Distinct signals that guide migration of mesenchymal stem cells (MSCs) to specific in vivo targets remain unknown. We have used rat MSCs to investigate the molecular mechanisms involved in such migration. Rat MSCs were shown to migrate to tumor microenvironment in vivo, and an in vitro migration assay was used under defined conditions to permit further mechanistic investigations. We hypothesized that distinct molecular signals are involved in the homing of MSCs to tumor sites and bone marrow. To test this hypothesis, gene expression profiles of MSCs exposed in vitro to conditioned medium (CM) from either tumor cells or bone marrow were compared. Analysis of the microarray gene expression data revealed that 104 transcripts were upregulated in rat MSCs exposed to CM from C85 human colorectal cancer cells for 24 hours versus control medium. A subset of 12 transcripts were found to be upregulated in rat MSCs that were exposed to tumor cell CM but downregulated when MSCs were exposed to bone marrow CM and included CXCL-12 (stromal cell-derived factor-1 [SDF-1]), CXCL-2, CINC-2, endothelial cell specific molecule-1, fibroblast growth factor-7, nuclear factor-B p105, and thrombomodulin. Exposure to tumor cell CM enhanced migration of MSCs and correlated with increased SDF-1 protein production. Moreover, knockdown of SDF-1 expression in MSCs inhibited migration of these cells to CM from tumor cells, but not bone marrow cells, confirming the importance of SDF-1 expression by MSCs in this differential migration. These results suggest that increased SDF-1 production by MSCs acts in an autocrine manner and is required for migratory responses to tumor cells. STEM CELLS 2007;25:520 -528
J. Neurochem. (2008) 104, 1494–1503. Abstract Reduced derivatives of folic acid (folates) play a critical role in the development, function and repair of the CNS. However, the molecular systems regulating folate uptake and homeostasis in the central nervous system remain incompletely defined. Choroid plexus epithelial cells express high levels of folate receptor α (FRα) suggesting that the choroid plays an important role in CNS folate trafficking and maintenance of CSF folate levels. We have characterized 5‐methyltetrahydrofolate (5‐MTHF) uptake and metabolism by primary rat choroid plexus epithelial cells in vitro. Two distinct processes are apparent; one that is FRα dependent and one that is independent of the receptor. FRα binds 5‐MTHF with high affinity and facilitates efficient uptake of 5‐MTHF at low extracellular folate concentrations; a lower affinity FRα independent system accounts for increased folate uptake at higher concentrations. Cellular metabolism of 5‐MTHF depends on the route of folate entry into the cell. 5‐MTHF taken up via a non‐FRα ‐mediated process is rapidly metabolized to folylpolyglutamates, whereas 5‐MTHF that accumulates via FRα remains non‐metabolized, supporting the hypothesis that FRα may be part of a pathway for transcellular movement of the vitamin. The proton‐coupled folate transporter, proton‐coupled folate transporter (PCFT), mRNA was also shown to be expressed in choroid plexus epithelial cells. This is consistent with the role we have proposed for proton‐coupled folate transporter in FRα‐mediated transport as the mechanism of export of folates from the endocytic compartment containing FRα.
Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.
Schizophrenia is a widely prevalent neuropsychiatric disorder of unknown etiology. The most widely accepted neurochemical model of schizophrenia, the dopamine model, proposes that schizophrenia is associated with functional hyperactivity of brain dopaminergic systems (Stein and Wise 1971;Davis et al. 1991;Jentsch and Roth 1999). This model is supported by the observations that amphetamine and other dopaminergic agents induce psychotic symptoms that closely resemble those of schizophrenia and that currently available antipsychotic agents function primarily by blocking dopamine (D2) receptors. Mechanisms underlying dopamine dysfunction in schizophrenia, however, remain obscure.Over the past decade, increasing attention has been paid to alternative neurochemical conceptualizations of schizophrenia based upon the phencyclidine/ N -methyl-D -aspartate (PCP/NMDA) model (Javitt 1987;Javitt and Zukin 1991). This hypothesis is based upon the observation that PCP and other dissociative anesthetictype psychotomimetics (e.g., ketamine, MK-801) induce symptoms that closely resemble those of schizophrenia but differ somewhat from the symptoms induced by amphetamine (Luby et al. 1959(Luby et al. , 1962Domino and Luby 1981 Javitt and Zukin 1991;Olney and Farber 1995;Newcomer et al. 1999;Jentsch and Roth 1999).The present study investigates the degree to which continuous treatment with PCP leads to schizophrenialike disturbances in dopamine regulation. This issue has been complicated until recently by the relative paucity of information concerning endogenous dopamine levels in schizophrenia. Over the past several years, however, several studies using in vivo radioreceptor label studies have demonstrated significant striatal hyperreactivity to amphetamine-stimulated dopamine release in schizophrenia (Laruelle et al. 1996(Laruelle et al. , 1999Breier et al. 1997;Abi-Dargham et al. 1998). Enhanced striatal dopamine levels were also observed following ketamine administration in normal volunteers (Breier et al. 1998), supporting a potential role for NMDA receptors in dopamine hyperactivity in schizophrenia. Similar effects of acute administration of NMDA antagonists are observed in rodents (Hiramatsu et al. 1989;Lillrank et al. 1994;Yonezawa et al. 1995).Given that schizophrenia is a chronic condition potentially arising from persistent dysfunction of NMDA receptor-mediated neurotransmission, continuous PCP administration provides a superior dosing paradigm than does acute administration (Sams-Dodd 1999;Jentsch et al. 1998). Further, continuous administration permits amphetamine-induced effects to be measured against a constant background PCP level. For the present study, rats were treated chronically with PCP, and dopamine response to amphetamine was measured in striatum using in vivo microdialysis to investigate the degree to which continuous PCP treatment leads to enhanced responsiveness to amphetamine challenge. PCP was administered by osmotic minipump to maintain as constant a level of PCP as possible, in order to model a persis...
Subpopulations of bone marrow-derived cells can be induced to assume a number of endothelial properties in vitro. However, their ability to form a functional vascular barrier has not been demonstrated. We report that human CD14 ؉ peripheral blood monocytes cultured under angiogenic conditions develop a number of phenotypic and functional properties similar to brain microvascular endothelial cells. These cells express the tight junction proteins zonula occludens 1 (ZO-1) and occludin and form a barrier with a transcellular electrical resistance (TCER) greater than 100 ohm cm 2 and low permeability to 4 kDa and 20 kDa dextrans. The TCER of the cellular barrier is decreased by bradykinin and histamine.We also demonstrate that these cells associate with repairing vasculature in areas of brain and skin injury. Our data suggest that CD14 ؉ peripheral blood monocytes participate in the repair of the vascular barrier after brain injury. (Blood. 2006;107:940-946)
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