Exp Neurobiol.  2019 Dec;28(6):679-696. 10.5607/en.2019.28.6.679.

Glial Cell Line-derived Neurotrophic Factor-overexpressing Human Neural Stem/Progenitor Cells Enhance Therapeutic Efficiency in Rat with Traumatic Spinal Cord Injury

• Hwang K
• Jung K
• Kim IS
• Kim M
• Han J
• Lim J
• Shin JE
• Jang JH
• Park KI

• KMID: 2468885
• DOI: http://doi.org/10.5607/en.2019.28.6.679

Abstract

Spinal cord injury (SCI) causes axonal damage and demyelination, neural cell death, and comprehensive tissue loss, resulting in devastating neurological dysfunction. Neural stem/progenitor cell (NSPCs) transplantation provides therapeutic benefits for neural repair in SCI, and glial cell line-derived neurotrophic factor (GDNF) has been uncovered to have capability of stimulating axonal regeneration and remyelination after SCI. In this study, to evaluate whether GDNF would augment therapeutic effects of NSPCs for SCI, GDNF-encoding or mock adenoviral vector-transduced human NSPCs (GDNF-or Mock-hNSPCs) were transplanted into the injured thoracic spinal cords of rats at 7 days after SCI. Grafted GDNF-hNSPCs showed robust engraftment, long-term survival, an extensive distribution, and increased differentiation into neurons and oligodendroglial cells. Compared with Mock-hNSPC- and vehicle-injected groups, transplantation of GDNF-hNSPCs significantly reduced lesion volume and glial scar formation, promoted neurite outgrowth, axonal regeneration and myelination, increased Schwann cell migration that contributed to the myelin repair, and improved locomotor recovery. In addition, tract tracing demonstrated that transplantation of GDNF-hNSPCs reduced significantly axonal dieback of the dorsal corticospinal tract (dCST), and increased the levels of dCST collaterals, propriospinal neurons (PSNs), and contacts between dCST collaterals and PSNs in the cervical enlargement over that of the controls. Finally grafted GDNF-hNSPCs substantially reversed the increased expression of voltage-gated sodium channels and neuropeptide Y, and elevated expression of GABA in the injured spinal cord, which are involved in the attenuation of neuropathic pain after SCI. These findings suggest that implantation of GDNF-hNSPCs enhances therapeutic efficiency of hNSPCs-based cell therapy for SCI.

Keyword

Spinal cord injuries; Glial cell line-derived neurotrophic factor; Neural stem/progenitor cells; Cell-based therapy; Mechanical allodynia; Paraplegia

MeSH Terms

Animals
Axons
Cell Death
Cell Movement
Cell- and Tissue-Based Therapy
Cicatrix
Demyelinating Diseases
gamma-Aminobutyric Acid
Glial Cell Line-Derived Neurotrophic Factor
Humans*
Hyperalgesia
Myelin Sheath
Neuralgia
Neurites
Neuroglia*
Neurons
Neuropeptide Y
Paraplegia
Pyramidal Tracts
Rats*
Regeneration
Spinal Cord Injuries*
Spinal Cord*
Therapeutic Uses
Transplants
Voltage-Gated Sodium Channels
Glial Cell Line-Derived Neurotrophic Factor
Neuropeptide Y
Therapeutic Uses
Voltage-Gated Sodium Channels
gamma-Aminobutyric Acid