Osteogenic stimulatory conditions enhance growth and maturation of endothelial cell microvascular networks in culture with mesenchymal stem cells

To optimize culture conditions for in vitro prevascularization of tissue-engineered bone constructs, the development of organotypic blood vessels under osteogenic stimulatory conditions (OM) was investigated. Coculture of endothelial cells and mesenchymal stem cells was used to assess proangiogenic effects of mesenchymal stem cells on endothelial cells. Four different culture conditions were evaluated for their effect on development of microvascular endothelial cell networks. Mineralization, deposition of extracellular matrix, and perivascular gene expression were studied in OM. After 3 days, endothelial cells established elongated capillary-like networks, and upregulated expression of vascular markers was seen. After 15 days, all parameters evaluated were significantly increased for cultures in OM. Mature networks developed in OM presented lumens enveloped by basement membrane-like collagen IV, with obvious mineralization and upregulated perivascular gene expression from mesenchymal stem cells. Our results suggest osteogenic stimulatory conditions to be appropriate for in vitro development of vascularized bone implants for tissue engineering

Neurobiological Mechanisms That Contribute to Stress-related Cocaine Use

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress-induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake-dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a “stage setter” for drug use – increasing sensitivity to cocaine and drug-associated cues – under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven