Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain

Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is associated with recovery after stroke, we investigated the ability of transplanted human neural progenitor cells to enhance this structural plasticity. Our results show the first evidence that human neural progenitor cell treatment can significantly increase dendritic plasticity in both the ipsi- and contralesional cortex and this coincides with stem cell-induced functional recovery. Moreover, stem cell-grafted rats demonstrated increased corticocortical, corticostriatal, corticothalamic and corticospinal axonal rewiring from the contralesional side; with the transcallosal and corticospinal axonal sprouting correlating with functional recovery. Furthermore, we demonstrate that axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment, thus identifying another novel potential mechanism of action of transplanted cells. Finally, we established in vitro co-culture assays in which these stem cells mimicked the effects observed in vivo. Through immunodepletion studies, we identified vascular endothelial growth factor, thrombospondins 1 and 2, and slit as mediators partially responsible for stem cell-induced effects on dendritic sprouting, axonal plasticity and axonal transport in vitro. Thus, we postulate that human neural progenitor cells aid recovery after stroke through secretion of factors that enhance brain repair and plasticity

Manipulation of dendritic cells for cancer immunotherapy circumventing VEGF inhibition

Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.The American Cancer Society predicts 1,638,910 new cancer cases during 2012. 577,190 of these cases will result in death, a rate of 35.2%. The high death rate coupled with the adverse side effects and reduced quality of life that result from traditional cancer therapies highlight the importance of searching for more effective and tolerable treatments. Under most conditions, foreign invaders are recognized by antigen presenting cells (APCs) including dendritic cells (DCs) that initiate an immune response to remove the threat. However, tumor cells are not foreign invaders, but rather arise from host cells. Tumors are able to use their origin as a means to evade an immune response by taking advantage of the immune system's self-tolerance. Other escape mechanisms include release of inhibitory factors by tumor cells such as vascular endothelial growth factor (VEGF). VEGF affects the activation of NF-kB signaling required for the maturation of DCs, rendering DCs unable to stimulate cytotoxic T cells to target and kill tumor cells. Despite these complications, DCs are remain the most potent APC and are uniquely capable of promoting T cell activation and differentiation into effector cells. These qualities make DCs ideal candidates for cancer immunotherapy in clinical studies. Current DC-based cancer immunotherapy loading ex vivo or in vitro generated DCs with tumor antigens from a various sources. Ex vivo or in vitro manipulation enables researchers to control the quality and maturation of DCs to help circumvent the effects of VEGF, and thereby significantly increase the ability of DCs to present and activate T cells. This review aims to explore the mechanism by which VEGF inhibits natural DC function to better understand the necessary adjustments to make in ex vivo/in vitro manipulation. Additionally, we will present various methods of DC therapy as well as the results of successful clinical trials in order to suggest which of these methods may be the most effective and the focus of future studies