Rehabilitation combined with neural progenitor cell grafts enables functional recovery in chronic spinal cord injury
Paul Lu, Camila M. Freria, Lori Graham, Amanda N. Tran, Ashley Villarta, Dena Yassin, J. Russell Huie, Adam R. Ferguson, Mark H. Tuszynski
Paul Lu, Camila M. Freria, Lori Graham, Amanda N. Tran, Ashley Villarta, Dena Yassin, J. Russell Huie, Adam R. Ferguson, Mark H. Tuszynski
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Research Article Neuroscience

Rehabilitation combined with neural progenitor cell grafts enables functional recovery in chronic spinal cord injury

Abstract

We reported previously that neural progenitor cell (NPC) grafts form neural relays across sites of subacute spinal cord injury (SCI) and support functional recovery. Here, we examine whether NPC grafts after chronic delays also support recovery and whether intensive rehabilitation further enhances recovery. One month after severe bilateral cervical contusion, rats received daily intensive rehabilitation, NPC grafts, or both rehabilitation and grafts. Notably, only the combination of rehabilitation and grafting significantly improved functional recovery. Moreover, improved functional outcomes were associated with a rehabilitation-induced increase in host corticospinal axon regeneration into grafts. These findings identify a critical and synergistic role of rehabilitation and neural stem cell therapy in driving neural plasticity to support functional recovery after chronic and severe SCI.

Authors

Paul Lu, Camila M. Freria, Lori Graham, Amanda N. Tran, Ashley Villarta, Dena Yassin, J. Russell Huie, Adam R. Ferguson, Mark H. Tuszynski

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Figure 1

Engraftment and differentiation of transplanted neural progenitor cells.

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Engraftment and differentiation of transplanted neural progenitor cells....
(A and B) GFAP (red), GFP (green), and NeuN (blue) immunolabeling in the horizontal plane of the C6 bilateral spinal cord contusion. (A) Lesion appearance in ungrafted animal near the level of the central canal. There is a large lesion cavity that involves both gray and white matter. (B) Transplanted neural progenitor cells (NPCs) (green) survive and fill the large lesion site. (C) GFP (green), NeuN (red), and DAPI (blue) triple-fluorescence immunolabeling reveals colocalization of grafted GFP-expressing cells with neuronal marker NeuN. (D) GFP (green) and GFAP (red) double-fluorescence immunolabeling reveals colocalization of grafted GFP-expressing cells with GFAP (astrocytes). (E) GFP (green) and APC (red) double-fluorescence immunolabeling reveals colocalization of grafted GFP-expressing NPCs with the oligodendrocyte marker APC. (F–H) Quantification of differentiation of transplanted NPCs shows that rehabilitation did not significantly alter cell fate reflected in the proportion of graft neurons labeled for (F) NeuN, (G) GFAP, and (H) APC (± SEM; Student’s 1-tailed t test). Scale bar: 1 mm (A and B); 30 μm (C–E); 10 μm (inset images, C–E).