Transcriptional Profiling of Mesenchymal Stem Cells Identifies Distinct Neuroimmune Pathways Altered by CNS Disease.

ABSTRACT

BACKGROUND AND OBJECTIVES: Bone marrow mesenchymal stem cells (BM-MSCs) are an attractive cell based therapy in the treatment of CNS demyelinating diseases such as multiple sclerosis (MS). Preclinical studies demonstrate that BM-MSCs can effectively reduce clinical burden and enhance recovery in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. However, a number of recent clinical trials have not shown significant functional benefit following BM-MSC infusion into MS patients. One possibility for the discrepancy between animal and human studies is the source of the cells, as recent studies suggest BM-MSCs from MS patients or animals with EAE lack reparative efficacy compared to naïve cells. We sought to define important transcriptional and functional differences between diseased and naïve MSCs. METHODS AND RESULTS: We utilized RNA Sequencing (RNA-Seq) to assess changes in gene expression between BM-MSCs derived from EAE animals and those derived from healthy controls. We show that EAE alters the expression of a large number of genes in BM-MSCs and changes in gene expression are more pronounced in chronic versus acute disease. Bioinformatic analysis revealed extensive perturbations in BM-MSCs in pathways related to inflammation and the regulation of neural cell development. These changes suggest that signals from EAE derived BM-MSCs inhibit rather than enhance remyelination, and in-vitro studies showed that conditioned medium from EAE MSCs fails to support the development of mature oligodendrocytes, the myelinating cells of the CNS. CONCLUSIONS: These data provide insight into the failure of autologous BM-MSCs to promote recovery in MS and support the concept of utilizing non-autologous MSCs in future clinical trials.