TY - JOUR
T1 - GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents
AU - Khazaei, Mohamad
AU - Ahuja, Christopher S.
AU - Nakashima, Hiroaki
AU - Nagoshi, Narihito
AU - Li, Lijun
AU - Wang, Jian
AU - Chio, Jonathon
AU - Badner, Anna
AU - Seligman, David
AU - Ichise, Ayaka
AU - Shibata, Shinsuke
AU - Fehlings, Michael G.
N1 - Funding Information:
We thank T. Worden and P. Bradshaw for critical reading of the manuscript. We thank M. Chamankhah for optimizing and validating RNA isolation the quantitative PCR assays for the tissue and J. Bhavsar, S.K.K. Lau, and S.Y. Chen for helping in animal care and behavioral assessments. This study was supported by funding from the Ontario Institute of Regenerative Medicine, Wings for Life, Krembil Fundation, and Canadian Institutes of Health Research all to M.G.F. M.G.F. is supported by the Halbert Chair in Neural Repair and Regeneration, Krembil Foundation, and the Dezwirek Foundation.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2020/1/8
Y1 - 2020/1/8
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aau3538
DO - 10.1126/scitranslmed.aau3538
M3 - Article
C2 - 31915299
AN - SCOPUS:85077702874
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 525
M1 - eaau3538
ER -