载CCL5和Link N的HAP水凝胶招募干细胞修复压力诱导的椎间盘退变

Decreased quantity and descended quality of disc cell is one of the most important mechanism of intervertebral disc(IVD) degeneration. There is similar characteristics and very close relationship between IVD stem cells and mesenchymal cells. Intra-disc migration of these cells, which compensates both quality and quantity of disc cells is a necessary part of disc self-reparation. Over pressure plays an important key in intervertebral disc degeneration; and we have reported that it affects migration of IVD stem cells. CCL5 is a key chemoattractant released by degenerative IVDs. Link N is a matrix component that can help mesenchymal cells differentiate toward nucleus pulposus like cells. Thermoreversible hyaluronan-poly (N-isopropylacrylamide) (HAP) hydrogel can both support mesenchymal cell differentiation toward nucleus pulposus and support sustained-release of drugs. In this study, we try to form CCL-5 and Link N loading HAP hydrogel, and investigate its effects on IVD stem cell migration,

细胞质、量的下降是椎间盘退变的重要机制。椎间盘干细胞与间充质干细胞特性相似，关系极其密切。这些干细胞向椎间盘内迁移，补充椎间盘内细胞的质、量，是椎间盘自我修复机制的重要组成部分。过度压力是椎间盘退变的关键诱因，我们此前报道，它对干细胞向椎间盘内迁移也会造成影响。CCL-5是退变的椎间盘释放的关键干细胞趋化因子，Link N是能够促进间充质干细胞向髓核样细胞分化的基质成分，而温敏透明质酸-聚异丙基丙烯酰胺（HAP）水凝胶具有促进干细胞向髓核样细胞分化和缓释药物的能力。本研究拟构建载有CCL-5和Link N的HAP水凝胶，考察其对椎间盘干细胞和间充质干细胞迁移、增殖和分化的影响；检测其在体内招募干细胞治疗压力诱导的椎间盘退变的疗效。本研究将加深对椎间盘干细胞迁移及其调控的认识，探索增强椎间盘自我修复机制的椎间盘退变治疗新思路。

压力已经被证实为椎间盘退变的重要诱因，能够导致椎间盘细胞质、量的下降。椎间盘干细胞向椎间盘内迁移并修复退变的椎间盘是椎间盘内源性修复的重要方式之一。CCL-5是退变的椎间盘释放的关键干细胞趋化因子，Link-N是能够促进干细胞向髓核样细胞分化的基质成分，温敏型水凝胶PLGA-PEG-PLGA具有促进干细胞向髓核样细胞分化和缓释药物的能力。在体外，我们发现了CCL-5通过CCL-5/CCR4信号轴激活下游PI3K/Akt信号通路显著促进细胞骨架的形成以及髓核干细胞的迁移。在体内，我们构建了载CCL-5-Link N 的PLGA-PEG-PLGA温敏水凝胶，并检测了其对椎间盘干细胞迁移、增殖和分化的影响；发现了其在体内招募干细胞治疗压力诱导的椎间盘退变具有显著的疗效。本研究加深了对椎间盘干细胞迁移及其调控的认识，将改进椎间盘退变治疗、组织工程学治疗的疗效，并且为探索椎间盘自我修复机制以及椎间盘退变的治疗提供新的思路和理论依据。