Research ArticleSpinal Cord Injury

GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaau3538
DOI: 10.1126/scitranslmed.aau3538

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The fate-determining factor

Neural progenitor cells (NPCs) emerged as a potential therapeutic approach for repairing and regenerating neurons after spinal cord injury. However, the hostile microenvironment of the injured spinal cord contributes to the limited degree of recovery observed after NPC transplant in rodents. Now, Khazaei et al. have shown that activation of Notch signaling in the spinal cord after injury reduces the therapeutic potential of the transplanted NPCs. Counteracting Notch activation by expressing GDNF in transplanted NPCs promoted differentiation toward a neuronal cell fate and improved motor function after injury in rodents. The results suggest that modulating the injured microenvironment might improve recovery after stem cell transplant.

Abstract

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.

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