The recruitment of alkaline phosphatase-positive endogenous neural stem cells enables robust neurogenesis and neural pathways reconstruction following spinal cord injury

Transected spinal cord injury (SCI) results in significant structural disruption of the spinal cord. The reconstruction of neural pathways following SCI faces several key challenges, including inadequate endogenous neural stem cells (NSCs) and poor neurogenesis in natural repair process, and concerns related to the long-term survival of neurons following allogeneic transplantation. In the present study, we report a strategy using an oligonucleotide aptamer drug (Apt19S) for the first time following SCI, to recruit alkaline phosphatase positive (ALPL + ) endogenous NSCs with robust proliferation and neuronal differentiation abilities to the injury site. To further counteract the inhibitory microenvironment in spinal cord, we constructed a central nervous system (CNS) extracellular matrix rich in neurotrophin-3 to simulate the development stage and promote endogenous neurogenesis. This strategy effectively recruited a significant number of ALPL + endogenous NSCs, established a neurogenic niche that facilitated vigorous neuronal differentiation and neuronal relay formation. Regenerated nerve fibers including 5-hydroxytryptamine-positive nerve fibers and corticospinal tract grew robustly into the injury site and generated synaptic connections with the excitatory newborn neurons. Collectively, our findings indicate that the recruitment of ALPL + NSCs into a developmental CNS microenvironment elicits a vigorous neurogenesis process in situ , breaking the limitations imposed by poor self-repair ability in the adult spinal cord.