Temporal Response of Neural Progenitor Cells to Disease Onset and Progression in Amyotrophic Lateral Sclerosis-Like Transgenic Mice

Abstract

Regenerative medicine through neural stem cells (NSCs) or neural progenitor cells (NPCs) has been proposed as an alterative avenue for restoring neurological dysfunction in amyotrophic lateral sclerosis (ALS). It is critical to understand the organization and distribution of endogenous adult NPCs in response to motor neuron degeneration before regenerative medicine can be applied for ALS therapy. For this reason, we analyzed the temporal response of NPCs to motor neuron degeneration in the spinal cord and brain using nestin enhancer-driven LacZ reporter transgenic mice (pNes-Tg mice, control) and bi-transgenic mice containing both the nestin enhancer-driven LacZ reporter gene and mutant G93A-SOD1 gene (Bi-Tg mice). We observed an increase of NPCs in the dorsal horns of the spinal cord at the disease onset and progression stages in the Bi-Tg mice compared with that of age-matched pNes-Tg control mice. In contrast, an increase of NPCs in the ventral horns was detected at the disease progression stage. On the other hand, an increase of NPCs in the motor cortex at the disease-onset stage, but not at the disease progression stage, was detected. Furthermore, a decrease of NPCs in the lateral ventricle at the disease progression stage was observed, whereas no difference in the number of NPCs in the hippocampus was detected at the disease onset and progression stages. Some of the NPCs differentiate into neuron-like cells in response to motor neuron degeneration. The organization and distribution of endogenous adult NPCs in the ALS-like transgenic mice at the disease onset and progression stages provide fundamental bases for consideration of regenerative therapy of ALS by increasing de novo neurogenesis.