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.
ABSTRACT
Mesenchymal stem cells (MSCs) have emerged as a potentially powerful cellular therapy for autoimmune diseases including multiple sclerosis (MS). Based on their success in treating animal models of MS like experimental autoimmune encephalomyelitis (EAE), MSCs have moved rapidly into clinical trials for MS. The majority of these trials use autologous MSCs derived from MS patients, although it remains unclear how CNS disease may affect these cells. Here, we report that bone marrow MSCs derived from EAE mice lack therapeutic efficacy compared to naïve MSCs in their ability to ameliorate EAE. Treatment with conditioned medium from EAE-MSCs also fails to modulate EAE, and EAE-MSCs secrete higher levels of many pro-inflammatory cytokines compared to naïve MSCs. Similarly, MSCs derived from MS patients have less therapeutic efficacy than naïve MSCs in treating EAE and secrete higher levels of some of the same pro-inflammatory cytokines. Thus diseases like EAE and MS diminish the therapeutic functionality of bone marrow MSCs, prompting reevaluation about the ongoing use of autologous MSCs as a treatment for MS.
