Lee Seung Hoon, Kim Yongsun, Rhew Daeun, Kim Ahyoung, Jo Kwang Rae, Yoon Yongseok, Choi Kyeung Uk, Jung Taeseong, Kim Wan Hee, Kweon Oh-Kyeong
BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Cytotherapy. 2016 Oct 28. doi: 10.1016/j.jcyt.2016.09.014.
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).
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 × 10 cells) and chABC were transplanted 3 weeks after SCI in all groups, and IV injection of MSC-GFP (1 × 10 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.
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.
We suggest that transplantation of combined chABC and BDNF-expressing MSCs, along with IV injection of MSCs, is the optimal therapy for chronic SCI.
由于胶质瘢痕形成，慢性损伤的脊髓微环境不利于轴突再生。为改善这一情况，已采用了多种治疗策略。我们研究了联合移植软骨素酶ABC（chABC）和经基因修饰以分泌脑源性神经营养因子（BDNF）的间充质基质细胞（MSCs），并静脉注射MSCs是否能促进慢性脊髓损伤（SCI）后后肢功能的恢复。
使用慢病毒包装方案生成表达犬BDNF的MSCs。将12只实验性诱导慢性SCI的比格犬分为chABC/MSC-绿色荧光蛋白（GFP）组、chABC/MSC-BDNF组和chABC/MSC-BDNF/IV组。所有组在SCI后3周移植MSCs（1×10个细胞）和chABC，chABC/MSC-BDNF/IV组在MSCs移植后1周和2周静脉注射MSC-GFP（1×10个细胞）。移植后8周采集脊髓。
与chABC/MSC-GFP组相比，chABC/MSC-BDNF组的犬在移植后8周功能恢复明显改善。与chABC/MSC-BDNF组相比，chABC/MSC-BDNF/IV组的动物在6、7和8周时功能恢复有显著改善。chABC/MSC-BDNF/IV组的纤维化改变明显减少。我们还观察到chABC/MSC-BDNF/IV组中肿瘤坏死因子-α、白细胞介素-6、COX-2、胶质纤维酸性蛋白和半乳糖脑苷脂的表达水平显著降低，BDNF、β3-微管蛋白神经丝中型和巢蛋白的表达水平升高。
我们认为联合移植chABC和表达BDNF的MSCs并静脉注射MSCs是慢性SCI的最佳治疗方法。
