The regenerative potential of adult Nestin+ cerebellar astroglia is limited compared to in neonates

Abstract

There is a crucial need for strategies that stimulate repair in the adult brain. The neonatal mouse cerebellum can regenerate via the adaptive reprogramming of nestin (Nes)-expressing progenitors (NEPs). However, analysis of Nes+ cells of the adult cerebellum is limited. Using reporter lines and genetic inducible fate mapping, we show that adult Nes+ cells are mainly Bergmann glia (Nes+ Bg) that have in vitro sphere-forming ability. Following injury, Nes+ Bg increase in number due to upregulation of Nes in Hopx-expressing Bg, but the cells exhibit limited regeneration. ATAC-seq of Nes+ Bg reveals that silencing of developmental genes compared to neonatal NEPs contributes to the impaired regeneration. Activating sonic hedgehog signalling augments the number of Nes+ Bg after injury but not neurogenesis, showing additional cues are required. Our results demonstrate an age-dependent decline in the regenerative potential of NEPs and highlight Nes+ Bg as potential injury-responsive cells that could facilitate regeneration.