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

Research output: Contribution to journalArticle

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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Nerve Growth Factors
Neuroglia
Rodentia
Spinal Cord
Induced Pluripotent Stem Cells
Transplants
Spinal Cord Injuries
Clustered Regularly Interspaced Short Palindromic Repeats
Glial Cell Line-Derived Neurotrophic Factor
Cell Transplantation
Astrocytes
Cell Survival
Stem Cells
Wounds and Injuries
Therapeutics
Genes

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 journalArticle

Khazaei, M, Ahuja, CS, Nakashima, H, Nagoshi, N, Li, L, Wang, J, Chio, J, Badner, A, Seligman, D, Ichise, A, Shibata, S & Fehlings, MG 2020, 'GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents', Science translational medicine, vol. 12, no. 525. https://doi.org/10.1126/scitranslmed.aau3538
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. / GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. In: Science translational medicine. 2020 ; Vol. 12, No. 525.
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