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

Mohamad Khazaei, Christopher S. Ahuja, Hiroaki Nakashima, Narihito Nagoshi, Lijun Li, Jian Wang, Jonathon Chio, Anna Badner, David Seligman, Ayaka Ichise, Shinsuke Shibata, Michael G. Fehlings

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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.

Original languageEnglish
JournalScience translational medicine
Volume12
Issue number525
DOIs
Publication statusPublished - 2020 Jan 8

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. (2020). GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. Science translational medicine, 12(525). https://doi.org/10.1126/scitranslmed.aau3538