title: Neurogenin-2-transduced human neural progenitor cells attenuate neonatal hypoxic-ischemic brain injury.
abstract: Neonatal hypoxic-ischemic (HI) brain injury leads to high mortality and neurodevelopmental disabilities. Multipotent neural progenitor cells (NPCs) with self-renewing capacity have the potential to reduce neuronal loss and improve the compromised environment in the HI brain injury. However, the therapeutic efficacy of neuronal-committed progenitor cells and the underlying mechanisms of recovery are not yet fully understood. Therefore, this study investigated the regenerative ability and action mechanisms of neuronally committed human NPCs (hNPCs) transduced with neurogenin-2 (NEUROG2) in neonatal HI brain injury. NEUROG2- or green fluorescent protein (GFP)-encoding adenoviral vector-transduced hNPCs (NEUROG2- or GFP-NPCs) were transplanted into neonatal mouse brains with HI injury. Grafted NEUROG2-NPCs showed robust dispersion and engraftment, prolonged survival, and neuronal differentiation in HI brain injury. NEUROG2-NPCs significantly improved neurological behaviors, decreased cellular apoptosis, and increased the neurite outgrowth and axonal sprouting in HI brain injury. In contrast, GFP-NPC grafts moderately enhanced axonal extension with limited behavioral recovery. Notably, NEUROG2-NPCs showed increased secretion of multiple factors, such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NTF3), fibroblast growth factor 9 (FGF9), ciliary neurotrophic factor (CNTF), and thrombospondins 1 and 2 (THBS 1/2), which promoted SH-SY5Y neuroblastoma cell survival and neurite outgrowth. Thus, we postulate that NEUROG2-expressing human NPCs facilitate functional recovery after neonatal HI brain injury via their ability to secrete multiple factors that enhance neuronal survival and neuroplasticity.
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Il-Shin
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyo Yeon
authors.initials: KY
authors.lastname: Koo
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kwangsoo
authors.initials: K
authors.lastname: Jung
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Miri
authors.initials: M
authors.lastname: Kim
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Il-Sun
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyujin
authors.initials: K
authors.lastname: Hwang
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Seokhwan
authors.initials: S
authors.lastname: Yun
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Haejin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Shin
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea; Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: kipark@yuhs.ac.
authors.forename: Kook In
authors.initials: KI
authors.lastname: Park
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001930:Brain Injuries / Q000628:therapy*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D005786:Gene Expression Regulation; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D051379:Mice; D039902:Multipotent Stem Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C491183:NEUROG2 protein, human