Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice

• Published in: Molecular therapy 2020-01, Vol.28 (1), p.100-118
• Main Authors: Ozuru, Ryo, Wakao, Shohei, Tsuji, Takahiro, Ohara, Naoya, Matsuba, Takashi, Amuran, Muhammad Y., Isobe, Junko, Iino, Morio, Nishida, Naoki, Matsumoto, Sari, Iwadate, Kimiharu, Konishi, Noriko, Yasuda, Kaori, Tashiro, Kosuke, Hida, Misato, Yadoiwa, Arisato, Kato, Shinsuke, Yamashita, Eijiro, Matsumoto, Sohkichi, Kurozawa, Yoichi, Dezawa, Mari, Fujii, Jun
• Format: Article
• Language: English
• Subjects: acute encephalopathy; Adult; Aged, 80 and over; Animals; Antigens; Apoptosis; Body weight; Body weight loss; Bone marrow; Brain - pathology; Brain Diseases - epidemiology; Brain Diseases - metabolism; Brain Diseases - microbiology; Brain Diseases - therapy; Cell differentiation; Cell Transplantation - methods; Cerebrospinal fluid; Clinical trials; Colitis; Colonies; Colony-stimulating factor; Diabetes mellitus; Disease Models, Animal; Disease Outbreaks; E coli; Encephalopathy; Escherichia coli Infections - epidemiology; Escherichia coli Infections - microbiology; Escherichia coli Infections - therapy; Female; Fibroblasts; Granulocyte colony-stimulating factor; Hemolytic uremic syndrome; Hemorrhage; Humans; Immunoglobulin G; Immunomodulation; Infections; Inflammation; Injection; Injections; Injections, Intravenous; Intravenous administration; Japan - epidemiology; Leukocytes (granulocytic); Male; Mesenchymal Stem Cell Transplantation - methods; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Inbred NOD; Mice, SCID; Monoclonal antibodies; Muse cells; Neurological complications; Original; Regenerative medicine; Shiga Toxin 2 - metabolism; Shiga toxin-producing Escherichia coli; Shiga-Toxigenic Escherichia coli - metabolism; Spinal cord; Stem cells; Treatment Outcome; Tumor necrosis factor-TNF
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.09.023

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 immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (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, Musecells 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 non-obese diabetic/severe combined immunodeficiency (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 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death 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. [Display omitted] NOD-SCID mice orally inoculated with 9 × 109 colony-forming units of Shiga toxin-producing Escherichia coli (STEC) O111 and treated 48 h later with an intravenous injection of 5 × 104 human bone marrow-derived multilineage-differentiating stress-enduring (Muse) cells exhibited 100% survival. Thus, the intravenous administration of Muse cells might be a candidate therapeutic approach for preventing acute encephalopathy after STEC infection.