Development of Combinatorial Strategies Employing Neural Stem Cells and Polymer Scaffold for Spinal Cord Repair

Abstract

"ABSTRACT-

Development of Combinatorial Strategies Employing Neural Stem Cells and Polymer Scaffold for Spinal Cord Repair

Stem cell-based therapy holds promise to enhance functional recovery following spinal cord injury (SCI). Most evidence that transplantation of neural stem cells can produce beneficial outcomes after SCI has been derived from rodent models. Before being translated to human patients, it would be needed to examine the therapeutic effects in larger animal models where weight-bearing locomotion should be much more challenging. The present study examined therapeutic effects of a combinatorial strategy centering on human neural stem cells (hNSCs) in a canine hemisection SCI model. After traumatic injuries to the spinal cord, secondary injuries aggravate the extent of damage, expanding cystic cavities at the lesion site. Cavity wall is surrounded by glial scar and severely impedes axonal regrowth. Therefore, any regenerative strategy could be complemented with an attempt to bridge lesion cavities. In the current study, we implanted poly (lactic-co-glycolic acid) (PLGA) scaffolds to facilitate the delivery of neural stem cells. We sought to enhance therapeutic efficacy by ectopic expression of neurotrophin-3 (NT-3) in the hNSCs. NT-3 overexpressing hNSCs (NT3.F3) were produced by retroviral transduction of the immortalized hNSC line (F3) with human NT-3 cDNA. NT3.F3 cells were seeded into a predesigned PLGA (65:35) scaffolds, and the PLGA scaffolds with hNSCs (PLGA-NT3.F3) were implanted immediately after left hemisection at T11 in female dogs weighing 20-30 kg. The PLGA scaffold seemed to nicely fill the lesion cavity, showing a varying degree of biodegradation by 12 weeks. Survival of grafted cells was confirmed at 2 weeks, and some of the grafted cells migrated to the host tissue. There were very few regenerating axons into the scaffold in both groups. Moreover, the ventral horns caudal to the hemisected region were more profusely innervated by serotonergic axons in animals with PLGA-NT3.F3. These findings raise a possibility that implantation of PLGA-NT3.F3 can produce beneficial motor outcomes by promoting axonal remodeling below the lesion. This study suggests that the therapeutic strategy combining multidisciplinary approaches can be feasible and effective for spinal cord repair in larger species.

Key words: spinal cord injury; neural stem cells; NT3; PLGA scaffold; serotonergic axon

"