Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell-derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF's effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell-derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

中文翻译：

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GDNF通过减弱啮齿动物受伤脊髓中的Notch信号来挽救神经祖细胞的命运。

神经祖细胞（NPC）移植是一种治疗脊髓损伤（SCI）的有前途的策略。在这项研究中，我们表明在脊髓微环境中，损伤诱导的Notch激活将啮齿动物NPC的命运偏向星形胶质细胞。在筛选可能的临床相关因素以调节Notch信号的筛选中，我们鉴定了神经胶质细胞源性神经营养因子（GDNF）。GDNF通过介导δ样1同源物（DLK1）表达来减弱Notch信号，这与GDNF对细胞存活的影响无关。当将其移植到宫颈SCI的啮齿动物模型中时，与对照细胞相比，表达GDNF的人诱导多能干细胞来源的NPC（hiPSC-NPC）表现出更高的向神经元分化的能力。此外，GDNF的表达促进了内源性组织的节制并增强了移植细胞的电整合，从而共同改善了神经行为的恢复。CRISPR诱导的表达GDNF的hiPSC-NPC中DLK1基因的敲除减弱了对功能恢复的影响，表明该作用部分是通过DLK1表达介导的。这些结果代表了hiPSC-NPC治疗的机械驱动优化，可将移植的细胞重定向至神经元命运并增强其整合。