Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons

Christophe Heinrich,Benedikt Berninger,Steffen Tiedt,Rodrigo Sánchez,Sergio Gascón,Timm Schroeder,Magdalena Götz,Giacomo Masserdotti,Pratibha Tripathi,Robert Blum

doi:10.1371/journal.pbio.1000373

Abstract

Author SummaryThe brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease.

Highlights

While exerting diverse functions within the brain parenchyma [1], astroglia are remarkable in that they function as neural stem or progenitor cells in specific regions of the postnatal and adult brain [2], such as the ventricular subependymal zone [3] and the subgranular zone of the hippocampus [4,5]
Evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue
We show that nonneurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons

Summary

Introduction

While exerting diverse functions within the brain parenchyma [1], astroglia are remarkable in that they function as neural stem or progenitor cells in specific regions of the postnatal and adult brain [2], such as the ventricular subependymal zone [3] and the subgranular zone of the hippocampus [4,5]. We could previously show that astroglia from the early postnatal cerebral cortex can be reprogrammed in vitro towards the generation of neurons capable of action potential (AP) firing by a single transcription factor, such as Pax or its target, the proneural transcription factor neurogenin-2 (Neurog2) [6,7]. These findings may open interesting avenues towards the potential activation of endogenous astroglia for neuronal repair of injured brain tissue

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