Caleb Ellis

Introduction. Multiple Sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system that leads to progressively worsening and permanent neurological defects.¹ MS is characterized by the activation of aberrant T-cells which then recognize and destroy myelinated neurons and oligodendrocytes, causing a massive inflammatory event and permanent neurological symptoms.^{1, 2} Current treatment options all hinge upon symptomatic management of the disease, however, mesenchymal stem cells have emerged as potential candidates for regenerative therapy for MS.¹ MSCs have been shown to have an immunosuppressive effect by inhibiting inflammatory T-cells and inducing anti-inflammatory T-regulatory cells.³ Specifically, MSCs are known to influence the differentiation of these inflammatory and regulatory T-cells by secreted soluble factors and direct cell-to-cell contact.^3,4 These findings all suggest a therapeutic potential for MSCs to mitigate the progression of MS. Methods. The majority of studies investigating the therapeutic potential of MSCs in autoimmune disease consist of in-vitro studies at a laboratory bench. These studies will soon transition to in-vivo models, and some already have, however this project focused on the mechanistic therapeutic action of MSCs in-vitro. Transwell co-culturing techniques were used to distinguish differences between soluble factors and direct cell-to-cell contact.^3,5,7 Other studies have progressed to test the therapeutic potential of MSCs in the experimental autoimmune encephalitis (EAE) model in mice with promising results.² Freud’s adjuvant is the preferred preparation to induce EAE.² Results. Human MSCs have been shown to ultimately secrete TGF-β1 and CCL18 into the microenvironment to skew differentiation of naïve T-cells into CD4+CD25+FOX3P regulatory T cells.³ Indirect skewing of monocytes into Type II anti-inflammatory macrophages by secretion of M-CSF and CCL18 played a key role in the induction of T-regs.³ MSC expression of ICOS ligand was critical for cell-to-cell contact induced T-reg differentiation.⁷ Release of the proinflammatory cytokine IL-1β activates MSC expression of ICOSL, spurring contact with naïve T-cell ICOS receptors, thus activating the phosphoinositine-3-kinase-AKT pathway which ultimately yields gene products that promote T-reg proliferation.⁷ Conclusions. MSCs have long been known to possess potential as therapeutic agents for autoimmune and inflammatory disease mediated by the innate and adaptive immune systems.^4,8 Many studies have yielded collaborating results that elucidate the mechanisms by which MSCs enact this immunomodulatory effect, primarily, through secreted mediators and direct cell-to-cell contact.^4,7,9 As studies progress to in-vivo trials in animal and human models, MSCs hold promising potential as a therapeutic agent to combat the complex pathogenesis of MS.

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9. Mónica Kurte, Patricia Luz-Crawford, Ana María Vega-Letter, et. al.. IL17/IL17RA as a novel signaling axis Driving Mesenchymal stem cell Therapeutic Function in experimental autoimmune encephalomyelitis. Front Immunol. 2018; 9: 802.