Abstract

Oligodendroglial progenitor/precursor cells (OPCs) represent the main cellular source for the generation of new myelinating oligodendrocytes in the adult central nervous system (CNS). In demyelinating diseases such as multiple sclerosis (MS) myelin repair activities based on recruitment, activation and differentiation of resident OPCs can be observed. However, the overall degree of successful remyelination is limited and the existence of an MS-derived anti-oligodendrogenic milieu prevents OPCs from contributing to myelin repair. It is therefore of considerable interest to understand oligodendroglial homeostasis and maturation processes in order to enable the development of remyelination therapies. Mesenchymal stem cells (MSC) have been shown to exert positive immunomodulatory effects, reduce demyelination, increase neuroprotection and to promote adult neural stem cell differentiation towards the oligodendroglial lineage. We here addressed whether MSC secreted factors can boost the OPC’s oligodendrogenic capacity in a myelin non-permissive environment. To this end, we analyzed cellular morphologies, expression and regulation of key factors involved in oligodendroglial fate and maturation of primary rat cells upon incubation with MSC-conditioned medium. This demonstrated that MSC-derived soluble factors promote and accelerate oligodendroglial differentiation, even under astrocytic endorsing conditions. Accelerated maturation resulted in elevated levels of myelin expression, reduced glial fibrillary acidic protein expression and was accompanied by downregulation of prominent inhibitory differentiation factors such as Id2 and Id4. We thus conclude that apart from their suggested application as potential anti-inflammatory and immunomodulatory MS treatment, these cells might also be exploited to support endogenous myelin repair activities.

Highlights

  • Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) and a leading cause of fixed neurological disability of young adults in Western countries

  • We have previously shown that co-culture of bone marrow derived Mesenchymal stem cells (MSC) and adult neural stem cell (aNSC) instructs neural stem cells to become oligodendroglial

  • In order to investigate mesenchymal mediated effects on oligodendroglial cells, Oligodendroglial progenitor/precursor cells (OPCs) were grown in control condition or mesenchymal stem cell conditioned medium (MSC-CM) and the distribution of cellular morphologies was determined as described previously [14,15]

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Summary

Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) and a leading cause of fixed neurological disability of young adults in Western countries. Naked axons are highly susceptible to the overall inflammatory environment resulting in neuronal damage and neurodegeneration, the extent of which dictates the level of permanent neurological disability. Repair activities are generally limited within the adult CNS, a certain degree of remyelination can be observed. This regenerative process is dependent on successful cell replacement, which is mainly mediated via endogenous oligodendroglial progenitor/precursor cell (OPC) activation [1]. Overall remyelination efficiency remains poor due to limited cellular differentiation and migration [2,3] or as a consequence of astrocytic cues, such as bone morphogenetic proteins (BMPs), as they have been shown to instruct progenitor cells to differentiate into glial cells expressing astrocyte characteristics [4]

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