Adipose-Derived Mesenchymal Stem Cells Ameliorate Chronic Experimental Autoimmune Encephalomyelitis

Abstract

Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated a4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that a4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS. STEM CELLS

Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…This property has not only sparked clinical trials demonstrating effi cacy in graftversus-host disease (GVHD) but also expanded research to explore potential application in other infl ammatory and autoimmune diseases. For instance, systemic administration of autologous MSC suppresses antigen-specifi c T-cell immunity and subsequent central nervous system (CNS) infl ammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) [4][5][6][7][8][9]. MSC regulate multiple cellular components of the immune system such as the maturation and differentiation of antigen-presenting cells (APC), the activation of natural killer (NK) cells, and the activation and expansion of CD4 + and CD8 + T cells [10][11][12][13][14].…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…Adipose tissue contains hundreds of thousands of MSCs in each gram of fat (Sen et al, 2001), whereas BMMSCs in the bone marrow fraction constitute a mere 0.0001-0.01% of all nucleated cells (Pittenger et al, 1999). In particular, ADMSCs differentiate into several cell types (Constantin et al, 2009), and, unlike embryonic stem cells, are an ethically uncontroversial source for stem cell therapy (Díaz-Prado et al, 2011).…”

Adipose-derived stromal/stem cells

“…Independent teams have reported positive outcomes in murine models of allergic rhinitis, arthritis, graft vs. host disease, and systemic lupus erythematosis. [45][46][47][48] The 49 This correlated with increased levels of cytokines associated with Th2 helper cells, such as interleukin 4 and 10. 49 Both murine and human SVF cells and ASCs delivered intraperitoneally at the time of antigen exposure offered comparable protection in the murine EAE model (B. Bunnell, manuscript in preparation).…”