Chemokines and Inflammatory Mediators Interact to Regulate Adult Murine Neural Precursor Cell Proliferation, Survival and Differentiation

Alisa Turbic,Ann M Turnley,Soo Yuen Leong,Malú G Tansey

doi:10.1371/journal.pone.0025406

Abstract

Adult neural precursor cells (NPCs) respond to injury or disease of the CNS by migrating to the site of damage or differentiating locally to replace lost cells. Factors that mediate this injury induced NPC response include chemokines and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), which we have shown previously promotes neuronal differentiation. RT-PCR was used to compare expression of chemokines and their receptors in normal adult mouse brain and in cultured NPCs in response to IFNγ and TNFα. Basal expression of many chemokines and their receptors was found in adult brain, predominantly in neurogenic regions, with OB≫SVZ>hippocampus and little or no expression in non-neurogenic regions, such as cortex. Treatment of SVZ-derived NPCs with IFNγ and TNFα (alone and in combination) resulted in significant upregulation of expression of specific chemokines, with CXCL1, CXCL9 and CCL2 most highly upregulated and CCL19 downregulated. Unlike IFNγ, chemokine treatment of NPCs in vitro had little or no effect on survival, proliferation or migration. Neuronal differentiation was promoted by CXCL9, CCL2 and CCL21, while astrocyte and total oligodendrocyte differentiation was not affected. However, IFNγ, CXCL1, CXCL9 and CCL2 promoted oligodendrocyte maturation. Therefore, not only do NPCs express chemokine receptors, they also produce several chemokines, particularly in response to inflammatory mediators. This suggests that autocrine or paracrine production of specific chemokines by NPCs in response to inflammatory mediators may regulate differentiation into mature neural cell types and may alter NPC responsiveness to CNS injury or disease.

Highlights

Effective neural repair is likely to require a multi-factorial approach, including blockage of neuronal death and replacement of lost cells by differentiation of neural precursor cells (NPCs)
Neurogenic regions of the adult brain (SVZ and hippocampus) have previously been shown to express the chemokine receptors CXCR3, CXCR4, CCR1, CCR2 and CCR5 [19]. We have extended these studies to analyze expression of CXC chemokines, CXC receptors, CCR receptors and CX3C and XC chemokines and receptors in neurogenic regions and the olfactory bulb, the destination of subventricular zone (SVZ)-derived NPCs versus non-neurogenic cortex by qPCR (Fig. 1) and semi-quantitative RT-PCR (Table 3)
Expression of the CXC and CC receptors was largely restricted to neurogenic regions, with only CXCR3, CXCR4, CXCR6, CCR2, CCR6 and CCR9 expressed at low levels in cortex

Summary

Introduction

Effective neural repair is likely to require a multi-factorial approach, including blockage of neuronal death and replacement of lost cells by differentiation of neural precursor cells (NPCs). The role of selected chemokines alone or in combination with IFNc, on neural precursor proliferation, survival, migration and differentiation was examined

Materials and Methods

Results

Discussion