Abstract
Neural stem cell (NSC) grafts have demonstrated significant effects in animal models of spinal cord injury (SCI), yet their clinical translation remains challenging. Significant evidence suggests that the supporting matrix of NSC grafts has a crucial role in regulating NSC effects. Here we demonstrate that grafts based on porous collagen-based scaffolds (PCSs), similar to biomaterials utilized clinically in induced regeneration, can deliver and protect embryonic NSCs at SCI sites, leading to significant improvement in locomotion recovery in an experimental mouse SCI model, so that 12 weeks post-injury locomotion performance of implanted animals does not statistically differ from that of uninjured control animals. NSC-seeded PCS grafts can modulate key processes required to induce regeneration in SCI lesions including enhancing NSC neuronal differentiation and functional integration in vivo, enabling robust axonal elongation, and reducing astrogliosis. Our findings suggest that the efficacy and translational potential of emerging NSC-based SCI therapies could be enhanced by delivering NSC via scaffolds derived from well-characterized clinically proven PCS.
Highlights
Traumatic spinal cord injury (SCI) results in devastating disabilities that affect millions of patients worldwide
The present study demonstrates that grafts based on wellcharacterized PCS26,27, similar to Food and Drug Administration (FDA)-approved scaffolds utilized in regenerative medicine[22,25,28], can deliver and protect embryonic Neural stem cell (NSC) at SCI sites, leading to a statistically significant improvement in locomotion recovery in a mouse dorsal column crush SCI model, so that 12 weeks postinjury locomotion performance was not statistically different than uninjured animals
Strong evidence, including the poor efficacy reported in the first clinical trial of human NSCs in SCI patients[13], suggests that the supporting matrix is a key mediator of NSC effects[10]
Summary
Traumatic spinal cord injury (SCI) results in devastating disabilities that affect millions of patients worldwide. Current clinical treatment of SCI is limited to surgical intervention for spinal cord decompression[1] and the delivery of methylprednisolone, a corticosteroid of controversial efficacy[2]. The development of effective SCI treatments is still an unmet clinical need, as no treatment has demonstrated consistent efficiency and safety[3]. The multifactorial, complex nature of SCI4 motivated the development of combinatorial treatments that would integrate the effects of diffusible factors (small molecules, neurotrophic factors, and biologics5,6), cell therapies, and biomaterials. Cell-based treatments utilize stem cells to replace cells lost during SCI and enhance axonal elongation and synaptic plasticity[7]. Several NSC-based grafts have provided encouraging results in rodent and primate SCI models[9,10,11,12]
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