Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury
Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury
复制标题
DOI：
10.1016/j.actbio.2017.07.024
复制
发表时间：
2017-09-15
影响因子：
9.7
通讯作者：
Blesch, Armin
中科院分区：
文献类型：
--
作者：
Liu, Shengwen;Sandner, Beatrice;Blesch, Armin
将细胞接种的藻酸盐毛细管水凝胶移植到脊髓损伤部位提供轴突桥，同时以线性模式物理引导再生轴突生长。然而，没有额外的生长刺激，桥接轴突不能延伸到远端宿主脊髓。在这里，我们研究了一个组合的策略是否会支持再生的下行轴突跨越颈部（C5）侧半横断损伤的大鼠脊髓。脊髓横断后，将施旺细胞（SC）接种的藻酸盐水凝胶移植到病变部位，并向尾部注射在四环素调节启动子控制下表达脑源性神经营养因子（BDNF）的AAV 5。此外，我们研究了SC注射到尾侧脊髓实质是否会进一步增强下行轴突的再生，以重新进入宿主脊髓。我们的数据表明，由生物素化葡聚糖胺（BDA）追踪的轴突和下行轴突延伸到整个支架。当尾部脑源性神经营养因子表达被激活时，再生轴突的数量显着增加，并且瞬时脑源性神经营养因子递送能够在基因表达关闭后维持轴突。下行轴突仅限于尾部移植物/宿主界面，即使连续表达BDNF 8周。只有与尾部注射的SC，促进轴突再生的途径，通过主机/移植物接口产生允许轴突成功地重新进入尾部spinal cord.Statement of SignificanceRecovery脊髓损伤是穷人由于有限的再生观察到在成年哺乳动物中枢神经系统。生物材料、细胞移植和生长因子可以引导轴突穿过损伤部位，提供细胞基质，刺激轴突生长，并在增加再生轴突的生长距离方面显示出一定的前景。在本研究中，我们结合了线性通道的藻酸盐生物材料与雪旺细胞内和病变部位以外的移植和脑源性神经营养因子（BDNF）的瞬时表达的可调节载体的注射。我们的数据显示，只有完全组合的轴突延伸穿过损伤部位，并且BDNF的表达超过4周不会进一步增加再生轴突的数量。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8 weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord.Statement of SignificanceRecovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4 weeks does not further increase the number of regenerating axons. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.