graduate student Sun Yat-sen University 广州, Guangdong, China (People's Republic)
Abstract: Stem cell neurogenic differentiation is crucial for physiological and pathological process of nervous system, but the underlying mechanisms regulating differentiation are elusive. The neurogenetic cells undergo dramatic cellular morphological changes. However, the specific mechanisms regulating these cellular architecture remodeling and how it contribute to neurogenic differentiation are unclear. Here, we showed that neuro-differentiated stem cells displayed apoptosis-like features, including cell membrane changes, nuclear morphology alterations, and heterochromatin accumulation. RNA sequencing of these neuro-differentiated cells revealed an early apoptotic profile, confirmed by the expression of various apoptotic proteins such as activated Caspase 3, increased levels of Bcl-2, and decreased expression of GSDMD. Conversely, proteins associated with neural differentiation increased following sub-apoptotic stimulation, which accelerated neural differentiation. Inhibition of Caspase 3 resulted in decreased neural differentiation of the stem cells, whereas the knockdown and knockout of GSDMD led to enhanced neural differentiation. Notably, caspase 3-/- mice exhibited lower behavioral activity, while gsdmd-/- mice demonstrated increased behavioral activity. Mechanistically, we showed that nuclear remodeling was detected in both apoptotic cells and Neuro-differentiated stem cells, and the enhanced heterochromatin accumulation and increased H3K9me3 expression are responsible for Caspase3 and GSDMD-mediated neurogenic differentiation. Therefore, injection of siGSDMD plasmid supply with sub-apoptotic induction in the hippocampus notably improved the cognitive impairment of aging mice. This study reveals a previous unrecognized sub-apoptotic state that controls the neurogenic differentiation of stem cells and provides potential targets for developing therapeutic approaches of neurodegenerative diseases.
