Investigation of Sequential Growth Factor Delivery during Cuprizone Challenge in Mice Aimed to Enhance Oligodendrogliogenesis and Myelin Repair

Jennifer K Sabo,Trevor J Kilpatrick,Holly S Cate,Tim D Aumann,Brahim Nait-Oumesmar

doi:10.1371/journal.pone.0063415

Jennifer K Sabo, Trevor J Kilpatrick + Show 3 more

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https://doi.org/10.1371/journal.pone.0063415

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Abstract

Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Furthermore, electron microscopy analysis revealed no change in average myelin thickness in the corpus callosum between vehicle infused and BMP4-Noggin infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone.

Highlights

Survival of oligodendrocytes is crucial for myelin integrity, which allows rapid saltatory conduction of action potentials to occur along axons [1]
The mini-osmotic pump delivering vehicle or BMP4 was replaced with a new pump delivering vehicle or Noggin for the final 7 days of a 6-week cuprizone challenge
There was a significant increase in density of Olig2+ and GFAP+ cells in the corpus callosum of BMP4-vehicle infused mice compared to vehiclevehicle (Figure 2A–D), while the density of GFAP+ cells was decreased in the vehicle-Noggin infused mice compared to BMP4vehicle (Figure 2B,D)

Summary

Introduction

Survival of oligodendrocytes is crucial for myelin integrity, which allows rapid saltatory conduction of action potentials to occur along axons [1]. In demyelinating diseases such as Multiple Sclerosis, oligodendrocytes undergo apoptotic death [2], which can lead to axons losing their myelin sheaths, degeneration of the axon and neuronal loss [1]. Overexpression of epidermal growth factor (EGF) in vivo enhanced oligodendrogliogenesis and remyelination in lysolecithin-demyelinated corpus callosum [6]. The deletion of brain-derived neurotrophic factor (BDNF) in vivo, increased numbers of OPCs during cuprizone-induced demyelination and decreased levels of myelin proteins during remyelination, suggesting impairment in OPC differentiation [7]. Work in our laboratory has shown that intraventricular infusion of Noggin, an inhibitor of Bone Morphogenic Protein (BMP) signalling, increased the number of oligodendrocytes within the remyelinating corpus callosum [8]

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