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Cellular Response of Ventricular-Subventricular Neural Progenitor/Stem Cells to Neonatal Hypoxic-Ischemic Brain Injury and Their Enhanced Neurogenesis

 Jeong Eun Shin  ;  Haejin Lee  ;  Kwangsoo Jung  ;  Miri Kim  ;  Kyujin Hwang  ;  Jungho Han  ;  Joohee Lim  ;  Il Sun Kim  ;  Kwang Il Lim  ;  Kook In Park 
 YONSEI MEDICAL JOURNAL, Vol.61(6) : 492-505, 2020-06 
Journal Title
Issue Date
Animals ; Animals, Newborn ; Basic Helix-Loop-Helix Transcription Factors / metabolism ; Bromodeoxyuridine / metabolism ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Hypoxia-Ischemia, Brain / pathology ; Hypoxia-Ischemia, Brain / therapy* ; Lateral Ventricles / cytology* ; Mice, Inbred ICR ; Nerve Tissue Proteins / metabolism ; Nestin / metabolism ; Neural Stem Cells / cytology* ; Neurogenesis*
Neural stem cells ; brain ; cell differentiation ; cell movement ; cell proliferation ; hypoxia-ischemia
Purpose: To elucidate the brain's intrinsic response to injury, we tracked the response of neural stem/progenitor cells (NSPCs) located in ventricular-subventricular zone (V-SVZ) to hypoxic-ischemic brain injury (HI). We also evaluated whether transduction of V-SVZ NSPCs with neurogenic factor NeuroD1 could enhance their neurogenesis in HI. Materials and methods: Unilateral HI was induced in ICR neonatal mice. To label proliferative V-SVZ NSPCs in response to HI, bromodeoxyuridine (BrdU) and retroviral particles encoding LacZ or NeuroD1/GFP were injected. The cellular responses of NSPCs were analyzed by immunohistochemistry. Results: Unilateral HI increased the number of BrdU+ newly-born cells in the V-SVZ ipsilateral to the lesion while injury reduced the number of newly-born cells reaching the ipsilateral olfactory bulb, which is the programmed destination of migratory V-SVZ NSPCs in the intact brain. These newly-born cells were directed from this pathway towards the lesions. HI significantly increased the number of newly-born cells in the cortex and striatum by the altered migration of V-SVZ cells. Many of these newly-born cells differentiated into active neurons and glia. LacZ-expressing V-SVZ NSPCs also showed extensive migration towards the non-neurogenic regions ipsilateral to the lesion, and expressed the neuronal marker NeuN. NeuroD1+/GFP+ V-SVZ NSPCs almost differentiated into neurons in the peri-infarct regions. Conclusion: HI promotes the establishment of a substantial number of new neurons in non-neurogenic regions, suggesting intrinsic repair mechanisms of the brain, by controlling the behavior of endogenous NSPCs. The activation of NeuroD1 expression may improve the therapeutic potential of endogenous NSPCs by increasing their neuronal differentiation in HI.
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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
Yonsei Authors
Park, Kook In(박국인) ORCID logo https://orcid.org/0000-0001-8499-9293
Shin, Jeong Eun(신정은) ORCID logo https://orcid.org/0000-0002-4376-8541
Lim, Joo Hee(임주희) ORCID logo https://orcid.org/0000-0003-4376-6607
Han, Jung Ho(한정호) ORCID logo https://orcid.org/0000-0001-6661-8127
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