Liu Dun, Niu Runyan, Wang Siliang, Shao Lihua, Yang Xian, Liu Xuexue, Ma Xiaolong, Zhu Zezhang, Zhang Jinping, Shi Benlong, Ni Huanyu, Du Xiao
Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Department of Pharmacy, Nanjing Medical Center for Clinical Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
ACS Nano. 2025 Jan 21;19(2):2591-2614. doi: 10.1021/acsnano.4c14261. Epub 2024 Dec 26.
Neural stem cell (NSCs) transplantation is a promising therapeutic strategy for spinal cord injury (SCI), but its efficacy is greatly limited by the local inhibitory microenvironment. In this study, based on l-arginine (l-Arg)-loaded mesoporous hollow cerium oxide (AhCeO) nanospheres, we constructed an injectable composite hydrogel (AhCeO-Gel) with microenvironment modulation capability. AhCeO-Gel protected NSCs from oxidative damage by eliminating excess reactive oxygen species while continuously delivering Nitric Oxide to the lesion of SCI in a pathological microenvironment, the latter of which effectively promoted the neural differentiation of NSCs. The process was confirmed to be closely related to the up-regulation of the cAMP-PKA pathway after NO-induced calcium ion influx. In addition, AhCeO-Gel significantly promoted the polarization of microglia toward the M2 subtype as well as enhanced the regeneration of spinal nerves and myelinated axons. The prepared bioactive hydrogel system also efficiently facilitated the integration of transplanted NSCs with host neural circuits, replenished damaged neurons, alleviated neuroinflammation, and inhibited glial scar formation, thus significantly accelerating the recovery of motor function in SCI rats. Therefore, AhCeO-Gel synergized with NSCs transplantation has great potential as an integrated therapeutic strategy to treat SCI by comprehensively reversing the inhibitory microenvironment.
神经干细胞（NSCs）移植是脊髓损伤（SCI）一种很有前景的治疗策略，但其疗效受到局部抑制性微环境的极大限制。在本研究中，基于负载L-精氨酸（L-Arg）的介孔空心氧化铈（AhCeO）纳米球，我们构建了一种具有微环境调节能力的可注射复合水凝胶（AhCeO-Gel）。AhCeO-Gel通过消除过量的活性氧保护神经干细胞免受氧化损伤，同时在病理微环境中持续向脊髓损伤病灶递送一氧化氮，后者有效地促进了神经干细胞的神经分化。该过程被证实与一氧化氮诱导钙离子内流后cAMP-PKA信号通路的上调密切相关。此外，AhCeO-Gel显著促进小胶质细胞向M2亚型极化，并增强脊髓神经和有髓轴突的再生。所制备的生物活性水凝胶系统还有效地促进了移植的神经干细胞与宿主神经回路的整合，补充受损神经元，减轻神经炎症，并抑制胶质瘢痕形成，从而显著加速脊髓损伤大鼠运动功能的恢复。因此，AhCeO-Gel与神经干细胞移植协同作用，作为一种综合治疗策略，通过全面逆转抑制性微环境，在治疗脊髓损伤方面具有巨大潜力。
