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

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.

Source: Science Translational Medicine - January 7, 2020 Category: Biomedical Science Authors: Khazaei, M., Ahuja, C. S., Nakashima, H., Nagoshi, N., Li, L., Wang, J., Chio, J., Badner, A., Seligman, D., Ichise, A., Shibata, S., Fehlings, M. G. Tags: Research Articles Source Type: research