Upregulation of the Oct3/4 network in basal breast cancer is associated with its metastatic potential and shows tissue dependent variability

Adaptive plasticity of Breast Cancer stem cells (BCSCs) is strongly correlated with cancer progression and resistance, leading to a poor prognosis. In this study, we report the expression profile of several pioneer transcription factors of th

Stem Cells and Neuroprotection: Understanding the Players

The use of neuroprotective therapies begs the question of how such therapies could affect preexisting stem cell populations within the host, as well as those introduced through cell-replacement therapy. Multiple mechanisms may mediate stem cell responses to neuroprotectants such as host/donor age and gender, cellular lineage/differentiation status, and mitochondrial dynamics. Current therapeutic sources for stem cells are embryonic, somatic, or induced pluripotent, with very little known about the effects of gender, age, cell type, and mitochondrial dynamics. With the advent of therapies to stimulate and recruit endogenous stem cells or transplant donor cells into damage areas in the hopes of recuperative regeneration of lost neurons, it is important to discuss mechanisms that dictate the winning players in the neuroprotection game. This review will focus on our current understanding of the characteristics of renewing stem cells that may affect neuroprotection

Neurotoxicity Screening in a Multipotent Neural Stem Cell Line Established from the Mouse Brain

Neural stem cells (NSCs) have mainly been applied to neurodegeneration in some medically intractable neurologic diseases. In this study, we established a novel NSC line and investigated the cytotoxic responses of NSCs to exogenous neurotoxicants, glutamates and reactive oxygen species (ROS). A multipotent NSC line, B2A1 cells, was established from long-term primary cultures of oligodendrocyte-enriched cells from an adult BALB/c mouse brain. B2A1 cells could be differentiated into neuronal, astrocytic and oligodendroglial lineages. The cells also expressed genotypic mRNA messages for both neural progenitor cells and differentiated neuronoglial cells. B2A1 cells treated with hydrogen peroxide and L-buthionine-(S,R)-sulfoximine underwent 30-40% cell death, while B2A1 cells treated with glutamate and kainate showed 25-35% cell death. Cytopathologic changes consisting of swollen cell bodies, loss of cytoplasmic processes, and nuclear chromatin disintegration, developed after exposure to both ROS and excitotoxic chemicals. These results suggest that B2A1 cells may be useful in the study of NSC biology and may constitute an effective neurotoxicity screening system for ROS and excitotoxic chemicals

Neural progenitor cells from an adult patient with fragile X syndrome

BACKGROUND: Currently, there is no adequate animal model to study the detailed molecular biochemistry of fragile X syndrome, the leading heritable form of mental impairment. In this study, we sought to establish the use of immature neural cells derived from adult tissues as a novel model of fragile X syndrome that could be used to more fully understand the pathology of this neurogenetic disease. METHODS: By modifying published methods for the harvest of neural progenitor cells from the post-mortem human brain, neural cells were successfully harvested and grown from post-mortem brain tissue of a 25-year-old adult male with fragile X syndrome, and from brain tissue of a patient with no neurological disease. RESULTS: The cultured fragile X cells displayed many of the characteristics of neural progenitor cells, including nestin and CD133 expression, as well as the biochemical hallmarks of fragile X syndrome, including CGG repeat expansion and a lack of FMRP expression. CONCLUSION: The successful production of neural cells from an individual with fragile X syndrome opens a new avenue for the scientific study of the molecular basis of this disorder, as well as an approach for studying the efficacy of new therapeutic agents

Neurogenesis in the chronic lesions of multiple sclerosis

Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains

Cell Lineage and Regional Identity of Cultured Spinal Cord Neural Stem Cells and Comparison to Brain-Derived Neural Stem Cells

Neural stem cells (NSCs) can be isolated from different regions of the central nervous system. There has been controversy whether regional differences amongst stem and progenitor cells are cell intrinsic and whether these differences are maintained during expansion in culture. The identification of inherent regional differences has important implications for the use of these cells in neural repair. Here, we compared NSCs derived from the spinal cord and embryonic cortex. We found that while cultured cortical and spinal cord derived NSCs respond similarly to mitogens and are equally neuronogenic, they retain and maintain through multiple passages gene expression patterns indicative of the region from which they were isolated (e.g Emx2 and HoxD10). Further microarray analysis identified 229 genes that were differentially expressed between cortical and spinal cord derived neurospheres, including many Hox genes, Nuclear receptors, Irx3, Pace4, Lhx2, Emx2 and Ntrk2. NSCs in the cortex express LeX. However, in the embryonic spinal cord there are two lineally related populations of NSCs: one that expresses LeX and one that does not. The LeX negative population contains few markers of regional identity but is able to generate LeX expressing NSCs that express markers of regional identity. LeX positive cells do not give rise to LeX-negative NSCs. These results demonstrate that while both embryonic cortical and spinal cord NSCs have similar self-renewal properties and multipotency, they retain aspects of regional identity, even when passaged long-term in vitro. Furthermore, there is a population of a LeX negative NSC that is present in neurospheres derived from the embryonic spinal cord but not the cortex

Genetic Modifier Screens Reveal New Components that Interact with the Drosophila Dystroglycan-Dystrophin Complex

The Dystroglycan-Dystrophin (Dg-Dys) complex has a capacity to transmit information from the extracellular matrix to the cytoskeleton inside the cell. It is proposed that this interaction is under tight regulation; however the signaling/regulatory components of Dg-Dys complex remain elusive. Understanding the regulation of the complex is critical since defects in this complex cause muscular dystrophy in humans. To reveal new regulators of the Dg-Dys complex, we used a model organism Drosophila melanogaster and performed genetic interaction screens to identify modifiers of Dg and Dys mutants in Drosophila wing veins. These mutant screens revealed that the Dg-Dys complex interacts with genes involved in muscle function and components of Notch, TGF-β and EGFR signaling pathways. In addition, components of pathways that are required for cellular and/or axonal migration through cytoskeletal regulation, such as Semaphorin-Plexin, Frazzled-Netrin and Slit-Robo pathways show interactions with Dys and/or Dg. These data suggest that the Dg-Dys complex and the other pathways regulating extracellular information transfer to the cytoskeletal dynamics are more intercalated than previously thought

Neural Stem/Progenitor Cells from the Adult Human Spinal Cord Are Multipotent and Self-Renewing and Differentiate after Transplantation

Neural stem/progenitor cell (NSPC) transplantation is a promising therapy for spinal cord injury (SCI). However, little is known about NSPC from the adult human spinal cord as a donor source. We demonstrate for the first time that multipotent and self-renewing NSPC can be cultured, passaged and transplanted from the adult human spinal cord of organ transplant donors. Adult human spinal cord NSPC require an adherent substrate for selection and expansion in EGF (epidermal growth factor) and FGF2 (fibroblast growth factor) enriched medium. NSPC as an adherent monolayer can be passaged for at least 9 months and form neurospheres when plated in suspension culture. In EGF/FGF2 culture, NSPC proliferate and primarily express nestin and Sox2, and low levels of markers for differentiating cells. Leukemia inhibitory factor (LIF) promotes NSPC proliferation and significantly enhances GFAP expression in hypoxia. In differentiating conditions in the presence of serum, these NSPC show multipotentiality, expressing markers of neurons, astrocytes, and oligodendrocytes. Dibutyryl cyclic AMP (dbcAMP) significantly enhances neuronal differentiation. We transplanted the multipotent NSPC into SCI rats and show that the xenografts survive, are post-mitotic, and retain the capacity to differentiate into neurons and glia

Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia

Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2BIntron5, at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2BIntron5. In Rab8 mutant synapses, c-Jun N-terminal kinase (JNK)/activator protein-1 and TGF-β signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes