During the myeloid differentiation induced by either dimethylsulfoxide (DMSO) or retinoic acid (RA), CDH, paragloboside (PG), and gangliosides having longer sugar moieties characteristically increased with a concomitant decrease of GSLs with shorter sugar chains, such as ceramide monohexoside (CMH) and GM3, and the GSL composition profile of myeloid differentiation-induced HL-60 cells became more similar to that of normal human granulocytes. However, some marked differences were noted between the induced HL-60 cells and the normal granulocytes, especially in the ganglioside compositions. These differences might reflect either some deficiency in the in vitro myeloid differentiation or some leukemic properties of HL-60 cells. In marked contrast to the change of GSL composition during myeloid differentiation, a remarkable increase of GM3, with a concurrent marked decrease of CDH, was observed in the process of cell differentiation into macrophage-like cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which suggested an increase in the biosynthesis of GM3. These results demonstrate that HL-60 cells express distinct GSL profiles, depending not only on maturation stages but also on differentiation directions.

Cell Line↗
PubMed2005

Ikaros induces quiescence and T-cell differentiation in a leukemia cell line.

Ikaros is a hematopoietic cell-specific zinc finger DNA binding protein that plays an important role in lymphocyte development. Genetic disruption of Ikaros results in T-cell transformation. Ikaros null mice develop leukemia with 100% penetrance. It has been hypothesized that Ikaros controls gene expression through its association with chromatin remodeling complexes. The development of leukemia in Ikaros null mice suggests that Ikaros has the characteristics of a tumor suppressor gene. In this report, we show that the introduction of Ikaros into an established mouse Ikaros null T leukemia cell line leads to growth arrest at the G0/G1 stage of the cell cycle. This arrest is associated with up-regulation of the cell cycle-dependent kinase inhibitor p27kip1, the induction of expression of T-cell differentiation markers, and a global and specific increase in histone H3 acetylation status. These studies provide strong evidence that Ikaros possesses the properties of a bona fide tumor suppressor gene for the T-cell lineage and offer insight into the mechanism of Ikaros's tumor suppressive activity.

Acetylation↗