A tissue-engineered rostral migratory stream for directed neuronal replacement

Abstract

New neurons are integrated into the circuitry of the olfactory bulb throughout the lifespan in the mammalian 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-engineered 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 replacement 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-principle evidence that it promotes and directs migration of immature neurons.

Keywords

• rostral migratory stream; glial tube; astrocyte; neuroblast; brain injury; neural repair; neural regeneration; tissue engineering