Abstract：
Motor functional improvement represents a paramount treatment objective in the post-spinal cord injury (SCI) recovery process. However, neuronal cell death and axonal degeneration following SCI disrupt neural signaling, impeding the motor functional recovery. In this study, we developed a multifunctional decellularized spinal cord-derived extracellular matrix (dSECM), crosslinked with glial cell-derived neurotrophic factor (GDNF), to promote differentiation of stem cells into neural-like cells and facilitate axonogenesis and remyelination. After decellularization, the immunogenic cellular components were effectively removed in dSECM, while the crucial protein components were retained which supports stem cells proliferation and differentiation. Furthermore, sustained release of GDNF from the dSECM facilitated axonogenesis and remyelination by activating the PI3K/Akt and MEK/Erk pathways. Our findings demonstrate that the dSECM-GDNF platform promotes neurogenesis, axonogenesis, and remyelination to enhance neural signaling, thereby yielding promising therapeutic effects for motor functional improvement after SCI. STATEMENT OF SIGNIFICANCE: The dSECM promotes the proliferation and differentiation of MSCs or NSCs by retaining proteins associated with positive regulation of neurogenesis and neuronal differentiation, while eliminating proteins related to negative regulation of neurogenesis. After crosslinking, GDNF can be gradually released from the platform, thereby promoting neural differentiation, axonogenesis, and remyelination to enhance neural signaling through activation of the PI3K/Akt and MEK/Erk pathways. In vivo experiments demonstrated that dSECM-GDNF/MSC@GelMA hydrogel exhibited the ability to facilitate neuronal regeneration at 4 weeks post-surgery, while promoting axonogenesis and remyelination at 8 weeks post-surgery, ultimately leading to enhanced motor functional recovery. This study elucidates the ability of neural regeneration strategy to promote motor functional recovery and provides a promising approach for designing multifunctional tissue for SCI treatment.
摘要：
运动功能改善是脊髓损伤后（SCI）恢复过程中最重要的治疗目标。然而,SCI后神经元细胞死亡和轴突变性破坏神经信号，阻碍电机功能恢复。在这项研究中,我们开发了一种多功能的脱细胞脊髓源性细胞外基质（dSECM），与胶质细胞源性神经营养因子（GDNF）交联，促进干细胞分化为神经样细胞，促进轴突生成和髓鞘再生。去细胞化后,免疫原性细胞成分在dSECM中被有效去除，同时保留了支持干细胞增殖和分化的关键蛋白质成分。此外，从dSECM持续释放GDNF通过激活PI3K/Akt和MEK/Erk途径促进轴突生成和髓鞘再生。我们的研究结果表明，dSECM-GDNF平台促进神经发生，轴突发生，和髓鞘再生以增强神经信号，从而对SCI后的运动功能改善产生有希望的治疗效果。意义陈述：dSECM通过保留与神经发生和神经元分化的正向调节相关的蛋白来促进MSCs或NSCs的增殖和分化，同时消除与神经发生负调节相关的蛋白质。交联后,GDNF可以逐渐从平台上消失，从而促进神经分化，轴突发生，和髓鞘再生以通过激活PI3K/Akt和MEK/Erk途径来增强神经信号传导。体内实验表明，dSECM-GDNF/MSC@GelMA水凝胶在手术后4周表现出促进神经元再生的能力，在术后8周促进轴突生成和髓鞘再生，最终导致增强的电机功能恢复。这项研究阐明了神经再生策略促进运动功能恢复的能力，并为设计用于SCI治疗的多功能组织提供了有希望的方法。
