CXCL12通过增强细胞间通讯调控神经血管单元促进脊髓损伤修复

Acute spinal cord injury (SCI) is a major refractory trauma with high incidence. Its functional rehabilitation depends on the repair and functional reconstruction of the injured nerve. At present, neurological rehabilitation and neuromodulation have achieved initial efficacy, but most of them are very limited. Mesenchymal stem cell （MSC）transplantation has been used in several clinical trials，and in addition to regulate immune function, function and the mechanism of regulation of the neurovascular unit（NVU）, there is no attention. On the other hand, angiogenesis plays an critical role in the process of nerve repair.It is important that the new endothelial cells （EC）communicate with the cells of the endogenous neural stem cells（NPC）for NVU. Our previous studies have investigated the important paracrine factor chemokine CXCL12 for many years. The purpose of this study is to investigate the key function in vascular remodeling and neural repair by observing the efforts of CXCL12 in NVU. This project will answer the following scientific questions: 1) CXCL12 initiately regulates formation and functional reconstruction of NVU; 2) in vitro tissue or animal model， cell communication between EC and NPC promotes NVU through EC exosomes.

急性脊髓损伤是较多发生的难治的重大创伤，其功能康复依赖于损伤神经的修复和功能重建。目前神经修复和神经调控手段取得了初步的疗效，但多数效果非常有限。间充质干细胞（MSC）移植已经在多个临床试验中应用，MSC除免疫调节功能之外，是否调控神经血管单元（Neuovascular unit，NVU）的形成和功能，尚未受到重视。申请人既往对MSC的重要旁分泌因子，趋化因子CXCL12进行多年的研究。本课题旨在通过观察CXCL12对NVU的作用，揭示这一重要细胞因子对血管重建和神经修复的重要意义。本课题将回答以下科学问题：1）CXCL12定向调控NVU的形成与重建；2）内皮细胞（EC）与内源性神经干细胞（NPC）通过外泌体的细胞间通讯促进NVU形成。

神经损伤后损伤区新生血管的功能状态严重影响神经修复过程，其中新生血管的重要组成部分--血管内皮细胞（epithelial cell，EC）对损伤区微环境发挥调控作用。通过建立EC和神经祖细胞（neural progenitor cell，NPC）共培养模型，模拟神经血管单元（NVU）中两种细胞间的通讯。应用增殖、凋亡、迁移等实验发现EC促进NPC的生存力，其作用机制与EC分泌的外泌体（Exo）相关；利用电镜、Western blot、NTA鉴定外泌体后，设置不同浓度Exo的条件培养基模拟改善后的微环境培养NPC，通过多种实验手段验证了内皮细胞外泌体(EC-Exo)对NPC生存活力的良性作用，此实验结果进一步在动物模型中得到验证；因此，探索炎性微环境如何通过微环境调控细胞间通讯，激活NPC继而促进NVU的形成与重建，具有创新、可行性，重要科学意义和潜在应用临床价值。