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

Yonsei Medical Journal 2020년 61권 6호 p.492 ~ 505
신정은 ( Shin Jeong-Eun ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics

이해진 ( Lee Hae-Jin ) - Yonsei University College of Medicine Yonsei Biomedical Research Institute
정광수 ( Jung Kwang-Soo ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
김미리 ( Kim Mi-Ri ) - Yonsei University College of Medicine Yonsei Biomedical Research Institute
 ( Hwang Kyu-Jin ) - Yonsei University College of Medicine Brain Korea 21 PLUS Project for Medical Science
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
김일선 ( Kim Il-Sun ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics
 ( Lim Kwang-Il ) - Sookmyung Women’s University Department of Chemical and Biological Engineering
박국인 ( Park Kook-In ) - Yonsei University College of Medicine Severance Children’s Hospital Department of Pediatrics

Abstract


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.

키워드

Neural stem cells; hypoxia-ischemia; brain; cell proliferation; cell movement; cell differentiation
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