Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro, Adeno-associated virus serotype two overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo, targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy. NT-3 enhanced sprouting and synaptic formation of descending serotonergic, dopaminergic, and propriospinal axons on lumbar MNs, parallel to improved behavioral recovery. Thus, retrogradely transported NT-3 stimulated remodeling of lumbar neural circuitry and synaptic connectivity remote to a thoracic SCI, supporting a role for retrograde transport of NT-3 as a potential therapeutic strategy for SCI.

The benefits of transplanting cultured Schwann cells (SCs) for the treatment of spinal cord injury (SCI) have been systematically investigated in experimental animals since the early 1990s. Importantly, human SC (hSC) transplantation for SCI has advanced to clinical testing and safety has been established via clinical trials conducted in the USA and abroad. However, multiple barriers must be overcome to enable accessible and effective treatments for SCI patients. This review presents available information on hSC transplantation for SCI with the intention to uncover gaps in our knowledge and discuss areas for future development. To this end, we introduce the historical progression of the work that supports existing and prospective clinical initiatives and explain the reasons for the choice of hSCs while also addressing their limitations as cell therapy products. A search of the relevant literature revealed that rat SCs have served as a preclinical model of reference since the onset of investigations, and that hSC transplants are relatively understudied, possibly due to the sophisticated resources and expertise needed for the traditional processing of hSC cultures from human nerves. In turn, we reason that additional experimentation and a reexamination of the available data are needed to understand the therapeutic value of hSC transplants taking into consideration that the manufacturing of the hSCs themselves may require further development for extended uses in basic research and clinical settings.

DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7.In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced.In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.

Spinal cord injury (SCI) starts with a mechanical and/or bio-chemical insult, followed by a secondary phase, leading progressively to severe collapse of the nerve tissue. Compared to the peripheral nervous system, injured spinal cord is characterized by weak axonal regeneration, which leaves most patients impaired or paralyzed throughout lifetime. Therefore, confining, alleviating, or reducing the expansion of secondary injuries and promoting functional connections between rostral and caudal regions of lesion are the main goals of SCI therapy. Interleukin 10 (IL-10), as a pivotal anti-inflammatory and immunomodulatory cytokine, exerts a wide spectrum of positive effects in the treatment of SCI. The mechanisms underlying therapeutic effects mainly include anti-oxidative stress, limiting excessive inflammation, anti-apoptosis, antinociceptive effects, etc. Furthermore, IL-10 displays synergistic effects when combined with cell transplantation or neurotrophic factor, enhancing treatment outcomes. This review lists pleiotropic mechanisms underlying IL-10-mediated neuroprotection after SCI, which may offer fresh perspectives for clinical translation.