Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Abstract

Background Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods MSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis. Results MSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways. Conclusions NSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs.

Human olfactory mesenchymal stromal cell transplantation ameliorates experimental autoimmune encephalomyelitis revealing an inhibitory role for IL16 on myelination

“…We found little evidence of GFP tagged hOM-MSCs present after 24 h, suggesting they do not survive long term in recipient animals. Although secondary homing to inflammatory or injured sites has been shown to occur, likely due to BBB disruption [ 1 , 2 , 4 , 39 , 67 ], in this investigation we found no hOM-MSCs within brain or spinal cord sections; only a few GFP profiles were detected within what appeared to be blood vessels. hBM-MSCs and human embryonic derived MSCs (hES-MSCs) have been shown to home to the CNS microvasculature, however only hES-MSCs had the capacity to extravasate and migrate into the parenchyma [ 54 ].…”

“…Many different types of human adult-tissue-derived MSCs have been shown to have therapeutic potential in the EAE model, although there has been large variability in the efficacy between cell types [ 7 , 35 – 39 ]. Tissue-specific stem cells support the tissue from which they originate, suggesting that certain MSC types might be more suitable for the treatment of EAE [ 40 ].…”

“…Indeed, biodistribution studies have shown that although MSCs accumulate firstly in the lungs within a few hours after i.v. infusion [ 59 – 61 ] they relocalise predominantly in the spleen [ 39 , 62 ]. It is also considered that the number of recirculating MSCs remain low [ 63 ] and that infused cells can undergo apoptosis [ 64 , 65 ].…”

Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases

“…It is mainly concurred that autoreactive T cells, stimulated by either self-reactive or cross-reactive antigens, result in demyelination and progressive neurodegeneration of the CNS. In spite of the fact that available therapies like drugs help to the reduction of MS development or decrease disability in these patients, they lead to serious side effects and do not reverse the manifestations of MS [ 62 , 63 ].…”

Beneficial Effect of Melatonin Alone or in Combination with Glatiramer Acetate and Interferon β-1b on Experimental Autoimmune Encephalomyelitis

“…Interestingly, patients treated with IFN-β continue with inflammation and neurodegeneration [8]. Recently, it was described that mesenchymal stem cells transplanted in EAE mice induce neurogenesis and an anti-inflammatory response that ameliorates the symptoms of encephalomyelitis [9].…”