Transplantation of human adipose-derived stem cells overexpressing LIF/IFN-β promotes recovery in experimental autoimmune encephalomyelitis (EAE)

Abstract

Multiple Sclerosis (MS) is the most common demyelinating disease with inflammatory demyelination in the central nerve system. Besides the defect in the myelin repair process, the balance change in inflammatory and anti- inflammatory cytokines is one of the most significant factors in MS pathogenesis. This study aimed at evaluating the effects of co-overexpressing beta interferon (IFN-β) and Leukemia inhibitory factor (LIF) in human adipose-derived stem cells (IFN-β/LIF-hADSCs) on the experimental autoimmune encephalomyelitis (EAE). 12 days after the induction of EAE on female mice C57Bl/6 with MOG35-55 and the emergence of primary clinical signs, the IFN-β/LIF-hADSCs were injected into the mice tail vein of the EAE mice. The mice were sacrificed after 32 days and the spinal cords of the experimental groups were dissected out for the histopathologic and real-time RT-PCR studies. Here, we showed that the clinical scores and infiltration of mononuclear cells of treated mice with IFN-β/LIF-hADSCs were decreased significantly. Demyelination and the number of Olig2+ and MBP+ cells were significantly increased in the test (IFN-β/LIF-hADSCs) group. The findings revealed that the pattern of inflammatory and anti- inflammatory cytokines gene expression in the IFN-β/LIF-hADSCs group was reversed compared to the control group. Overexpression of LIF as a neurotrophic and IFN-β as an anti-inflammatory cytokine in hADSCs increases the immunomodulatory effect of hADSCs reduces the extent of demyelination, improves the number of Olig2+ cells, and also increases the amount of MBP protein which can increase the production of myelin in EAE model. This, besides hADSCs capacity for proliferation and differentiation, might enhance the treatment efficacy and provide a promising candidate for stem cell-based gene therapy of MS therapy in the future.

Pathogenic Role of Adipose Tissue-Derived Mesenchymal Stem Cells in Obesity and Obesity-Related Inflammatory Diseases

“…The role of ASCs in EAE has been indirectly proven by their beneficial therapeutic effects, since administration of healthy ASCs has been shown to delay the disease onset and reduce disease severity by inhibiting immune cell proliferation [162]. Supporting these results, Yousefi et al demonstrated that transplantation of ASC-overexpressing leukemia inhibitory factor (LIF), a neurotropic agent, and IFNβ, an anti-inflammatory cytokine, promoted the recovery from EAE due to (i) increased immunomodulatory effects, (ii) reduction of the extent of demyelination, (iii) enhancement of the number of oligodendrocytes, and (iv) increase of the amount of MBP protein and further myelin production [163]. However, the anthropometric status of ASC donors appears of particular importance, since transplantation of ASCs from obese donors exacerbated EAE disease by increasing the expression of pro-inflammatory cytokines and inducing proliferation and differentiation of CD4 and CD8+ T cells.…”

Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force?

“…More recent studies on EAE mice, following intravenous administration of hAT-MSCs overexpressing IFN-b/LIF, reported a reduction in demyelination, an increase in the number of Olig2+ cells, and an elevation in the myelin basic protein (MBP) expression. This can, in turn, increase the production of myelin (Yousefi et al, 2022).…”

Stem cell therapies: a new era in the treatment of multiple sclerosis

“…Critically, stem cells exhibit immunomodulatory effects that attenuate inflammatory processes, offering a novel approach to mitigating the progression of MS lesions ( 5 ). Empirical studies, including laboratory and animal model research, have demonstrated the therapeutic efficacy of hematopoietic, neural, and embryonic stem cells, indicating substantial therapeutic promise ( 6 , 7 ). Preliminary clinical trials have corroborated these findings, signaling a promising horizon for individuals afflicted with MS ( 8 ).…”