Shu Jiawei, Wang Chenggui, Tao Yiqing, Wang Shaoke, Cheng Feng, Zhang Yuang, Shi Kesi, Xia Kaishun, Wang Ronghao, Wang Jingkai, Yu Chao, Chen Jiangjie, Huang Xianpeng, Xu Haibin, Zhou Xiaopeng, Wu Haobo, Liang Chengzhen, Chen Qixin, Yan Shigui, Li Fangcai
International Institutes of Medicine The Fourth Affiliated Hospital, Zhejiang University School of Medicine Yiwu Zhejiang People's Republic of China.
Department of Orthopedics Surgery The Second Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou Zhejiang People's Republic of China.
Bioeng Transl Med. 2023 Jun 6;8(5):e10561. doi: 10.1002/btm2.10561. eCollection 2023 Sep.
Spinal cord injury (SCI) causes blood-spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel-based G protein-coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post-SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post-SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin-poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post-SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.
脊髓损伤（SCI）会导致血脊髓屏障（BSCB）破坏，进而引发继发性损伤，如出血性浸润、炎症反应和神经元细胞死亡。在SCI早期重建BSCB以减轻继发性损伤从而获得更好的预后具有重要意义。然而，目前关于BSCB重建的研究还不够充分。因此，我们提供了一种基于热敏水凝胶的G蛋白偶联受体124（GPR124）递送策略来重建BSCB。在此，我们首先发现SCI后GPR124的表达降低，并证明用重组GPR124治疗可通过恢复紧密连接（TJ）以及促进内皮细胞迁移和管腔形成来部分减轻SCI后BSCB的破坏。有趣的是，GPR124还能促进内皮细胞的能量代谢。然而，缺乏物理化学稳定性限制了GPR124的广泛应用。因此，我们制备了一种热敏肝素 - 泊洛沙姆（HP）水凝胶，其能持续产生GPR124并维持GPR124（HP@124）的生物活性，用于重建BSCB并最终促进SCI后功能性运动恢复。HP@124水凝胶可通过注射在损伤部位包裹GPR124，实现长效释放，保护受伤组织，并填充受损组织腔隙。因此，它通过阻断BSCB破裂、减少纤维化瘢痕形成、最小化炎症反应、促进髓鞘再生和轴突再生来诱导协同高效的综合调节。从机制上讲，给予GPR124可通过提高磷酸烯醇式丙酮酸羧激酶2（PCK2）的表达来激活能量代谢，并最终恢复内皮细胞的不良状态。这项研究表明除了作为SCI医学治疗的转化方法外，将GPR124与生物活性多功能水凝胶相结合进行早期干预对于恢复中枢神经系统疾病患者的运动功能可能具有巨大潜力。
