SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain

Summary

Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1 ⁺ neural progenitors and DCX ⁺ adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin ⁺ interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine.

Graphical Abstract

Highlights

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  SOX2 induces ASCL1-positive neural progenitors in the adult mouse brain

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  Ascl1 in resident astrocytes is required for SOX2-mediated in vivo reprogramming

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  Induced ASCL1-positive neural progenitors generate mature calretinin neurons

Abstract

In this article, Zhang and colleagues reveal that SOX2-mediated in vivo reprogramming of adult astrocytes transits through ASCL1-positive neural progenitors. These progenitors further generate DCX-positive neuroblasts and functionally mature neurons in the adult mouse striatum. This stepwise and expandable in vivo reprogramming process may be exploited for neural regeneration by using resident glial cells.