Interaction of syntenin-1 and the NG2 proteoglycan in migratory oligodendrocyte precursor cells

Migration of oligodendrocyte precursors along axons is a necessary prerequisite for myelination, but little is known about underlying mechanisms. NG2 is a large membrane proteoglycan implicated in oligodendrocyte migration. Here we show that a PDZ domain protein termed syntenin-1 interacts with NG2 and that syntenin-1 is necessary for normal rates of migration. The association of syntenin-1 with NG2, identified in a yeast two-hybrid screen, was confirmed by colocalization of both proteins within processes of oligodendroglial precursor cells and by coimmunoprecipitation from cell extracts. Syntenin-1 also colocalizes with NG2 in "co-capping" assays, demonstrating a lateral association of both proteins in live oligodendrocytes. RNA interference-mediated down-regulation of syntenin-1 in glial cells results in a significant reduction of migration in vitro, as does the presence of polyclonal antibody against NG2. Thus syntenin plays a role in the migration of oligodendroglial precursors, and we suggest that NG2-syntenin-1 interactions contribute to this.     

Cannabinoids and brain injury: therapeutic implications

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.     

NG2 cells in the brain: a novel glial cell population.

There exists a significantly large population of glial cells in the mammalian central nervous system (CNS) that can be identified by the expression of the NG2 proteoglycan. Cells that express NG2 (NG2 cells) are found in the developing and mature CNS and are distinct from neurons, astrocytes, microglia, and mature oligodendrocytes. They are often referred to as oligodendrocyte progenitor cells because of their ability to differentiate into oligodendrocytes in culture. However, the observation that a large number of NG2 cells persist uniformly and ubiquitously in the adult CNS and display a differentiated morphology is not entirely consistent with the notion that NG2 cells are all oligodendrocyte progenitor cells. The role of NG2 cells in oligodendrocyte regeneration and their non-progenitor role in the mature CNS are discussed in this review.     

Evidence for NG2-glia Derived,Adult-Born Functional Neurons in the Hypothalamus

Accumulating evidence suggests that the adult murine hypothalamus, a control site of several fundamental homeostatic processes, has neurogenic capacity. Correspondingly, the adult hypothalamus exhibits considerable cell proliferation that is ongoing even in the absence of external stimuli, and some of the newborn cells have been shown to mature into cells that express neuronal fate markers. However, the identity and characteristics of proliferating cells within the hypothalamic parenchyma have yet to be thoroughly investigated. Here we show that a subset of NG2-glia distributed throughout the mediobasal hypothalamus are proliferative and express the stem cell marker Sox2. We tracked the constitutive differentiation of hypothalamic NG2-glia by employing genetic fate mapping based on inducible Cre recombinase expression under the control of the NG2 promoter, demonstrating that adult hypothalamic NG2-glia give rise to substantial numbers of APC+ oligodendrocytes and a smaller population of HuC/D+ or NeuN+ neurons. Labelling with the cell proliferation marker BrdU confirmed that some NG2-derived neurons have proliferated shortly before differentiation. Furthermore, patch-clamp electrophysiology revealed that some NG2-derived cells display an immature neuronal phenotype and appear to receive synaptic input indicative of their electrical integration in local hypothalamic circuits. Together, our studies show that hypothalamic NG2-glia are able to take on neuronal fates and mature into functional neurons, indicating that NG2-glia contribute to the neurogenic capacity of the adult hypothalamus.     

Neuroprotective adaptations in hibernation: therapeutic implications for ischemia-reperfusion, traumatic brain injury and neurodegenerative diseases

Brains of hibernating mammals are protected against a variety of insults that are detrimental to humans and other nonhibernating species. Such protection is associated with a number of physiological adaptations including hypothermia, increased antioxidant defense, metabolic arrest, leukocytopenia, immunosuppression, and hypocoagulation. It is intriguing that similar manipulations provide considerable protection as experimental treatments for central nervous system injury. This review focuses on neuroprotective mechanisms employed during hibernation that may offer novel approaches in the treatment of stroke, traumatic brain injury, and neurodegenerative diseases in humans.     

Brain histogenesis in vitro: Reconstruction of brain tissue from dissociated cells

Summary Comparative studies of the aggregative behavior of cells dissociated from different areas of embryonic chick and mouse brains show that each of the regionally differentiated lobes (cerebrum, optic tectum, and cerebellum), and the stem areas (diencephalon and medulla), form characteristic aggregates distinctive in size and shape. Bispecific co-aggregates are produced by commingling dissociated mouse cerebrum cells with chick cells from various brain regions, or from non-nervous tissues; the size of these co-aggregates and the extent of internal sorting out of cell types is closely related to the degree of homology between the interacting cell populations, e.g. co-aggregates of the closely homologous mouse and chick cerebral cell types contain homogeneous tissue fabrics of intermingled mouse and chick cells. Cell surface constituents involved in selective recognition and association of nerve cells were sought and cell-free supernatant preparations were obtained from short-term monolayer cultures of embryonic cerebrum cells (of either mouse or chick origin) which caused a striking, specific enhancement of aggregation of homologous cerebrum cells. These materials had no such effect on heterologous tissues tested: optic tectum, cerebellum, medulla, neural retina, liver, kidney or limb bud. These findings are discussed in relation to control mechanisms governing normal brain histogenesis and to the specificity of neural associations. This work was supported by United States Public Health Service research grant HD-01253 to Aron Moscona and by the Louis Block Fund of the University of Chicago.     

AN2, the mouse homologue of NG2, is a surface antigen on glial precursor cells implicated in control of cell migration

Molecular studies have demonstrated that the murine AN2 antigen is the mouse homologue of the rat NG2 and human MCSP protein. The molecule is a single-pass transmembrane protein which carries a variable number of glyco- and glycosaminoglycan chains according to cell type and developmental stage. AN2/NG2 has two extracellular Laminin G-like domains which are classically involved in cell adhesion and recognition. It possesses a single PDZ binding motif in the short intracellular tail. The AN2/NG2 antigen is expressed by glial progenitor cells in developing and adult CNS and also by immature Schwann cells. Antibodies against AN2/NG2 inhibit the migration of antigen-positive cells in in vitroassays, suggesting that the molecule plays a role in migration. Many AN2/NG2-positive cells surround synapses in the developing and adult brain. A recently identified intracellular partner of AN2/NG2 is the glutamate receptor interacting protein GRIP, which binds to the GluRB subunit of the AMPA subclass of glutamate receptors. The AN2/NG2 protein may position AMPA receptors on perisynaptic glial cells towards active synapses by binding to a neuronal receptor. Many highly migratory neural tumors including melanomas express AN2/NG2. In the demyelinating disease Multiple Sclerosis, some patients synthesise antibodies against the protein. Such antibodies may play a pathological role by inhibiting the migration of oligodendrocyte progenitor cells to demyelinated axons thus blocking remyelination, as well as possibly interfering with glial neuronal signalling at synapses and nodes of Ranvier.     

Identity, distribution, and development of polydendrocytes: NG2-expressing glial cells

Cells that express the NG2 proteoglycan (NG2+ cells) comprise a unique population of glial cells in the central nervous system. While there is no question that some NG2+ cells differentiate into oligodendrocytes during development, the persistence of numerous NG2+ cells in the mature CNS has raised questions about their identity, relation to other CNS cell types, and functions besides their progenitor role. NG2+ cells also express the alpha receptor for platelet-derived growth factor (PDGF αR), a receptor that mediates oligodendrocyte progenitor proliferation during development. Antigenically, NG2+ cells are distinct from fibrous and protoplasmic astrocytes, resting microglia, and mature oligodendrocytes. Therefore, we propose the term polydendrocytesto refer to all NG2-expressing glial cells in the CNS parenchyma. This distinguishes them from the classical glial cell types and identifies them as the fourth major glial population in the CNS. Recent observations suggest that polydendrocytes are complex cells that physically and functionally interact with other cell types in the CNS. Committed oligodendrocyte progenitor cells arise from restricted foci in the ventral ventricular zone in both spinal cord and brain. It remains to be clarified whether there are multiple sources of oligodendrocytes, and if so whether polydendrocytes (NG2+ cells) represent progenitor cells of all oligodendrocyte lineages. Proliferation of NG2+ cells during early development appears to be dependent on PDGF, but the regulatory mechanisms that govern NG2+ cell proliferation in the mature CNS remain unknown. Pulse-chase labeling with bromodeoxyuridine indicates that polydendrocytes that proliferate in the postnatal spinal cord differentiate into oligodendrocytes. Novel experimental approaches are being developed to further elucidate the functional properties and differentiation potential of polydendrocytes.     

Glioblastoma stem cells:Molecular characteristics and therapeutic implications

Glioblastoma Multiforme(GBM)is a grade IV astrocytoma,with a median survival of 14.6 mo.Within GBM,stem-like cells,namely glioblastoma stem cells(GSCs),have the ability to self-renew,differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models.More importantly,GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches.They are,therefore,very important therapeutic targets.Although the functional criteria defining GSCs are well defined,their molecular characteristics,the mechanisms whereby they establish the cellular hierarchy within tumors,and their contribution to tumor heterogeneity are not well understood.This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view.A better characterization of GSCs is crucial for designing effective GSCtargeted therapies.     

Calponin control of cerebrovascular reactivity: therapeutic implications in brain trauma

Calponin (Cp) is an actin-binding protein first characterized in chicken gizzard smooth muscle (SM). This review discusses the role of Cp in mediating SM contraction, the biochemical process by which Cp facilitates SM contraction and the function of Cp in the brain. Recent work on the role of Cp in pathological states with emphasis on traumatic brain injury is also discussed. Based on past and present data, the case is presented for targeting Cp for novel genetic and pharmacological therapies aimed at improving outcome following traumatic brain injury (TBI).     

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

Dendritic cells (DC) are essential for the development and regulation of adaptive host immune responses against tumors. DC are heterogeneous and comprised of diverse cellular subsets. They are best known for mediating a crucial role in the initiation of acquired immunity by serving as professional antigen presenting cells (APC) that take up antigens in their local microenvironment, which are then processed and presented to na?ve T cells in the context of major histocompatibility complex (MHC) class I and II molecules. In addition to these functions, DC can modulate the types of T cell responses they generate, and can also influence the responses of innate effectors, such as NK cells. There is also now evidence that they may mediate a more primordial role as innate, effector cells that are tumoricidal. 'Killer' DC (KDC) may represent a true 'multi-tasking' cell type that can sequentially act as a 'hunter-gatherer' of antigens; as well as, an instructor, then enforcer/regulator, of antigen-specific anti-tumor T-cell responses in vivo. In this review, we will critically examine the published record regarding KDC, their mechanism(s) of action, and then consider the potential integration of KDC into novel immunotherapies for patients with cancer.     

Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions

Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.     

Adult neurogenesis in the crayfish brain: Proliferation,migration, and possible origin of precursor cells

The birth of new neurons and their incorporation into functional circuits in the adult brain is a characteristic of many vertebrate and invertebrate organisms, including decapod crustaceans. Precursor cells maintaining life‐long proliferation in the brains of crayfish (Procambarus clarkii, Cherax destructor) and clawed lobsters (Homarus americanus) reside within a specialized niche on the ventral surface of the brain; their daughters migrate to two proliferation zones along a stream formed by processes of the niche precursors. Here they divide again, finally producing interneurons in the olfactory pathway. The present studies in P. clarkii explore (1) differential proliferative activity among the niche precursor cells with growth and aging, (2) morphological characteristics of cells in the niche and migratory streams, and (3) aspects of the cell cycle in this lineage. Morphologically symmetrical divisions of neuronal precursor cells were observed in the niche near where the migratory streams emerge, as well as in the streams and proliferation zones. The nuclei of migrating cells elongate and undergo shape changes consistent with nucleokinetic movement. LIS1, a highly conserved dynein‐binding protein, is expressed in cells in the migratory stream and neurogenic niche, implicating this protein in the translocation of crustacean brain neuronal precursor cells. Symmetrical divisions of the niche precursors and migration of both daughters raised the question of how the niche precursor pool is replenished. We present here preliminary evidence for an association between vascular cells and the niche precursors, which may relate to the life‐long growth and maintenance of the crustacean neurogenic niche. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009     

Functional heterogeneity of mesenchymal stem cells: implications for cell therapy

The term mesenchymal stem cell (MSCs) was adopted in the 1990s to describe a population of bone-marrow-derived cells that demonstrated the capacity for tri-lineage differentiation at a clonal level. Research conducted during the ensuing decades has demonstrated that MSCs fulfill many functions in addition to connective tissue progenitors including contributing to the HSC niche and regulating the function of immune effector cells of both the innate and adaptive immune system. Despite these advances, fundamental aspects of MSC biology remain indeterminate. For example, the embryonic origin of MSCs and their niche in vivo remains a highly debated topic. More importantly, the mechanisms that regulate self-renewal and lineage specification have also been largely unexplored. The later is significant in that MSC population's exhibit considerable donor-to-donor and intra-population heterogeneity but knowledge regarding how different functional attributes of MSCs are specified at the population level is unknown. This poses significant obstacles in research and in efforts to develop clinical manufacturing protocols that reproducibly generate functionally equivalent MSC populations. Herein, I discuss data demonstrating that MSC populations are intrinsically heterogeneous, elaborate on the molecular basis for this heterogeneity, and discuss how heterogeneity impacts clinical manufacturing and the therapeutic potency of MSCs.