Dynamics of neural stem cell-mediated neuroprotection in the presence of oxidative stress: studies in vitro and in vivo
The interaction of transplanted neural stem cells (NSCs) with the diseased CNS environment can stimulate protection/regeneration of host cells exposed to oxidative stress. To better understand the cellular and molecular principles involved, we first assessed cell survival and levels of reactive oxygen species (ROS) in NSCs and post-mitotic neural progenitors (PNPs) at steady-state and under 3-nitropropionic acid (3-NP)-induced oxidative stress. Subsequently, we studied the interaction between NSCs and their microenvironment in vitro (co-cultures of NSCs and primary striatal cells) and in vivo (NSC-transplanted mice), again under 3-NP insult. In the first segment of our studies, comparing NSCs and the more mature PNPs, we found that NSCs were marked by greater basal mitochondrial activity, lower intracellular ROS levels, and higher expression of key antioxidant enzymes. Further, while 3-NP exposure induced oxidative stress and cell death in PNPs, NSCs survived due to stronger up-regulation of their antioxidant activity. In the second segment of our studies which examined NSC interactions with its microenvironment, both in vitro and in vivo, the presence of NSCs before intoxication decreased free radical production and improved cell survival. In the grafted animals, this resulted in reduced behavioral symptoms, less vascular damage, and prevention of striatal cell loss in comparison to vehicle-injected controls. Intriguingly, during this process of neuroprotection, NSCs were found to rely in their "protective" function on the assistance of bystander cells like the primary or host glial and endothelial cells. Only the resulting network of NSCs, astrocytes, and endothelial cells allowed an up-regulation and secretion of neuroprotective factors high enough to induce antioxidant defense mechanisms that could create the necessary milieu for the observed neuroprotection. In summary, the present dissertation identifies two important characteristics of NSCs not understood before, namely (1) their innate alertness to oxidative stress, and (2) their ability to interact with and induce plastic responses from host cells. These NSC properties, allows them to not only survive in a hostile CNS environment, but also empowers them to protect the host from the arriving impact of oxidative stress.