A tissue-engineered rostral migratory stream for directed neuronal replacement

New neurons are integrated into the circuitry of the olfactory bulb throughout the lifespan in the mamma- lian brain--including in humans. These new neurons are born in the subventricular zone and subsequently mature as they are guided over long distances via the rostral migratory stream through mechanisms we are only just beginning to understand. Regeneration after brain injury is very limited, and although some neuroblasts from the rostral migratory stream will leave the path and migrate toward cortical lesion sites, this neuronal replacement is generally not sustained and therefore does not provide enough new neurons to alleviate functional deficits. Using newly discovered microtissue engineering techniques, we have built the first self-contained, implantable constructs that mimic the architecture and function of the rostral migratory stream. This engineered microtissue emulates the dense cord-like bundles of astrocytic somata and processes that are the hallmark anatomical feature of the glial tube. As such, our living microtissue-en- gineered rostral migratory stream can serve as an in vitro test bed for unlocking the secrets of neuroblast migration and maturation, and may potentially serve as a living transplantable construct derived from a patient＇s own cells that can redirect their own neuroblasts into lesion sites for sustained neuronal replace- ment following brain injury or neurodegenerative disease. In this paper, we summarize the development of fabrication methods for this microtissue-engineered rostral migratory stream and provide proof-of-princi- ple evidence that it promotes and directs migration of immature neurons.

Neurogenesis in the adult olfactory bulb

Neurogenesis is the process by which cells divide, migrate, and subsequently differentiate into a neuronal phenotype. Significant rates of neurogenesis persist into adulthood in two brain regions, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricles. Cells of the subventricular zone divide and migrate via the rostral migratory stream to the olfactory bulb where they differentiate into granule and pefiglomerular cells. With the discovery of large-sca^e neurogenesis in the adult brain, there have been significant efforts to identify the mechanisms that control this process as well as the role of these cells in neuronal functioning. Although many questions remain unanswered, new insights appear daily about adult neurogenesis, regulatory mechanisms, and the fates of the progeny. In this review we highlight the main studies investigating factors that regulate neurogenesis in the subventricular zone, neuronal migration to the olfactory bulb, neuronal integration into the existing bulbar network and shortly discuss the functional meaning of this process.