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 language | English |
|---|---|
| Journal | Science translational medicine |
| Volume | 12 |
| Issue number | 525 |
| DOIs | |
| Publication status | Published - 2020 Jan 8 |
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ASJC Scopus subject areas
- Medicine(all)
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GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. / Khazaei, Mohamad; Ahuja, Christopher S.; Nakashima, Hiroaki; Nagoshi, Narihito; Li, Lijun; Wang, Jian; Chio, Jonathon; Badner, Anna; Seligman, David; Ichise, Ayaka; Shibata, Shinsuke; Fehlings, Michael G.
In: Science translational medicine, Vol. 12, No. 525, 08.01.2020.Research output: Contribution to journal › Article
}
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.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85077702874&partnerID=8YFLogxK
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
ER -