Exp Neurobiol.  2019 Feb;28(1):85-103. 10.5607/en.2019.28.1.85.

Restorative Mechanism of Neural Progenitor Cells Overexpressing Arginine Decarboxylase Genes Following Ischemic Injury

• Kim JY
• Kim JY
• Kim JH
• Jung H
• Lee WT
• Lee JE

• KMID: 2439009
• DOI: http://doi.org/10.5607/en.2019.28.1.85

Abstract

Cell replacement therapy using neural progenitor cells (NPCs) following ischemic stroke is a promising potential therapeutic strategy, but lacks efficacy for human central nervous system (CNS) therapeutics. In a previous in vitro study, we reported that the overexpression of human arginine decarboxylase (ADC) genes by a retroviral plasmid vector promoted the neuronal differentiation of mouse NPCs. In the present study, we focused on the cellular mechanism underlying cell proliferation and differentiation following ischemic injury, and the therapeutic feasibility of NPCs overexpressing ADC genes (ADC-NPCs) following ischemic stroke. To mimic cerebral ischemia in vitro , we subjected the NPCs to oxygen-glucose deprivation (OGD). The overexpressing ADC-NPCs were differentiated by neural lineage, which was related to excessive intracellular calcium-mediated cell cycle arrest and phosphorylation in the ERK1/2, CREB, and STAT1 signaling cascade following ischemic injury. Moreover, the ADC-NPCs were able to resist mitochondrial membrane potential collapse in the increasingly excessive intracellular calcium environment. Subsequently, transplanted ADC-NPCs suppressed infarct volume, and promoted neural differentiation, synapse formation, and motor behavior performance in an in vivo tMCAO rat model. The results suggest that ADC-NPCs are potentially useful for cell replacement therapy following ischemic stroke.

Keyword

Ischemic stroke; Cell replacement therapy; Neural progenitor cells; Arginine decarboxylase; Cell cycle arrest; Neural differentiation

MeSH Terms

Animals
Arginine*
Brain Ischemia
Calcium
Cell Cycle Checkpoints
Cell Proliferation
Central Nervous System
Humans
In Vitro Techniques
Membrane Potential, Mitochondrial
Mice
Models, Animal
Neurons
Phosphorylation
Plasmids
Stem Cells*
Stroke
Synapses
Zidovudine
Arginine
Calcium
Zidovudine