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PubMed2004

Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway.

In the developing vertebrate nervous system, multipotent neural stem cells produce both neurons and glia. OLIG2 is a basic helix-loop-helix transcription factor that plays critical roles in oligodendrocyte and motor neuron development; however, its role in astrocytic development remains elusive. In this study, we analyzed an effect of OLIG2 on cytokine-induced astrocytic differentiation from mouse telencephalic neuroepithelial cells. We show that the presence of OLIG2 protein leads to inhibition of the promoter activation of astrocyte-specific glial fibrillary acidic protein gene. We found that OLIG2 abolishes complex formation between a transcriptional coactivator p300 and a transcription factor, signal transducer and activator of transcription 3 (STAT3), which is activated by astrocytic differentiation-inducing cytokines, such as leukemia inhibitory factor (LIF). The enforced expression of OLIG2 in neuroepithelial cells inhibits the LIF-induced astrocytic differentiation. We also show that the OLIG2 protein in the nuclei of neural precursor cells disappears in accordance with astrocytic differentiation during culture with LIF. Together, these results reveal a novel molecular function of OLIG2 on the astrocyte development. Cell Death and Differentiation (2004) 11, 196-202. doi:10.1038/sj.cdd.4401332 Published online 24 October 2003

Animals↗
PubMed2006

Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse.

Long-term exposure to pyschostimulants and opioids induced neuronal plasticity. Accumulating evidence suggests that astrocytes actively participate in synaptic plasticity. We show here that a glial modulator propentofylline (PPF) dramatically diminished the activation of astrocytes induced by drugs of abuse, such as methamphetamine (METH) and morphine (MRP). In vivo treatment with PPF also suppressed both METH- and MRP-induced rewarding effects. On the other hand, intra-nucleus accumbens (N.Acc.) administration of astrocyte-conditioned medium (ACM) aggravated the development of rewarding effects induced by METH and MRP via the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, which modulates astrogliosis and/or astrogliogenesis. Furthermore, ACM, but not METH itself, clearly induced the differentiation of multipotent neuronal stem cells into glial fibrillary acidic protein-positive astrocytes, and this effect was reversed by cotreatment with the Jak/STAT inhibitor AG490. Intra-cingulate cortex (CG) administration of ACM also enhanced the rewarding effect induced by METH and MRP. In contrast to ACM, intra-N.Acc. administration of microglia-conditioned medium failed to affect the rewarding effects of METH and MRP in mice. These findings suggest that astrocyte-, but not microglia-, related soluble factors could amplify the development of rewarding effect of METH and MRP in the N.Acc. and CG. The present study provides direct evidence that astrocytes may, at least in part, contribute to the synaptic plasticity induced by drugs of abuse during the development of rewarding effects induced by psychostimulants and opioids.

Analysis of Variance↗
PubMed1994

Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder thought to arise in a multipotent haemopoietic stem cell. A distinct clinical feature is a tendency to thrombosis, with a particular predilection for the hepatic veins (Budd-Chiari syndrome). We report here on two patients with PNH who developed hepatic vein thrombosis (HVT) and who were treated with tissue plasminogen activator (t-PA). Both patients had a marked clinical and radiological improvement following the t-PA treatment and remain well over 2 years and 6 years after the treatment. This method of thrombolysis for HVT occurring in PNH has only been reported in two previous patients with limited follow-up. We suggest that this therapy is a useful first-line treatment for PNH patients who develop HVT.

Adult↗
PubMed2006

Role of delta-opioid receptor function in neurogenesis and neuroprotection.

The present study was undertaken to evaluate the implication of delta-opioid receptor function in neurogenesis and neuroprotection. We found that the stimulation of delta-opioid receptors by the selective delta-opioid receptor agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (10 nm) promoted neural differentiation from multipotent neural stem cells obtained from embryonic C3H mouse forebrains. In contrast, either a selective micro-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), or a specific kappa-opioid receptor agonist, (-)-trans-(1S,2S)-U-50488 hydrochloride (U50,488H), had no such effect. In addition to neural differentiation, the increase in cleaved caspase 3-like immunoreactivity induced by H2O2 (3 microm) was suppressed by treatment with SNC80 in cortical neuron/glia co-cultures. These effects of SNC80 were abolished by a Trk-dependent tyrosine kinase inhibitor: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one (K-252a). The SNC80-induced neural differentiation was also inhibited by treatment with the protein kinase C (PKC) inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitor, mitogen-activated protein kinase kinase (MEK) inhibitor or Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These findings raise the possibility that delta-opioid receptors play a crucial role in neurogenesis and neuroprotection, mainly through the activation of Trk-dependent tyrosine kinase, which could be linked to PI3K, PKC, CaMKII and MEK.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Phenotypic and genotypic switch in Philadelphia-positive, BCR-positive blast crisis of chronic myeloid leukemia.

We report a case of Ph1-positive, bcr-positive chronic myeloid leukemia blast crisis (CML-BC) which at presentation showed a mixed myeloid/B-lymphoid immunophenotype along with TdT positivity and, at the molecular level, an oligoclonal rearrangement of the immunoglobulin heavy chain (IgH) gene region. After obtaining a successful remission, at the time of relapse the patient underwent a phenotypic and genotypic switch from mixed to myeloid phenotype, characterized by the loss of the lymphoid markers and TdT expression and by a germline configuration of the IgH gene region. The same bcr rearrangement was, however, found in both phases of the disease, supporting the suggestion of a true phenotypic and genotypic conversion. This report confirms that the neoplastic event in CML may take place at an early multipotent stem-cell level, prior to a well-defined phenotypic and genotypic lineage expression. Moreover, it is suggested that different factors (chemotherapy? growth factors?) may have either eradicated the bcr+/IgH+ clone and promoted the growth of bcr+/IgH- leukemic cells or, alternatively, supported the lymphoid differentiation program and induced a myeloid lineage shift.

Adult↗
PubMed2006

A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fms gene.

Hematopoietic stem cells and multipotent progenitors exhibit low-level transcription and partial chromatin reorganization of myeloid cell-specific genes including the c-fms (csf1R) locus. Expression of the c-fms gene is dependent on the Ets family transcription factor PU.1 and is upregulated during myeloid differentiation, enabling committed macrophage precursors to respond to colony-stimulating factor 1. To analyze molecular mechanisms underlying the transcriptional priming and developmental upregulation of the c-fms gene, we have utilized myeloid progenitors lacking the transcription factor PU.1. PU.1 can bind to sites in both the c-fms promoter and the c-fms intronic regulatory element (FIRE enhancer). Unlike wild-type progenitors, the PU.1(-/-) cells are unable to express c-fms or initiate macrophage differentiation. When PU.1 was reexpressed in mutant progenitors, the chromatin structure of the c-fms promoter was rapidly reorganized. In contrast, assembly of transcription factors at FIRE, acquisition of active histone marks, and high levels of c-fms transcription occurred with significantly slower kinetics. We demonstrate that the reason for this differential activation was that PU.1 was required to promote induction and binding of a secondary transcription factor, Egr-2, which is important for FIRE enhancer activity. These data suggest that the c-fms promoter is maintained in a primed state by PU.1 in progenitor cells and that at FIRE PU.1 functions with another transcription factor to direct full activation of the c-fms locus in differentiated myeloid cells. The two-step mechanism of developmental gene activation that we describe here may be utilized to regulate gene activity in a variety of developmental pathways.

Animals↗
PubMed2006

Mouse modeling in oncologic preclinical and translational research.

Through scientific and technological advancements, our ability to manipulate the mouse genome has allowed us to evaluate the effect of specific genetic alterations on in vivo tumorigenesis. This has allowed and will allow us to define molecular pathways describing the processes of tumor initiation, invasion, and progression to metastatic disease. Additionally, these models may serve as an excellent platform for the identification of novel molecular targets for therapy as well as to evaluate the efficacy of targeted therapies. Ultimately this will translate from preclinical mouse model trials to the development of clinical trials and protocols for cancer patients. Here we review the usefulness of mouse modeling in oncologic translational research.

Animals↗
PubMed2005

A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases.

Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.

Amino Acid Substitution↗
PubMed2005

Pathogenesis of myelofibrosis with myeloid metaplasia.

The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell-derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.

Animals↗
PubMedDate not supplied

Bone and fat: old questions, new insights.

Until recently, adipose tissue was considered to serve only as a triglyceride reservoir and was relegated to a passive endocrine role. With the discovery of leptin and other adipokines, adipose tissue is now recognized as an active participant in systemic metabolism. This review focuses on the complex relationship existing between adipose tissue and bone metabolism and differentiation. It explores the paradigms that have shaped the past decade's research and what these findings forecast for the future. Particular attention is given to the multipotent adult stem cell populations that reside within bone and fat. These adult stem cells have critical importance to the emerging field of tissue engineering and regenerative medicine.

Adipose Tissue↗
PubMed2004

Distinct neural precursors in the developing human spinal cord.

Both embryonic and adult central nervous system have been shown to contain multipotent neural stem cells, but it is not yet clear whether they consist of a single or distinct populations of neural precursors. Since embryonic human neural precursors, particularly in the spinal cord, have not been extensively characterized, we have studied their behaviour at different days of gestation and in different culture conditions. Depending on dissociation and culture conditions, neurospheres which contain nestin- and vimentin-positive or only vimentin-positive neural precursors can be isolated. Whereas the former can be isolated only at early developmental stages, the latter appear to be present at all the stages examined, between 45 and 89 days of gestation. Furthermore, comparison of the effect of FGF, EGF and the two factors in combination on colony formation shows an additive effect of the two growth factors, indicating the existence of more than one type of neural precursor. Overall our results suggest that the human spinal cord contains distinct and dynamic populations of neural precursors which are developmentally regulated.

Cell Differentiation↗
PubMed1999

Generation of tyrosine hydroxylase-producing neurons from precursors of the embryonic and adult forebrain.

We have explored the plastic ability of neuronal precursors to acquire different identities by manipulating their surrounding environment. Specifically, we sought to identify potential signals involved in the specification of forebrain dopaminergic neurons. Here we describe culture conditions under which tyrosine hydroxylase (TH) expression is induced in neuronal precursors, which were derived directly from the embryonic striatum and adult subependyma (SE) of the lateral ventricle or generated from multipotent forebrain stem cells. TH was successfully induced in all of these cell types by 24 hr exposure to basic fibroblast growth factor (FGF2) and glial cell conditioned media (CM). The greatest magnitude of the inductive action was on embryonic striatal precursors. Although FGF2 alone induced limited TH expression in striatal cells (1.1 +/- 0.2% of neurons), these actions were potentiated 17.5-fold (19.6 +/- 1.5% of neurons) when FGF2 was coadministered with B49 glial cell line CM. Of these TH-immunoreactive cells, approximately 15% incorporated bromodeoxyuridine (BrdU), indicating that they were newly generated, and 95% coexpressed the neurotransmitter GABA. To investigate whether precursors of the adult forebrain subependyma were competent to respond to the instructive actions of FGF2+CM, they were first labeled in vivo with a pulse of BrdU. Although none of the cells expressed TH in control, 0.2% of total cells showed TH immunoreactivity in FGF2+CM-treated cultures. Under these same conditions only, in vitro-generated precursors from epidermal growth factor-responsive stem cells exhibited TH expression in 10% of their total neuronal progeny. Regulation of neurotransmitter phenotype in forebrain neuronal precursors, by the synergistic action of FGF2 and glial-derived diffusible factors, may represent a first step in understanding how these cells are generated in the embryonic and adult brain and opens the prospect for their manipulation in vitro and in vivo for therapeutic use.

Animals↗
PubMed1998

A review of myeloproliferative disease with presentation in the head and neck region.

The diagnosis of an essential thrombocytosis is demonstrated in this presentation of a well-looking 53 year old man who had a five-year history of increasing facial asymmetry as evidenced by deviation of his mandible to the right and malocclusion. The enlarged mandibular condyle was the first manifestation of his underlying myeloproliferative disorder. His management will be discussed. Neoplastic diseases of the multipotent haematopoietic stem cells result in four major diseases: chronic myelogenous leukaemia (CML); polycythaemia vera (PV); agnogenic myeloid metaplasia with myelofibrosis (AMM/MF); essential thrombocytosis (ET). CML: demonstrates increased production of neutrophils and marked splenomegaly. It is divided into a chronic phrase typified by hyperplasia of mature bone marrow elements and a blastic or acute phase which evolves into a proliferation of immature marrow elements and can develop into acute myelogenous leukaemia. PV: associated with increased production of all myeloid cells but dominated by increased red blood cells with splenomegaly. AMM/MF: allows the neoplastic stem cells to proliferate and lodge in multiple sites outside the bone marrow. Splenomegaly and fibrosis of marrow spaces also occurs. ET: resulting in a markedly elevated platelet count in the absence of a recognizable stimulus. Treatment revolves around measures to maintain hydration, to relieve arthralgias, to prevent thrombotic episodes, and to prevent infections.

Diagnosis, Differential↗
PubMed2000

Molecular aspects of polycythemia vera (review).

Polycythemia vera (PV) is a rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.

Cytogenetics↗
PubMed2004

5-azacitidine: An alternative treatment of myelodysplastic syndromes in patient with refractory response to hematopoietic growth factor, a case report and review of literatures.

Myelodysplastic Syndrome (MDS) comprises a heterogeneous group of clonal hemopathies derived from an abnormality affecting a multipotent hematopoietic stem cell and characterized by maturation defects resulting in ineffective hematopoiesis. It most frequently occurs in elderly patients. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Most MDS patients, due to their age and co morbidity, are not eligible for allogeneic hematopoietic stem cell transplantation; the only established curative regimen. The effect of available lineage-specific growth factors is limited to improvement of single lineages and has not resulting in the survival benefit. Treatment with low dose Ara-C is disappointing in regard to response rate or duration. No benefit has been demonstrated in differentiation inducers such as retinoids and Vitamin D3 as single agents. We report a case of a patient with transfusion dependent MDS who was not a candidate for allogeneic stem cell transplantation or cytotoxic chemotherapy, who also failed to response to erythropoietin support but had a favorable response to 5-azacitidine. His blood transfusion requirement reduced significantly, and was correlated with the remarkable improvement of the pancytopenia, particularly anemia and thrombocytopenia after receiving the investigational therapy with 5-azacitidine. In summary, 5-azacitidine appears to be a promising alternative therapy for patient with refractory anemia secondary to MDS.

Aged↗
PubMedDate not supplied

[Diagnostic and therapeutic management of essential thrombocythemia in children].

BACKGROUND: Essential thrombocythemia is a myeloproliferative disease resulting from the clonal proliferation of a multipotent myeloid stem cell with an increased platelet count in peripheral blood. In 2% of cases the cause remains unknown. It is then called idiopathic essential thrombocythemia. THE AIM: The objective of this study was to present the diagnostic and therapeutic management of essential thrombocythemia in children. MATERIAL AND METHODS: The authors analysed complete medical records of 5 patients treated for essential thrombocythemia in the Department of Children Haematology and Oncology, Medical University Lublin during a 6 years (1996-2002) period. The investigated group consisted of 5 children: 3 boys and 2 girls with mean age of 7 years and 8 months (varying from 5 years and 3 months to 11 years and 8 months). RESULTS: The peripheral platelet count was above 1200 x 10(9)/L. Three patients developed functional symptoms of microvascular blood flow alteration (headaches, sensory disorders. paresthesiae). In 2 patients thrombocythemia was asymptomatic and the diagnosis was made incidentally. Diagnosis of essential thrombocythemia was made according to the criteria of the Polycythemia Vera Study Group and treatment with anagrelide hydrochloride was started. One patient due to bad drug tolerance was treated with hydroxyurea. Treatment of essential thrombocythemia in all patients resulted in: (1) decreased (500-600 x 10(9)/L) platelet count in peripheral blood; (2) resolving the symptoms of small vessels obturation (headaches, sensory disorders, paresthesiae); (3) low platelet separating megakaryocytes count in control myelograms (4) no transformation into acute neoplastic disease. CONCLUSIONS: In the treatment of children with essential thrombocythemia anagrelid was effective in four of five patients.

Blood Platelets↗
PubMed2000

Australian Neuroscience Society--20th Annual Meeting. 30 January-2 February 2000, Melbourne, Australia.

This meeting presented a large array of high quality neuroscience research, some of which held possible relevance for therapeutic development. The potential use of multipotent neural stem cells harvested from adult brain for transplantation and regeneration therapy was highlighted, as was the increasingly central role of the p75 neurotrophin receptor in regulating neuronal cell death. Of particular interest were strategies for the prevention of neuronal death by systemic administration of p75 receptor antisense oligonucleotides. Other significant data included a possible synergy between prostaglandin receptors and opioid receptors in cellular responses, thought to underlie pain perception and opioid analgesia. Groups in Melbourne, Brisbane and Bath, UK, have isolated novel alpha-conotoxins from Conus marine snails, and characterized their effects on neuronal nicotinic acetylcholine receptors (nAChRs), highlighting their subunit specificity and effects on synaptic transmission. While none of these findings are close to effective clinical use as yet, they hold great promise for the future, underlining the necessity for basic research as a starting point for novel therapies.

Journal Article↗