NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

Abstract

Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury.spinal cord injury | NT3 | chitosan | functional recovery | endogenous neurogenesis

Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury

“…Taken together, our data from transcriptome WGCNA indicated that NT3-chitosan served primarily to enhance vascularization and suppress inflammatory immune responses, establishing an optimal microenvironment to support endogenous NSCs to differentiate into new neurons, which subsequently formed nascent local neural networks to participate in regeneration after SCI (15).…”

“…Moreover, these analyses revealed that a failure in generating new neurons from endogenous NSCs, due to the harsh inflammatory environment, could be a major obstacle to proper regeneration and functional recovery after SCI (15). One underlying premise for WGCNA is that genes functioning together are regulated together.…”

“…Numerous NF + cells were present in the NT3-chitosan tube, suggesting the addition of new neuronal components in the biomaterial, consistent with the transcriptome analyses. More detailed analyses were described in same issue (15), addressing the role of NT3-chitosan in the promotion of new neurogenesis, formation of a nascent local neural network, and subsequent connection to ascending and descending nerve fibers, leading to functional recovery.…”

Harness the power of endogenous neural stem cells by biomaterials to treat spinal cord injury

“…In the first study by Yang et al [2], the authors applied an innovative chitosan-NT3 biomaterial which not only bridged the transected spinal cord, but also released NT3 slowly to provide a favorable microenvironment for NSC activation and migration. They transected and extracted a 5 mm spinal cord segment at T7/8, filled the gap immediately after the injury with NT3-chitosan, and followed up the recovery at different stages after the injury (from 30 days up to 1 year).…”

“…As a whole, the two studies by the Li and Sun groups report promising results suggesting that the slow release of a neurotrophin (NT3) by a biomaterial (chitosan) can be effective in promoting physiological repair processes in SCI and in dampening the deleterious effects secondary to the progression of chronic neuro-inflammation [2]. Moreover, using WGCNA, the authors established a gene-module analysis approach corresponding to various pathological events at different times after SCI, which provides mechanistic clues to potentially more effective treatments for SCI [3].…”