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At least 991 records · Page 55Linked to original sources
PubMed2005

Bee venom modulates murine Th1/Th2 lineage development.

Administration of bee venom (BV) elicits anti-inflammatory, anti-nociceptive and anti-allergic effects in various animal models. This study was designed to evaluate the direct effects of BV on helper T cell activities and on Th1/Th2 lineage development using both in vitro and in vivo conditions. In the Th1 skewed condition, BV increased the expression of IFN-gamma mRNA and enhanced the expression of T-bet on purified CD4(+) T cells from splenocytes of BALB/c mice. On the other hand, BV treatment did not alter the expression of IL-4 or GATA-3 in a Th2 driven environment. To elucidate the effects of BV on Th1/Th2 lineage development under in vivo conditions, BV was given by intraperitonial injection to BALB/c mice. It significantly increased the CD4(+) T cell population and enhanced IFN-gamma expression, while IL-4 transcripts were not altered upon in vivo activation using an anti-CD3 antibody injection. Taken together, these results imply that BV induces Th1 lineage development from CD4(+) T cells by increasing the expression of a Th1-specific cytokine, IFN-gamma. In addition, this result may be mediated by inducing a Th1-specific transcription factor, T-bet.

Animals↗
PubMed2005

Efficient differentiation and integration of lineage-restricted neural precursors in the traumatically injured adult cat spinal cord.

Several recent studies have shown that highly undifferentiated neural stem cells (NSCs) grafted into the intact or injured adult spinal cord of animal either remain undifferentiated or show fate restriction to a astrocytic lineage. This indicates that functionally diverse roles expected of cellular replacement cannot be performed by the transplantation of highly immature precursors; rather, more differentiated or appropriate mixtures of more restricted neural precursors may be important in replacement strategies. In this study, we investigated the ability of lineage-restricted neural progenitors derived from adult mouse periventricular subependymal zone (SEZ) to integrate and differentiate into the chronically injured adult spinal cord. To this end, NSCs were grown as adherent cultures followed by expansion in non-adhesive dishes. This allowed us to grow NSCs as colonies of restricted neural precursors, illustrated by NCAM, nestin, Sox-2, A2B5, and GFAP immunostaining. The mixture of lineage-restricted precursors was directly implanted into the chronically injured spinal cord of immunosuppressed cats. The fate of the cells was traced with GFP fluorescence and immunocytochemistry for neural markers such as beta-III-tubulin, GFAP, and Ng2. After four weeks, transplanted cells survived, giving rise to neurons and in addition to cells with an astrocytic phenotype. We conclude that a mixture of more restricted neural precursors may be better suited than highly immature NSCs for neural replacement strategies after central nervous system (CNS) injuries.

Animals↗
PubMed2006

Towards an understanding of lineage specification in hematopoietic stem cells: a mathematical model for the interaction of transcription factors GATA-1 and PU.1.

In addition to their self-renewal capabilities, hematopoietic stem cells guarantee the continuous supply of fully differentiated, functional cells of various types in the peripheral blood. The process which controls differentiation into the different lineages of the hematopoietic system (erythroid, myeloid, lymphoid) is referred to as lineage specification. It requires a potentially multi-step decision sequence which determines the fate of the cells and their successors. It is generally accepted that lineage specification is regulated by a complex system of interacting transcription factors. However, the underlying principles controlling this regulation are currently unknown. Here, we propose a simple quantitative model describing the interaction of two transcription factors. This model is motivated by experimental observations on the transcription factors GATA-1 and PU.1, both known to act as key regulators and potential antagonists in the erythroid vs. myeloid differentiation processes of hematopoietic progenitor cells. We demonstrate the ability of the model to account for the observed switching behavior of a transition from a state of low expression of both factors (undifferentiated state) to the dominance of one factor (differentiated state). Depending on the parameter choice, the model predicts two different possibilities to explain the experimentally suggested, stem cell characterizing priming state of low level co-expression. Whereas increasing transcription rates are sufficient to induce differentiation in one scenario, an additional system perturbation (by stochastic fluctuations or directed impulses) of transcription factor levels is required in the other case.

Cell Differentiation↗
PubMed2004

Myelin transcription factor 1 (Myt1) modulates the proliferation and differentiation of oligodendrocyte lineage cells.

Myelin transcription factor 1 (Myt1) is a zinc finger DNA-binding protein that is expressed in neural progenitors and oligodendrocyte lineage cells. This study examines the role of Myt1 in oligodendrocyte lineage cells by overexpressing putative functional domains, a four-zinc finger DNA-binding region (4FMyt1) or a central protein-protein interaction domain (CDMyt1), without the predicted transcriptional activation domain. In the presence of mitogens, overexpression of 4FMyt1 inhibited proliferation of oligodendrocyte progenitors, but not cell types (astrocytes and NIH3T3 cells) lacking endogenous Myt1. Expression of 4FMyt1 inhibited the differentiation of oligodendrocyte progenitors into oligodendrocytes as assessed by morphology, immunostaining, and myelin gene expression. Progenitor differentiation was similarly inhibited by expression of CDMyt1 but only partially suppressed by overexpression of the intact Myt1. These data indicate that Myt1 may regulate a critical transition point in oligodendrocyte lineage development by modulating oligodendrocyte progenitor proliferation relative to terminal differentiation and up-regulation of myelin gene transcription.

Animals↗
PubMed2004

Potential of progenitors from postnatal cerebellar neuroepithelium and white matter: lineage specified vs. multipotent fate.

Progenitors that migrate through the white matter of the postnatal cerebellum give rise to interneurons, astrocytes, and oligodendrocytes. To investigate the lineage potential of progenitors from the neuroepithelium and the white matter, we performed an in vitro clonal analysis in the presence or absence of various growth factors. Clonal progeny of cells labeled with a green fluorescent protein (GFP)-expressing retrovirus was characterized using morphological features and lineage markers. The large majority of clones were homogeneous, containing astrocytes, oligodendrocytes, neurons, or hybrid progenitors-cells labeled with markers for astrocytes and oligodendrocytes. Heterogeneous clones consisted of astrocytes and oligodendrocytes, with only a few mixed glial-neuronal clones. The neuroepithelium contains a higher number of multipotent progenitors than the white matter, pointing to a lineage specification of most of the cerebellar progenitors before their migration to the white matter.

Animals↗
PubMed2004

SoxB transcription factors specify neuroectodermal lineage choice in ES cells.

Knowledge of lineage decision machinery in pluripotent embryonic stem (ES) cells may shed light on the process of germ layer segregation in the mammalian embryo and enable directed differentiation in vitro for biomedical applications. We have investigated the contribution of Class B1 Sox transcription factors to lineage choice during ES cell differentiation. We report that forced expression of Sox1 or Sox2 did not impair propagation of undifferentiated ES cells, but upon release from self-renewal promoted differentiation into neuroectoderm at the expense of mesoderm and endoderm. The efficient specification of a primary lineage by transcription factor manipulation provides a paradigm for instructing differentiation of ES cells for biopharmaceutical screening and cell therapy applications.

Animals↗
PubMed2004

Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1.

Brain structures derived from the mesencephalon (mes) and rhombomere 1 (r1) modulate distinct motor and sensory modalities. The precise origin and cellular behaviors underpinning the cytoarchitectural organization of the mes and r1, however, are unknown. Using a novel inducible genetic fate mapping approach in mouse, we determined the fate and lineage relationships of mes/r1 cells with fine temporal and spatial resolution. We demonstrate that the mes and r1 are neuromeres that along with the isthmic organizer are partitioned along the anterior-posterior axis by lineage restriction boundaries established sequentially between E8.5 and E9.5. Furthermore, a small group of cells originating from the most posterior mes exhibit anterior intracompartmental expansion and contribute throughout the inferior colliculus. Finally, we also uncovered transient and differential genetic lineages of ventral midbrain dopaminergic and ventral hindbrain serotonergic neuronal precursors with respect to Wnt1 and Gli1 expression.

Animals↗
PubMed2004

Lineage allocation and cell polarity during mouse embryogenesis.

The first developmental lineage allocation during the generation of the mouse blastocyst is to outer trophoblast or to inner pluriblast (inner cell mass; ICM) cells. This allocation seems to be initiated at the 8-cell stage, when blastomeres polarise. Polarisation is followed by differentiative divisions at the subsequent two cleavage divisions to generate polar outer and non-polar inner 16- and 32-cells. The key events in polarisation are regulated post-translationally through a cell contact-mediated pathway, which imposes a heritable determinant-like organisation on the blastomere cortex. Two proteins in particular, E-cadherin and ezrin, are intimately involved in the generation and stabilisation of developmentally significant information. Transcriptional differences between lineages appear to follow and may coincide with the lineage commitment of cells.

Animals↗
PubMed2005

Benzo(a)pyrene and 7,12-dimethylbenz(a)anthrecene differentially affect bone marrow cells of the lymphoid and myeloid lineages.

Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants that are carcinogenic and immunosuppressive. Benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) are two prototypic PAHs known to impair the cell-mediated and humoral immune responses. We have previously shown that, in C57BL/6J mice, total bone marrow (BM) cellularity decreased two-fold following intraperitoneal DMBA treatment but not BP treatment. Here, we have used flow cytometry to demonstrate that BP and DMBA differentially alter the lymphoid and myeloid lineages. Following DMBA treatment, the pro/pre B-lymphocytes (B220(lo)/IgM(-)) and the immature B-lymphocytes (B220(lo)/IgM(+)) significantly decreased, while the mature B-lymphocytes (B220(hi)/IgM(+)) remained unaffected. In contrast, BP treatment decreased the pro/pre B-lymphocytes, and did not affect the immature B-lymphocytes or mature B-lymphocytes. The Gr-1(+) cells of the myeloid lineage were depleted 50% following DMBA treatment and only minimally depleted following BP treatment. Interestingly, the monocytes (7/4(+)1A8(lo)) and neutrophils (7/4(+)1A8(hi)) within this Gr-1(+) population were differentially affected by these PAHs. Monocytes and neutrophils were depleted following DMBA treatment whereas neutrophils decreased and monocytes increased following BP treatment. Although TNFalpha and CYP1B1 are implicated as essential mediators of hypocellularity, the similar induction of TNFalpha mRNA and CYP1B1 mRNA in the BM by BP and DMBA suggests that they are not limiting factors in mediating the different effects of these PAHs. Given that similar amounts of BP and DMBA reach the BM when administered intraperitoneally, their differential effects on the lymphoid and myeloid lineages probably stem from differences in reactive metabolites such as PAH quinones and PAH-dihydrodiol-epoxides.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Mother-daughter precursor cell fate transformation after Cdc2 down-regulation in the Drosophila bristle lineage.

The Drosophila bristle lineage is an excellent system in which to study how cell cycle and fate determination are synchronized in invariant cell lineages. In this model, five different cells arise from a single precursor cell, pI, after four asymmetric cell divisions. Cell diversity is achieved by the asymmetric segregation of cell determinants, such as Numb and Neuralized (Neur), resulting in differential activation of the Notch (N) pathway. We show that down-regulation of Cdc2, by over-expressing Tribbles, Dwee1, and Dmyt1 (three negative regulators of Cdc2) or by using thermo-sensitive Cdc2 mutant flies, delayed pI mitosis, and altered the polarity and the number of subsequent cell divisions. These modifications were associated with a mother-daughter cell fate transformation as the pI cell acquired the identity of the secondary precursor cell, pIIb. This type of change in cell identity only occurred when the N signaling pathway was inactive since ectopic N signaling transformed pI to pIIa-progeny fate. These transformations in cell identity suggest that, although synchronized, cell cycle and fate determination are independent phenomena in the bristle lineage.

Animals↗
PubMed2005

Determinants of trophoblast lineage and cell subtype specification in the mouse placenta.

Cells of the trophoblast lineage make up the epithelial compartment of the placenta, and their rapid development is essential for the establishment and maintenance of pregnancy. A diverse array of specialized trophoblast subtypes form throughout gestation and are responsible for mediating implantation, as well as promotion of blood to the implantation site, changes in maternal physiology, and nutrient and gas exchange between the fetal and maternal blood supplies. Within the last decade, targeted mutations in mice and the study of trophoblast stem cells in vitro have contributed greatly to our understanding of trophoblast lineage development. Here, we review recent insights into the molecular pathways regulating trophoblast lineage segregation, stem cell maintenance, and subtype differentiation.

Animals↗
PubMed2006

Distinct roles of HF-1b/Sp4 in ventricular and neural crest cells lineages affect cardiac conduction system development.

The heterogeneous cell types of the cardiac conduction system are responsible for coordinating and maintaining rhythmic contractions of the heart. While it has been shown that the cells of the conduction system are derived from myocytes, additional cell types, including neural crest cells, may play a role in the development and maturation of these specialized cell lineages. Previous work has shown that the expression of the hf-1b gene is required for specification of the cardiac conduction system. Using Cre-Lox technology, we conditionally mutated the hf-1b gene in the ventricular and the neural crest cell lineages. Cx40 immunohistochemistry on HF-1b tissue-restricted knockouts revealed a requirement for HF-1b in the cardiomyogenic lineage. Electrophysiological studies identified a second requirement for HF-1b in the neural crest-derived cells. Absence of HF-1b in the neural crest led to atrial and atrioventricular dysfunction resulting from deficiencies in the neurotrophin receptor trkC. Therefore, in this study, we document that a single transcription factor, HF-1b, acts through two separate cell types to direct distinct functions of the cardiac conduction system.

Animals↗
PubMed2005

Regulation of neuronal lineage decisions by the HES-related bHLH protein REF-1.

Members of the HES subfamily of bHLH proteins play crucial roles in neural patterning via repression of neurogenesis. In C. elegans, loss-of-function mutations in ref-1, a distant nematode-specific member of this subfamily, were previously shown to cause ectopic neurogenesis from postembryonic lineages. However, while the vast majority of the nervous system in C. elegans is generated embryonically, the role of REF-1 in regulating these neural lineage decisions is unknown. Here, we show that mutations in ref-1 result in the generation of multiple ectopic neuron types derived from an embryonic neuroblast. In wild-type animals, neurons derived from this sublineage are present in a left/right symmetrical manner. However, in ref-1 mutants, while the ectopically generated neurons exhibit gene expression profiles characteristic of neurons on the left, they are present only on the right side. REF-1 functions in a Notch-independent manner to regulate this ectopic lineage decision. We also demonstrate that loss of REF-1 function results in defective differentiation of an embryonically generated serotonergic neuron type. These results indicate that REF-1 functions in both Notch-dependent and independent pathways to regulate multiple developmental decisions in different neuronal sublineages.

Animals↗
PubMed2006

Evidence for motoneuron lineage-specific regulation of Olig2 in the vertebrate neural tube.

Within the motoneuron precursor (pMN) domain of the developing spinal cord, the bHLH transcription factor, Olig2, plays critical roles in pattern formation and the generation of motor neuron and oligodendrocyte precursors. How are the multiple functions of Olig2 regulated? We have isolated a large BAC clone encompassing the human OLIG2 locus that rescues motor neuron and oligodendrocyte development but not normal pattern formation in Olig2(-/-) embryos. Within the BAC clone, we identified a conserved 3.6 kb enhancer sub-region that directs reporter expression specifically in the motor neuron lineage but not oligodendrocyte lineage in vivo. Our findings indicate complex regulation of Olig2 by stage- and lineage-specific regulatory elements. They further suggest that transcriptional regulation of Olig2 is involved in segregation of pMN neuroblasts.

Animals↗
PubMed2006

Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification.

Erythroid cell production results from passage through cellular hierarchies dependent on differential gene expression under the control of transcription factors responsive to changing niches. We have constructed Genetic Regulatory Networks (GRNs) describing this process, based predominantly on mouse data. Regulatory network motifs identified in E. coli and yeast GRNs are found in combination in these GRNs. Feed-forward motifs with autoregulation generate forward momentum and also control its rate, which is at its lowest in hematopoietic stem cells (HSCs). The simultaneous requirement for multiple regulators in multi-input motifs (MIMs) provides tight control over expression of target genes. Combinations of MIMs, exemplified by the SCL/LMO2 complexes, which have variable content and binding sites, explain how individual regulators can have different targets in HSCs and erythroid cells and possibly also how HSCs maintain stem cell functions while expressing lineage-affiliated genes at low level, so-called multi-lineage priming. MIMs combined with cross-antagonism describe the relationship between PU.1 and GATA-1 and between two of their target genes, Fli-1 and EKLF, with victory for GATA-1 and EKLF leading to erythroid lineage specification. These GRNs are useful repositories for current regulatory information, are accessible in interactive form via the internet, enable the consequences of perturbation to be predicted, and can act as seed networks to organize the rapidly accumulating microarray data.

Animals↗
PubMed2006

BMP and FGF regulate the differentiation of multipotential pericardial mesoderm into the myocardial or epicardial lineage.

Proepicardial cells give rise to epicardium, coronary vasculature and cardiac fibroblasts. The proepicardium is derived from the mesodermal lining of the prospective pericardial cavity that simultaneously contributes myocardium to the venous pole of the elongating primitive heart tube. Using proepicardial explant cultures, we show that proepicardial cells have the potential to differentiate into cardiac muscle cells, reflecting the multipotency of this pericardial mesoderm. The differentiation into the myocardial or epicardial lineage is mediated by the cooperative action of BMP and FGF signaling. BMP2 is expressed in the distal IFT myocardium and stimulates cardiomyocyte formation. FGF2 is expressed in the proepicardium and stimulates differentiation into the epicardial lineage. In the base of the proepicardium, coexpression of BMP2 and FGF2 inhibits both myocardial and epicardial differentiation. We conclude that the epicardial/myocardial lineage decisions are mediated by an extrinsic, inductive mechanism, which is determined by the position of the cells in the pericardial mesoderm.

Animals↗
PubMed2005

Skeletal muscle stem and progenitor cells: reconciling genetics and lineage.

Skeletal muscle provides a unique paradigm for studying stem to differentiated cell transitions, as well as the acquisition of cellular identity. Embryological and genetic studies over the last decades have unveiled key signaling pathways and regulatory genes which are involved in this process. In the adult, regeneration from fiber-associated satellite cells as well as non-muscle cells have opened the perspective for cell therapy studies. Paradoxically, however, the lineage has remained largely elusive. Recent studies have provided clues regarding the cellular organization in this lineage. Furthermore, the complexity of the genetic networks regulating global and local myogenic programs can be correlated with location and lineage. Finally, prenatal and postnatal developmental strategies have similarities and differences which will also be highlighted.

Animals↗
PubMed2006

Cell surface 5T4 antigen is transiently upregulated during early human embryonic stem cell differentiation: effect of 5T4 phenotype on neural lineage formation.

The 5T4 oncofoetal antigen is a cell surface glycoprotein that is transiently expressed during mouse ES cell differentiation and correlates with decreased pluripotency of such cells. We show that 5T4 antigen is transiently unregulated during HES4 and H1 human ES cell differentiation and its expression correlates with loss of the pluripotent markers OCT-4 and Tra-1-60 and upregulation of transcript markers associated with the three primary germ layers. To confirm that absence of cell surface 5T4 antigen represents a pluripotent hES cell phenotype, we performed mechanical transfer of either 5T4-ve or 5T4+ve HES4 colonies identified using live cell staining. 5T4-ve transfers maintained expression of OCT-4 in over 90% of resultant colonies, whereas 5T4+ve transfers exhibited significantly lower numbers of OCT-4-expressing colonies (92 +/- 1.4 vs. 2.9 +/- 2.0%). Interestingly, low cell density 5T4-ve colony transfers exhibited increased numbers of OCT-4-expressing colonies compared to large 5T4-ve transfers (92 +/- 1.4 vs. 63.2 +/- 1.9%). 5T4-ve and 5T4+ve HES4 and H1 ES cell lines expressed markers representative of neuroectoderm lineages, and we assessed the formation of neural lineages from these phenotypes in serum-containing medium and N2B27 medium. Expression of 5T4 was found to be inversely related to the yield of tyrosine-hydroxylase (TH+)-expressing neurons in N2B27 medium, with additional mesoderm and endoderm transcript markers detected. Homogeneous glial cell populations were derived from low cell density 5T4-ve colony transfers cultured in serum-containing medium, with TH+ neuronal formation inhibited in a cell-density-dependent manner. We conclude that the 5T4 antigen is a transient marker of hES cell differentiation and that 5T4 phenotype, colony seeding density and culture conditions significantly influence the maintenance of pluripotent hES cells and their differentiation to neural lineages.

Animals↗