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

Experimental Neurobiology 2019년 28권 6호 p.679 ~ 696
 ( Hwang Kyu-Jin ) - Yonsei University College of Medicine Brain Korea 21 PLUS Project for Medical Science

정광수 ( Jung Kwang-Soo ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
김일선 ( Kim Il-Sun ) - Yonsei University College of Medicine Yonsei Biomedical Research Institute
김미리 ( Kim Mi-Ri ) - Yonsei University College of Medicine Yonsei Biomedical Research Institute
한정호 ( Han Jung-Ho ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
임주희 ( Lim Joo-Hee ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
신정은 ( Shin Jeong-Eun ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
 ( Jang Jae-Hyung ) - Yonsei University Department of Chemical and Biomolecular Engineering
박국인 ( Park Kook-In ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics

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.

키워드

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