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Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy

BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be...

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Autores principales: Nitahara-Kasahara, Yuko, Nakayama, Soya, Kimura, Koichi, Yamaguchi, Sho, Kakiuchi, Yuko, Nito, Chikako, Hayashi, Masahiro, Nakaishi, Tomoyuki, Ueda, Yasuyoshi, Okada, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142496/
https://www.ncbi.nlm.nih.gov/pubmed/37106393
http://dx.doi.org/10.1186/s13287-023-03337-0
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author Nitahara-Kasahara, Yuko
Nakayama, Soya
Kimura, Koichi
Yamaguchi, Sho
Kakiuchi, Yuko
Nito, Chikako
Hayashi, Masahiro
Nakaishi, Tomoyuki
Ueda, Yasuyoshi
Okada, Takashi
author_facet Nitahara-Kasahara, Yuko
Nakayama, Soya
Kimura, Koichi
Yamaguchi, Sho
Kakiuchi, Yuko
Nito, Chikako
Hayashi, Masahiro
Nakaishi, Tomoyuki
Ueda, Yasuyoshi
Okada, Takashi
author_sort Nitahara-Kasahara, Yuko
collection PubMed
description BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be an option for DMD patients. We focused on amnion-derived mesenchymal stromal cells (AMSCs), a clinically viable cell source owing to their unique characteristics, such as non-invasive isolation, mitotic stability, ethical acceptability, and minimal risk of immune reaction and cancer. We aimed to identify novel immunomodulatory effects of AMSCs on macrophage polarization and their transplantation strategies for the functional recovery of skeletal and cardiac muscles. METHODS: We used flow cytometry to analyze the expression of anti-inflammatory M2 macrophage markers on peripheral blood mononuclear cells (PBMCs) co-cultured with human AMSCs (hAMSCs). hAMSCs were intravenously injected into DMD model mice (mdx mice) to assess the safety and efficacy of therapeutic interventions. hAMSC-treated and untreated mdx mice were monitored using blood tests, histological examinations, spontaneous wheel-running activities, grip strength, and echocardiography. RESULTS: hAMSCs induced M2 macrophage polarization in PBMCs via prostaglandin E(2) production. After repeated systemic hAMSC injections, mdx mice exhibited a transient downregulation of serum creatin kinase. Limited mononuclear cell infiltration and a decreased number of centrally nucleated fibers were indicative of regenerated myofibers following degeneration, suggesting an improved histological appearance of the skeletal muscle of hAMSC-treated mdx mice. Upregulated M2 macrophages and altered cytokine/chemokine expressions were observed in the muscles of hAMSC-treated mdx mice. During long-term experiments, a significant decrease in the grip strength in control mdx mice significantly improved in the hAMSC-treated mdx mice. hAMSC-treated mdx mice maintained running activity and enhanced daily running distance. Notably, the treated mice could run longer distances per minute, indicating high running endurance. Left ventricular function in DMD mice improved in hAMSC-treated mdx mice. CONCLUSIONS: Early systemic hAMSC administration in mdx mice ameliorated progressive phenotypes, including pathological inflammation and motor dysfunction, resulting in the long-term improvement of skeletal and cardiac muscle function. The therapeutic effects might be associated with the immunosuppressive properties of hAMSCs via M2 macrophage polarization. This treatment strategy could provide therapeutic benefits to DMD patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03337-0.
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spelling pubmed-101424962023-04-29 Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy Nitahara-Kasahara, Yuko Nakayama, Soya Kimura, Koichi Yamaguchi, Sho Kakiuchi, Yuko Nito, Chikako Hayashi, Masahiro Nakaishi, Tomoyuki Ueda, Yasuyoshi Okada, Takashi Stem Cell Res Ther Research BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be an option for DMD patients. We focused on amnion-derived mesenchymal stromal cells (AMSCs), a clinically viable cell source owing to their unique characteristics, such as non-invasive isolation, mitotic stability, ethical acceptability, and minimal risk of immune reaction and cancer. We aimed to identify novel immunomodulatory effects of AMSCs on macrophage polarization and their transplantation strategies for the functional recovery of skeletal and cardiac muscles. METHODS: We used flow cytometry to analyze the expression of anti-inflammatory M2 macrophage markers on peripheral blood mononuclear cells (PBMCs) co-cultured with human AMSCs (hAMSCs). hAMSCs were intravenously injected into DMD model mice (mdx mice) to assess the safety and efficacy of therapeutic interventions. hAMSC-treated and untreated mdx mice were monitored using blood tests, histological examinations, spontaneous wheel-running activities, grip strength, and echocardiography. RESULTS: hAMSCs induced M2 macrophage polarization in PBMCs via prostaglandin E(2) production. After repeated systemic hAMSC injections, mdx mice exhibited a transient downregulation of serum creatin kinase. Limited mononuclear cell infiltration and a decreased number of centrally nucleated fibers were indicative of regenerated myofibers following degeneration, suggesting an improved histological appearance of the skeletal muscle of hAMSC-treated mdx mice. Upregulated M2 macrophages and altered cytokine/chemokine expressions were observed in the muscles of hAMSC-treated mdx mice. During long-term experiments, a significant decrease in the grip strength in control mdx mice significantly improved in the hAMSC-treated mdx mice. hAMSC-treated mdx mice maintained running activity and enhanced daily running distance. Notably, the treated mice could run longer distances per minute, indicating high running endurance. Left ventricular function in DMD mice improved in hAMSC-treated mdx mice. CONCLUSIONS: Early systemic hAMSC administration in mdx mice ameliorated progressive phenotypes, including pathological inflammation and motor dysfunction, resulting in the long-term improvement of skeletal and cardiac muscle function. The therapeutic effects might be associated with the immunosuppressive properties of hAMSCs via M2 macrophage polarization. This treatment strategy could provide therapeutic benefits to DMD patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03337-0. BioMed Central 2023-04-27 /pmc/articles/PMC10142496/ /pubmed/37106393 http://dx.doi.org/10.1186/s13287-023-03337-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Nitahara-Kasahara, Yuko
Nakayama, Soya
Kimura, Koichi
Yamaguchi, Sho
Kakiuchi, Yuko
Nito, Chikako
Hayashi, Masahiro
Nakaishi, Tomoyuki
Ueda, Yasuyoshi
Okada, Takashi
Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title_full Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title_fullStr Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title_full_unstemmed Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title_short Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy
title_sort immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of duchenne muscular dystrophy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142496/
https://www.ncbi.nlm.nih.gov/pubmed/37106393
http://dx.doi.org/10.1186/s13287-023-03337-0
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