The Key to Spinal Cord Recovery: Harnessing p21 Inhibition to Boost Neural Stem/Progenitor Cell Proliferation

Spinal cord injury (SCI) is a devastating traumatic condition
of
the central nervous system (CNS), usually resulting in irreversible
motor and sensory deficits that severely compromise patients’
quality of life. Harnessing the untapped potential of endogenous neural
stem/progenitor cells (NSPCs) may yield revolutionary therapeutic
techniques for overcoming the limited NSPC proliferative capacity
following SCI in adults. Single-cell sequencing results demonstrated
that the limited proliferative capacity of NSPCs after SCI is associated
with the upregulation of the p21. Herein, we developed a cationic
liposome-based delivery system encapsulating p21 small interfering
RNA (P21siRNA@LP) to
enhance NSPC proliferation following SCI. P21siRNA@LP significantly increased the primary
NSPC proliferation rate (145.4% on day 1 and 144.7% on day 3, respectively)
while maintaining differentiation capacity in vitro. Transcriptomic and functional characterization showed that P21siRNA@LP modulated the
expression of cyclin-dependent kinases in NSPCs, enhancing cell cycle
pathways (enrichment score: 0.6691) and proliferation, with extracellular
matrix reorganization (col1a1, col5a1) and gliogenesis (olig1/2) identified
as key regulation pathways. Gelatin hydrogels incorporating P21siRNA@LP promoted dense tissue
cable formation in T9 SCI rats, facilitating NSPC migration and proliferation
at lesion sites, which accelerated locomotor function recovery. These
findings emphasize cell cycle manipulation as a promising method to
spinal cord regeneration, providing a basis for future therapeutic
advances in CNS disorders.