Therapeutic effects of human amniotic epithelial cells in a murine model of multiple sclerosis
2017-05-18T04:43:11Z (GMT) by
Multiple sclerosis (MS) is an inflammatory demyelinating disease that has 1/1000 prevalence in the Western world. Current therapies for MS are only partially effective and are accompanied by undesirable side effects. In this thesis I examined a newly emerged placental-derived cell, amniotic epithelial cell (hAEC), as cell therapy for a myelin oligodendrocyte glycoprotein (MOG) peptide-induced MS model of experimental autoimmune encephalomyelitis (EAE). I tested the effects of hAEC in preventing or intervening EAE disease course. In both instances I found milder neurological signs, reduced inflammation in the spinal cord accompanied by lowered peripheral immune responses against MOG peptide. In searching for mechanisms by which hAEC mediate their therapeutic roles, I found that hAEC inhibited antigen-nonspecific and antigen-specific splenocyte proliferation in a dose-dependent manner. Transforming growth factor-β (TGF-β) and prostaglandin E2 (PGE2) are essential for this suppression in vitro. Because MS is thought to be a T cell-mediated disease, the ability to modulate T cell response is key to control MS progression. I found that splenic T cells from hAEC-treated EAE mice showed elevated IL-5 production, and in the intervention model there was also elevated production of IL-2 and IL-5. Peripheral immune cell populations in spleens and lymph nodes were mainly unchanged except for elevated regulatory T cells found in the intervention model after corticosteroid-induced remission followed by hAEC treatment. There were also decreased secretions of MOG-specific antibodies in sera of mice in both the prevention and intervention models, reflecting the alleviated peripheral autoimmune responses after hAEC treatment. hAEC were found in the lung but not other organs after intravenous delivery to EAE mice. My data suggest that hAEC may have potential as cell therapy for MS to prevent and to alleviate relapse of MS. Compared to primary hAEC, expanded hAEC in culture showed morphological changes, reduced suppressive capacity and lower production of immunomodulatory molecules. hAEC-derived hepatocyte-like cells exhibit immunogenicity, which is not evident in primary hAEC, but still retain immunomodulatory properties via secreted factors. These findings suggest that hAEC may also be applied as cell therapy for organ-specific diseases and tissue transplantation.