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1.
J Endocrinol Invest ; 27(6 Suppl): 64-7, 2004.
Article in English | MEDLINE | ID: mdl-15481805

ABSTRACT

Multipotent stem cells are present in the majority of mammalian tissues where they are a renewable source of specialized cells. According to the several biological portions from which multipotent stem cells can be derived, they are characterized as a) embryonic stem cells (ESCs) isolated from the pluripotent inner-cell mass of the pre-implantation blastocyste-stage embryo; b) multipotent fetal stem cells (FSCs) from aborted fetuses; and c) adult stem cells (ASCs) localized in small zones of several organs known as "niche" where a subset of tissue cells and extracellular substrates can indefinitely house one or more stem cells and control their self-renewal and progeny production in vivo. ECSs have an high self-renewing capacity, plasticity and pluripotency over the years. Pluripotency is a property that makes a stem cell able to give rise to all cell type found in the embryo and adult animals.


Subject(s)
Neurons/physiology , Stem Cells/physiology , Animals , Brain/cytology , Brain/embryology , Cell Separation , Humans , Multipotent Stem Cells/physiology , Nerve Regeneration/physiology , Phenotype , Stem Cell Transplantation
2.
Exp Neurol ; 182(2): 335-45, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12895444

ABSTRACT

Brain deposition of the amyloid-beta protein (Abeta) is a frequent complication of Down's syndrome (DS) patients. Abeta peptide is generated by endoproteolytic processing of Abeta precursor protein by gamma and beta secretases. Recently a transmembrane aspartyl protease, BACE, has been identified as the beta-secretase, and its homologous BACE-2 has also been described. BACE-2 gene resides on chromosome 21 in the obligate DS region. It cleaves Abeta precursor protein at its beta site and more efficiently at a different site within Abeta. In the present study we characterized the BACE-2 gene and protein expression in the DS patients and healthy control. We analyzed, by using a nonradioactive ribonuclease protection assay, the levels of BACE-2 mRNA expression in primary skin fibroblasts. The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group. Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment. In the medium conditioned by fibroblast, we revealed an evident secretion of BACE-2 protein, represented by two different molecular weights, remarkably increased in DS fibroblasts. BACE-2 overexpression was also confirmed in the DS fetal brains and human neural embryonic DS stem cells in which conditioned media BACE-2 was secreted. These data highlight the importance of the extracellular compartment where BACE-2 overexpression could play a role in plaque formation in DS patients.


Subject(s)
Aspartic Acid Endopeptidases/biosynthesis , Brain/enzymology , Down Syndrome/enzymology , Fibroblasts/enzymology , Stem Cells/enzymology , Adult , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Blotting, Western , Brain/embryology , Brain Chemistry , Cells, Cultured , Culture Media, Conditioned/chemistry , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Molecular Weight , Neurons/cytology , Neurons/enzymology , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Reference Values , Stem Cells/cytology , Stem Cells/metabolism
3.
J Neurosurg Sci ; 47(1): 8-17, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12900727

ABSTRACT

AIM: Neural stem cells (NSC) are clonogenic cells, capable of self-renewal and multilineage differentiation, since, under the appropriated experimental conditions, they proliferate indefinitely as undifferentiated neurospheres or differentiate in neurons, astrocytes and oligodendrocytes. Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. METHODS: Here we investigated the suitability of recently identified and characterized neuronal progenitor cells at eliciting functional recovery in unilateral 6HODA-lesioned mice. We describe herein that intrastriatal engraftment of stem cell-derived neurons isolated from the olfactory bulb to give rise dopaminergic-like neurons results in long lasting functional recovery in 6OHDA-injured mice. RESULTS: Unilateral injection of 6OHDA resulted in a progressive neurodegeneration of the nigro-striatal pathway. Likewise, the systemic administration of L-DOPA in these mice elicited a marked contralateral turning which was evident 1 week post, increased during the following week and than stabilize throughout the time of the experiment. Conversely, the intrastriatal implantation of partially differentiated stem cells at 14 days postlesion, resulted in a profound decrease in L-DOPA-induced circling behavior; interestingly, the effect was evident 1 week after the engraftment and was retained during the following 9 weeks. Detailed biochemical and immunohistochemical evaluation is currently under investigation in our laboratory. Conclusion. Our observation opens new perspectives for the treatment of neurodegeneration in Parkinson's disease.


Subject(s)
Neurons/transplantation , Parkinson Disease, Secondary/surgery , Stem Cell Transplantation , Animals , Bromodeoxyuridine , Cell Differentiation , Immunohistochemistry , Mice , Mice, Inbred Strains , Neurons/enzymology , Neurons/physiology , Olfactory Bulb/cytology , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/genetics , Parkinson Disease, Secondary/pathology , Phenotype , Recovery of Function , Stem Cells/pathology , Stem Cells/physiology , Tyrosine 3-Monooxygenase/metabolism
4.
Stem Cells ; 18(4): 295-300, 2000.
Article in English | MEDLINE | ID: mdl-10924096

ABSTRACT

We have recently isolated stem cells deriving from the olfactory bulbs of adult patients undergoing particularly invasive neurosurgery. After improving our experimental conditions, we have now obtained neural stem cells according to clonal analysis. The cells can be expanded, established in continuous cell lines and differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). Also, after exposition to leukemia inhibitory factor, we are able to improve the number of neurons, an ideal biological source for transplantation in various neurodegenerative disorders.


Subject(s)
Astrocytes/cytology , Interleukin-6 , Neurons/cytology , Olfactory Bulb/cytology , Oligodendroglia/cytology , Stem Cells/cytology , Adult , Astrocytes/drug effects , Cell Count , Cell Culture Techniques/methods , Cell Separation , Cells, Cultured , Growth Inhibitors/pharmacology , Humans , Leukemia Inhibitory Factor , Lymphokines/pharmacology , Neurons/drug effects , Oligodendroglia/drug effects , Stem Cells/drug effects
5.
Dev Neurosci ; 22(1-2): 86-95, 2000.
Article in English | MEDLINE | ID: mdl-10657701

ABSTRACT

The generation of diverse types of neural cells during development occurs through the progressive restriction of the fate potential of neuroepithelial progenitor cells. This process is controlled by factors intrinsic and extrinsic to the cell. While the effect of extrinsic cues on multipotent stem cells of the murine central nervous system (CNS) is becoming clearer, little is known of neural stem cells of human origin. We sought to establish the roles played by two cytokines, leukemia inhibitory (LIF) and ciliary neurotrophic factor (CNTF), and by nerve growth factor (NGF) and platelet-derived growth factor (PDGF) in regulating neuronal and astroglial differentiation in cultured embryonic diencephalic human stem cells. While NGF did not influence either neuronal or glial formation, PDGF surprisingly decreased the percentage of stem cell-generated neurons, an effect opposite to that observed in murine progenitors. Furthermore, while we confirmed the known ability of LIF and CNTF to support astroglial differentiation, we also observed that, in contrast with their murine counterparts, the fraction of CNS stem cell-generated neurons in human cultures was enhanced twofold in the presence of both cytokines. These findings highlight important differences between humans and rodents in regard to the way epigenetic cues regulate the function of neural stem cells.


Subject(s)
Diencephalon/cytology , Diencephalon/embryology , Growth Inhibitors/physiology , Interleukin-6 , Lymphokines/physiology , Neurons/cytology , Stem Cells/cytology , Astrocytes/cytology , Becaplermin , Cell Count/drug effects , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Survival/drug effects , Cells, Cultured , Embryo, Mammalian/metabolism , Growth Inhibitors/pharmacology , Humans , Leukemia Inhibitory Factor , Leukemia Inhibitory Factor Receptor alpha Subunit , Lymphokines/pharmacology , Nerve Growth Factor/pharmacology , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , Receptor, Ciliary Neurotrophic Factor/genetics , Receptor, trkA/genetics , Receptors, Cytokine/genetics , Receptors, OSM-LIF , Receptors, Platelet-Derived Growth Factor/genetics
6.
J Neurosci ; 19(9): 3287-97, 1999 May 01.
Article in English | MEDLINE | ID: mdl-10212288

ABSTRACT

The subventricular zone (SVZ) of the adult mammalian forebrain contains kinetically distinct precursor populations that contribute new neurons to the olfactory bulb. Because among forebrain precursors there are stem-like cells that can be cultured in the presence of mitogens such as epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), we asked whether distinct subsets of stem-like cells coexist within the SVZ or whether the proliferation of a single type of SVZ stem-like cell is controlled by several GFs. We show that the latter is the case. Thus cells isolated from the SVZ coexpress the EGF and FGF receptors; by quantitative analysis, the number of stem-like cells isolated from the SVZ by either FGF2 or EGF is the same, whereas no additive effect occurs when these factors are used together. Furthermore, short-term administration of high-dose [3H]thymidine in vivo depletes both the EGF- and FGF2-responsive stem-like cell populations equally, showing they possess closely similar proliferation kinetics and likely belong to the constitutively proliferating SVZ compartment. By subcloning and population analysis, we demonstrate that responsiveness to more than one GF endows SVZ cells with an essential stem cell feature, the ability to vary self-renewal, that was until now undocumented in CNS stem-like cells. The multipotent stem cell-like population that expands slowly in the presence of FGF2 in culture switches to a faster growth mode when exposed to EGF alone and expands even faster when exposed to both GFs together. Analogous responses are observed when the GFs are used in the reverse order, and furthermore, these growth rate modifications are fully reversible.


Subject(s)
Epidermal Growth Factor/pharmacology , ErbB Receptors/genetics , Fibroblast Growth Factor 2/pharmacology , Neurons/cytology , Neurons/physiology , Prosencephalon/cytology , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Stem Cells/cytology , Animals , Cell Differentiation , Cell Division/drug effects , Cells, Cultured , Corpus Striatum/cytology , Corpus Striatum/physiology , Epidermal Growth Factor/physiology , ErbB Receptors/physiology , Fibroblast Growth Factor 2/physiology , Kinetics , Mice , Neurons/drug effects , Prosencephalon/physiology , Receptor Protein-Tyrosine Kinases/physiology , Receptor, Fibroblast Growth Factor, Type 1 , Receptors, Fibroblast Growth Factor/physiology , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/drug effects , Stem Cells/physiology
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