Abstract
Mesenchymal stem/stromal cells (MSCs) display potent immunomodulatory and regenerative capabilities through the secretion of bioactive factors, such as proteins, cytokines, chemokines as well as the release of extracellular vesicles (EVs). These functional properties of MSCs make them ideal candidates for the treatment of degenerative and inflammatory diseases, including multiple sclerosis (MS). MS is a heterogenous disease that is typically characterized by inflammation, demyelination, gliosis and axonal loss. In the current study, an induced experimental autoimmune encephalomyelitis (EAE) murine model of MS was utilized. At peak disease onset, animals were treated with saline, placenta-derived MSCs (PMSCs), as well as low and high doses of PMSC-EVs. Animals treated with PMSCs and high-dose PMSC-EVs displayed improved motor function outcomes as compared to animals treated with saline. Symptom improvement by PMSCs and PMSC-EVs led to reduced DNA damage in oligodendroglia populations and increased myelination within the spinal cord of treated mice. In vitro data demonstrate that PMSC-EVs promote myelin regeneration by inducing endogenous oligodendrocyte precursor cells to differentiate into mature myelinating oligodendrocytes. These findings support that PMSCs’ mechanism of action is mediated by the secretion of EVs. Therefore, PMSC-derived EVs are a feasible alternative to cellular based therapies for MS, as demonstrated in an animal model of the disease.
Highlights
Mesenchymal stem/stromal cells (MSCs) are highly proliferative fibroblast-like cells that can be isolated from multiple tissue sources and possess potent regenerative, immunomodulatory, neuroprotective and proangiogenic properties [1]
The exact molecular mechanism by which placenta-derived MSCs (PMSCs) confer therapeutic benefits for multiple sclerosis (MS) are largely unknown; these MSC functions have been shown to occur through paracrine signaling
Dose PMSC-extracellular vesicles (EVs)-treatment groups, suggesting that the PMSC secretory mechanism of action occurs. These findings demonstrate that the clinical benefits of PMSCs can be achieved by treatment through EV signaling in a dose-dependent manner
Summary
Mesenchymal stem/stromal cells (MSCs) are highly proliferative fibroblast-like cells that can be isolated from multiple tissue sources and possess potent regenerative, immunomodulatory, neuroprotective and proangiogenic properties [1]. The MSC secretome can include free proteins and contains extracellular vesicles (EVs), including exosomes, which are nanosized particles that are produced by budding from the endosomal membrane. MSCs provide therapeutic benefits and have immunoregulatory and neuroprotective properties that are achieved through multiple molecular mechanisms [5,6]. Studies have shown that MSC survival and integration within the host after transplantation are usually poor and that MSCs exert their therapeutic functions mainly via paracrine signaling mechanisms [8]. MSC-secreted EVs have promising cell-free-based regenerative therapeutic potential; the exact molecular mechanism by which MSCs and secreted-EVs exert immunoregulatory, neuroprotective and proangiogenic properties is poorly understood
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