Impact of local injection of brain-derived neurotrophic factor-expressing mesenchymal stromal cells (MSCs) combined with intravenous MSC delivery in a canine model of chronic spinal cord injury

Seung Hoon Lee; Yongsun Kim; Daeun Rhew; Ahyoung Kim; Kwang Rae Jo; Yongseok Yoon; Kyeung Uk Choi; Taeseong Jung; Wan Hee Kim; Oh-Kyeong Kweon

doi:10.1016/j.jcyt.2016.09.014

Impact of local injection of brain-derived neurotrophic factor-expressing mesenchymal stromal cells (MSCs) combined with intravenous MSC delivery in a canine model of chronic spinal cord injury

Cytotherapy. 2016 Oct 28:S1465-3249(16)30540-0. doi: 10.1016/j.jcyt.2016.09.014. Online ahead of print.

Authors

Affiliations

¹ BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
² BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address: ohkweon@snu.ac.kr.

PMID: 28029610
DOI: 10.1016/j.jcyt.2016.09.014

Abstract

Background aims: The microenvironment of the chronically injured spinal cord does not allow for axonal regeneration due to glial scarring. To ameliorate this, several therapeutic strategies have been used. We investigated whether combined transplantation of chondroitinase ABC (chABC) and mesenchymal stromal cells (MSCs) genetically modified to secrete brain-derived neurotrophic factor (BDNF) with intravenous (IV) administration of MSCs can promote recovery of hindlimb function after chronic spinal cord injury (SCI).

Methods: Canine BDNF-expressing MSCs were generated using a lentivirus packaging protocol. Twelve beagle dogs with experimentally induced chronic SCI were divided into chABC/MSC-green fluorescent protein (GFP), chABC/MSC-BDNF and chABC/MSC-BDNF/IV groups. The MSCs (1 × 10⁷ cells) and chABC were transplanted 3 weeks after SCI in all groups, and IV injection of MSC-GFP (1 × 10⁷ cells) was performed 1 and 2 weeks after MSC transplantation in the chABC/MSC-BDNF/IV group. Spinal cords were harvested 8 weeks after transplantation.

Results: The dogs in the chABC/MSC-BDNF included groups had significantly improved functional recovery 8 weeks after transplantation compared with those in the chABC/MSC-GFP group. The animals in the chABC/MSC-BDNF/IV group showed significant improvements in functional recovery at 6, 7 and 8 weeks compared with those in the chABC/MSC-BDNF group. Fibrotic changes were significantly decreased in the chABC/MSC-BDNF/IV group. We also observed significant decreases in the expression levels of tumor necrosis factor-α, interleukin-6, COX-2, glial fibrillary acidic protein and GalC and increased expression levels of BDNF, β3-tubulin neurofilament medium, and nestin in the chABC/MSC-BDNF/IV group.

Conclusions: We suggest that transplantation of combined chABC and BDNF-expressing MSCs, along with IV injection of MSCs, is the optimal therapy for chronic SCI.

Keywords: brain-derived neurotrophic factor; chondroitinase ABC; chronic spinal cord injury; intravenous injection; mesenchymal stromal cells.