Birgit Neuhuber, Alissa L. Barshinger, Courtney Paul, Jed S. Shumsky, Takahiko Mitsui and Itzhak Fischer
Using cellular transplants to treat spinal cord injury is a promising therapeutic strategy, but transplants grafted directly into the injury site can further damage the already compromised cord. To avoid additional trauma and to simplify translation to the clinic, it is advantageous to use less invasive delivery methods.
The authors compared the efficacy of intrathecal cell delivery at the lumbar region (lumbar puncture [LP]) to direct injection into a thoracic contusion injury using a mixed population of lineage-restricted neural precursor cells.
Direct injection resulted in a higher volume of neural precursor cells located throughout the injury site, whereas fewer LP-delivered cells accumulated at the dorsal aspect of the injured cord. Both grafting methods were neuroprotective, resulting in reduction of injury size and greater tissue sparing compared with controls. Functional recovery was evaluated by assessing motor and bladder function. Animals that received cells via direct injection performed significantly better in the open-field locomotor test than did operated controls, while LP-treated animals showed intermediate recovery of function that did not differ statistically from that of either operated controls or directly injected animals. Bladder function, however, was significantly improved in both directly injected and LP-treated animals.
Grafting of stem cells via LP resulted in localized accumulation of cells at the injury site, neuroprotection, and modest recovery of function. Further optimization of the LP procedure by increasing the number of cells that are delivered and determining the optimal delivery schedule may further improve recovery to levels comparable to direct injection.
Lauren Conova Grous, Jennifer Vernengo, Ying Jin, B. Timothy Himes, Jed S. Shumsky, Itzhak Fischer and Anthony Lowman
In a follow-up study to their prior work, the authors evaluated a novel delivery system for a previously established treatment for spinal cord injury (SCI), based on a poly(N-isopropylacrylamide) (PNIPAAm), lightly cross-linked with a polyethylene glycol (PEG) injectable scaffold. The primary aim of this work was to assess the recovery of both spontaneous and skilled forelimb function following a cervical dorsolateral funiculotomy in the rat. This injury ablates the rubrospinal tract (RST) but spares the dorsal and ventral corticospinal tract and can severely impair reaching and grasping abilities.
Animals received an implant of either PNIPAAm-g-PEG or PNIPAAm-g-PEG + brain-derived neurotrophic factor (BDNF). The single-pellet reach-to-grasp task and the staircase-reaching task were used to assess skilled motor function associated with reaching and grasping abilities, and the cylinder task was used to assess spontaneous motor function, both before and after injury.
Because BDNF can stimulate regenerating RST axons, the authors showed that animals receiving an implant of PNIPAAm-g-PEG with codissolved BDNF had an increased recovery rate of fine motor function when compared with a control group (PNIPAAm-g-PEG only) on both a staircase-reaching task at 4 and 8 weeks post-SCI and on a single-pellet reach-to-grasp task at 5 weeks post-SCI. In addition, spontaneous motor function, as measured in the cylinder test, recovered to preinjury values in animals receiving PNIPAAm-g-PEG + BDNF. Fluorescence immunochemistry indicated the presence of both regenerating axons and BDA-labeled fibers growing up to or within the host-graft interface in animals receiving PNIPAAm-g-PEG + BDNF.
Based on their results, the authors suggest that BDNF delivered by the scaffold promoted the growth of RST axons into the lesion, which may have contributed in part to the increased recovery rate.