TY - JOUR
T1 - Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice
AU - Ozuru, Ryo
AU - Wakao, Shohei
AU - Tsuji, Takahiro
AU - Ohara, Naoya
AU - Matsuba, Takashi
AU - Amuran, Muhammad Y.
AU - Isobe, Junko
AU - Iino, Morio
AU - Nishida, Naoki
AU - Matsumoto, Sari
AU - Iwadate, Kimiharu
AU - Konishi, Noriko
AU - Yasuda, Kaori
AU - Tashiro, Kosuke
AU - Hida, Misato
AU - Yadoiwa, Arisato
AU - Kato, Shinsuke
AU - Yamashita, Eijiro
AU - Matsumoto, Sohkichi
AU - Kurozawa, Yoichi
AU - Dezawa, Mari
AU - Fujii, Jun
N1 - Funding Information:
This study was partly funded by the Research Program of the International Platform for Dryland Research and Education, Tottori University , and Yakult Grants for Research on Lactic Acid Bacteria . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Animal Research Facility, Tottori University for mouse care support. We would like to thank Genostaff Co., Ltd., Japan for technical support of immunohistochemistry. This research was partly performed at the Tottori Bio Frontier, managed by Tottori prefecture. We would like to thank Hideki Nakazato (Charles River Laboratories, Japan) for providing NOD-SCID mice to adjust mouse body weight, Mr. Nobuyuki Endo (Keyence, Japan) for technical support of all-in-one microscopy, and Mr. Masato Takiguchi (ZEISS Research, Japan) for technical support of confocal microscopy LSM780. Finally, we thank Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan for providing MMC with free charge.
Funding Information:
This study was partly funded by the Research Program of the International Platform for Dryland Research and Education, Tottori University, and Yakult Grants for Research on Lactic Acid Bacteria. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Animal Research Facility, Tottori University for mouse care support. We would like to thank Genostaff Co. Ltd. Japan for technical support of immunohistochemistry. This research was partly performed at the Tottori Bio Frontier, managed by Tottori prefecture. We would like to thank Hideki Nakazato (Charles River Laboratories, Japan) for providing NOD-SCID mice to adjust mouse body weight, Mr. Nobuyuki Endo (Keyence, Japan) for technical support of all-in-one microscopy, and Mr. Masato Takiguchi (ZEISS Research, Japan) for technical support of confocal microscopy LSM780. Finally, we thank Kyowa Hakko Kogyo Co. Ltd. Tokyo, Japan for providing MMC with free charge.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Muse cells
KW - Shiga toxin-producing Escherichia coli
KW - acute encephalopathy
UR - http://www.scopus.com/inward/record.url?scp=85073060799&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073060799&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2019.09.023
DO - 10.1016/j.ymthe.2019.09.023
M3 - Article
C2 - 31607541
AN - SCOPUS:85073060799
SN - 1525-0016
JO - Molecular Therapy
JF - Molecular Therapy
ER -
