SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain

• DOI: 10.1016/j.stemcr.2015.03.006
• Publication Date: 2015-04-25T18:38:05Z
• Authors: Wenze Niu; Tong Zang; Derek K. Smith; Tou Yia Vue; Yuhua Zou; Robert Bachoo; Jane E. Johnson; Chun-Li Zhang
• Keywords: Neurons; 0301 basic medicine; Medicine (General); Doublecortin Protein; Patch-Clamp Techniques; QH301-705.5; SOXB1 Transcription Factors; Brain; Cellular Reprogramming; Immunohistochemistry; Article; 3. Good health; Mice; 03 medical and health sciences; R5-920; Neural Stem Cells; Interneurons; Astrocytes; Calbindin 2; Basic Helix-Loop-Helix Transcription Factors; Animals; Biology (General)

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.