Multiple sclerosis (MS) is characterized by an immunological attack of the myelin sheath which leads to demyelination and axonal degradation. This debilitating disorder typically manifests as a progressive loss of motor function, with most cases involving relapsing flare-ups throughout disease progression. The underlying pathophysiology of adult-onset MS is similar to pediatric MS, however pediatric disease typically displays more acute inflammatory responses leading to degeneration. According to the MS society, in the US alone, there are 8,000-10,000 children diagnosed with MS that suffer from frequent relapses. Current therapies for MS reduce the incidence of flare-ups, but do not prevent progressive axonal and neurological degeneration. Cell-based therapies using mesenchymal stem/stromal cells (MSCs) have been under investigation in clinical trials for neurogenerative diseases including adult MS. The placenta has been suggested to be a unique source of MSCs that possess robust immunomodulatory properties and have been reported to be beneficial in graft verse host diseases mouse models. MSCs derived from the placenta (PMSCs) may be a more appropriate cell source for pediatric diseases, because during pregnancy the placenta demonstrates fetomaternal tolerance, which is attributed to the expression of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule that inhibits natural killer cell (NK) killing. Unlike bone marrow derived MSCs (BM-MSCs), PMSCs express HLA-G on their surface in response to interferon gamma (IFN?), which is a key inflammatory mediator involved with the onset of MS. Therefore, the expression of HLA-G on PMSCs would make them a unique therapeutic cell source for the treatment of autoimmune diseases like pediatric MS. Currently, a clinical trial is underway using term placenta-derived PMSCs for adult MS and no paradoxical worsening of MS lesion counts was noted. Notably cell-based therapies are limited by potential immune rejection of donor cells and other safety concerns. Increasingly, 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. Conditioned media of BM-MSCs is shown to protect neurons from apoptosis, activate macrophages and be pro-angiogenic. In particular, hepatocyte growth factor (HGF) secreted by MSCs into conditioned medium mediates recovery in a murine model of MS. Currently, the use of MSC conditioned media is limited in that the secreted protein factors are unstable, which creates technical difficulties for off-the-shelf clinical use. MSC derived extracellular vesicles (EVs) alternatively, are stable under long term storage conditions compared to freely secreted proteins and may serve as a superior source for cell-free therapy. MSC-derived EVs readily cross the blood brain barrier (BBB) and deliver therapeutic cargo to reduce the effects of neuropathologic diseases, such as MS. It has been demonstrated that MSC-derived EVs exhibit systemic immunomodulatory effects and can facilitate neurological recovery in vitro. PMSC-EVs contain numerous proangiogenic, immunomodulatory, and neuroprotective proteins, including HGF. HGF is a pleiotropic factor shown to have neuronal and oligodendrocyte protective properties. In an experimental autoimmune encephalomyelitis (EAE) rodent model of MS, overexpression of HGF by neurons conferred neuroprotection by reducing inflammation in the CNS and activation of Tregs. HGF is secreted both in soluble form from MSCs and is also contained in exosomes; however, the effects of each form could lead to different cellular responses. It has been suggested that MSCs secrete multiple categories of exosomes, which are involved in differing cellular processes. Therefore, deciphering the molecular mechanism by which MSC-derived EVs alleviate the effects of neurodegenerative diseases is warranted. The goal of the current research project is to demonstrate the therapeutic potential of PMSC-EVs utilizing translational models of MS as well as to and to examine the role of HGF. These studies will be crucial as pre- investigational new drug data moving towards novel and bioengineered cell-free therapeutic treatments for MS patients.