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

Ryo Ozuru, Shohei Wakao, Takahiro Tsuji, Naoya Oohara, Takashi Matsuba, Muhammad Y. Amuran, Junko Isobe, Morio Iino, Naoki Nishida, Sari Matsumoto, Kimiharu Iwadate, Noriko Konishi, Kaori Yasuda, Kosuke Tashiro, Misato Hida, Arisato Yadoiwa, Shinsuke Kato, Eijiro Yamashita, Sohkichi Matsumoto, Yoichi KurozawaMari Dezawa, Jun Fujii

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
JournalMolecular Therapy
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Severe Combined Immunodeficiency
Brain Diseases
Intravenous Injections
Shiga-Toxigenic Escherichia coli
Escherichia coli
Granulocyte Colony-Stimulating Factor
Nervous System
Stem Cells
Escherichia coli Infections
Hemolytic-Uremic Syndrome
Plasma Exchange
Regenerative Medicine
Colitis
Sudden Death
RNA Interference
Intravenous Administration
Weight Loss
Anti-Inflammatory Agents
Therapeutics
Immunoglobulin G

Keywords

  • acute encephalopathy
  • Muse cells
  • Shiga toxin-producing Escherichia coli

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. / Ozuru, Ryo; Wakao, Shohei; Tsuji, Takahiro; Oohara, 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.

In: Molecular Therapy, 01.01.2019.

Research output: Contribution to journalArticle

Ozuru, R, Wakao, S, Tsuji, T, Oohara, N, Matsuba, T, Amuran, MY, Isobe, J, Iino, M, Nishida, N, Matsumoto, S, Iwadate, K, Konishi, N, Yasuda, K, Tashiro, K, Hida, M, Yadoiwa, A, Kato, S, Yamashita, E, Matsumoto, S, Kurozawa, Y, Dezawa, M & Fujii, J 2019, 'Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice', Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.09.023
Ozuru, Ryo ; Wakao, Shohei ; Tsuji, Takahiro ; Oohara, 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. / Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. In: Molecular Therapy. 2019.
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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 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.",
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AU - Ozuru, Ryo

AU - Wakao, Shohei

AU - Tsuji, Takahiro

AU - Oohara, 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

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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.

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KW - Shiga toxin-producing Escherichia coli

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