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

Abstract

Study Design. Laboratory study using a rat T9 contusion model of spinal cord injury.Objective. 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. Summary of Background Data. 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. Methods. 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. Results. 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. Conclusion. 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.

Spinal cord injury: molecular mechanisms and therapeutic interventions

“… 34 In this study, a combination treatment with pioglitazone (PGZ) and granulocyte colony-stimulating factor (GCSF) was applied in a rat T9 contusion model of SCI, and PGZ and GCSF treatment synergistically enhanced NSC numbers and improved functional recovery after SCI, which proved that this treatment can support NSCs directly and provide a sustainable microenvironment. 22 Electrical stimulation has generated promising evidence as a novel approach to activate NSCs to facilitate neural repair, and more recently, clinically focused therapies aimed at improving outcomes following SCI have investigated the application of epidural electric stimulation. To date, this has been proven to be a promising rehabilitation strategy when used in conjunction with physiotherapy.…”

“…1). [14][15][16][17][18][19][20][21][22][23] The remodeling of neural circuit is extremely difficult, and the analysis of pathological mechanism of SCI helps to identify more key intervention targets. The primary injury of SCI is unpredictable and irreversible, while the secondary injury is a target for therapeutic intervention and should be regarded as an important regulatory period for the treatment of SCI.…”

Research progress of hydrogels as delivery systems and scaffolds in the treatment of secondary spinal cord injury

“…During SSCI, endogenous NSCs can grow and differentiate, however, most differentiate into astrocytes rather than neurons without intervention. Hydrogels and drugs have the potential to recruit endogenous NSCs [( Lau and Wang, 2011 ; Chen et al, 2022a ; Zabarsky et al, 2022 ), thus some researchers have focused on promoting the differentiation of endogenous NSCs into neurons by loading drugs or bioactive substances on hydrogels. Some drugs and bioactive substances used by researchers in recent years and their biological functions are listed in Table 2 ( Zhao et al, 2016 ; Wang et al, 2017a ; Xu et al, 2018 ; He et al, 2019b ; Han et al, 2020 ; Nazemi et al, 2020 ; Raspa et al, 2021 ; Zhang et al, 2021 ; Gao et al, 2022 ; Shen et al, 2022 ; Xu et al, 2022 ).…”