Pharmacologic Recruitment of Endogenous Neural Stem/Progenitor Cells for the Treatment of Spinal Cord Injury.

Abstract

Laboratory study using a rat T9 contusion model of spinal cord injury. This study aims to examine whether a combinatory treatment of Pioglitazone (PGZ) and granulocyte colony-stimulating factor (GCSF) can support neural stem/progenitor cells (NSPCs) directly and provide a sustainable microenvironment through immunomodulatory mechanisms. Neuroinflammation plays a crucial role in the progression of spinal cord injury (SCI) and hinders NSPC-mediated repair and regeneration. Broad acting drugs that mitigate inflammation and support NSPC proliferation have not been tested together in SCI research models. Isolated NSPCs were treated with vehicle control, PGZ, GCSF, or both PGZ and GSCF for 24 hours and stained with proliferation marker Ki67. Adult female Sprague-Dawley rats sustained moderate-to-severe contusion-based SCI at T9 and were administered either vehicle control, PGZ, GCSF, or both PGZ and GCSF treatments. Immunocytochemistry revealed that cultured NSPCs treated with both drugs produced higher numbers of actively proliferating cells and total cell numbers. ELISA on spinal cord tissue lysates at 1, 3, and 7 days post-injury (DPI) demonstrated that animals treated with PGZ, GCSF, or combination therapy showed significantly higher doublecortin levels at 7 DPI compared to control animals (P < 0.05). Immunohistochemistry of injured tissue at 3, 7, and 14 DPI revealed no difference of ependymal NSPC proliferation between groups, but showed a significant decrease in lesion size with combination therapy compared to controls. Functional recovery was assessed by the Basso, Beattie, Bresnahan locomotor rating scale. Animals treated with both drugs had significantly higher levels of function at 1 (P < 0.001), 3 (P < 0.001), 7 (P < 0.05), and 14 (P < 0.05) DPI compared to controls. These results indicate that PGZ and GCSF treatment synergistically enhance NSPCs numbers and improve functional recovery after SCI. Our findings support an immunomodulatory strategy to recruit native NSPCs as a potential acute care intervention for SCI.Level of Evidence: N/A.