Rescue from Shiga toxin 2-producing Escherichia coli-associated encephalopathy by intravenous injection of Muse cells in NOD-SCID mice

Abstract Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including IgG immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Muse cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Muse cells accumulate to the damaged tissue where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised NOD-SCID mice orally inoculated with 9×109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5×104 human bone marrow-derived multilineage-differentiating stress-enduring (Muse) cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNA interference abolished the beneficial effects of Muse cells, leading to a 40% lower survival rate and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.