Induction of Neurogenesis and Angiogenesis in a Rat Hemisection Spinal Cord Injury Model With Combined Neural Stem Cell, Endothelial Progenitor Cell, and Biomimetic Hydrogel Matrix Therapy

Eric J Marrotte; Khari Johnson; Ryan M Schweller; Rachel Chapla; Brian E Mace; Daniel T Laskowitz; Jennifer L West

doi:10.1097/CCE.0000000000000436

Induction of Neurogenesis and Angiogenesis in a Rat Hemisection Spinal Cord Injury Model With Combined Neural Stem Cell, Endothelial Progenitor Cell, and Biomimetic Hydrogel Matrix Therapy

Crit Care Explor. 2021 Jun 14;3(6):e0436. doi: 10.1097/CCE.0000000000000436. eCollection 2021 Jun.

Authors

Eric J Marrotte^{1

2}, Khari Johnson³, Ryan M Schweller³, Rachel Chapla³, Brian E Mace², Daniel T Laskowitz², Jennifer L West³

Affiliations

¹ Department of Neurology, Division of Neurocritical Care, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
² Department of Neurology, Division of Neurocritical Care, Duke University, Durham NC.
³ Department of Biomedical Engineering, Duke University, Durham, NC.

Abstract

Acute spinal cord injury is a devastating injury that may lead to loss of independent function. Stem-cell therapies have shown promise; however, a clinically efficacious stem-cell therapy has yet to be developed. Functionally, endothelial progenitor cells induce angiogenesis, and neural stem cells induce neurogenesis. In this study, we explored using a multimodal therapy combining endothelial progenitor cells with neural stem cells encapsulated in a bioactive biomimetic hydrogel matrix to facilitate stem cell-induced neurogenesis and angiogenesis in a rat hemisection spinal cord injury model.

Design: Laboratory experimentation.

Setting: University laboratory.

Subjects: Female Fischer 344 rats.

Interventions: Three groups of rats: 1) control, 2) biomimetic hydrogel therapy, and 3) combined neural stem cell, endothelial progenitor cell, biomimetic hydrogel therapy underwent right-sided spinal cord hemisection at T9-T10. The blinded Basso, Beattie, and Bresnahan motor score was obtained weekly; after 4 weeks, observational histologic analysis of the injured spinal cords was completed.

Measurements and main results: Blinded Basso, Beattie, and Bresnahan motor score of the hind limb revealed significantly improved motor function in rats treated with combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy (p < 0.05) compared with the control group. The acellular biomimetic hydrogel group did not demonstrate a significant improvement in motor function compared with the control group. Immunohistochemistry evaluation of the injured spinal cords demonstrated de novo neurogenesis and angiogenesis in the combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy group, whereas, in the control group, a gap or scar was found in the injured spinal cord.

Conclusions: This study demonstrates proof of concept that multimodal therapy with endothelial progenitor cells and neural stem cells combined with a bioactive biomimetic hydrogel can be used to induce de novo CNS tissue in an injured rat spinal cord.

Keywords: angiogenesis; biomedical engineering; biomimetic extracellular matrix; endothelial progenitor cells; hydrogel; neural stem cells; neurogenesis; polyethylene glycol; regenerative medicine; spinal cord injury.