Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

With the extensive utilization of radioactive materials for medical, industrial, agricultural, military, and research purposes, medical researchers are trying to identify new methods to treat acute radiation syndrome (ARS). Radiation may cause injury to different tissues and organs, but no single drug has been proven to be effective in all circumstances. Radioprotective agents are always effective if given before irradiation, but many nuclear accidents are unpredictable. Medical countermeasures that can be beneficial to different organ and tissue injuries caused by radiation are urgently needed. Cellular therapy, especially stem cell therapy, has been a promising approach in ARS. Hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) are the two main kinds of stem cells which show good efficacy in ARS and have attracted great attention from researchers. There are also some limitations that need to be investigated in future studies. In recent years, there are also some novel methods of stem cells that could possibly be applied on ARS, like “drug” stem cell banks obtained from clinical grade human induced pluripotent stem cells (hiPSCs), MSC-derived products, and infusion of HSCs without preconditioning treatment, which make us confident in the future treatment of ARS. This review focuses on major scientific and clinical advances of hematopoietic stem cells and mesenchymal stromal cells on ARS.

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PLX-R18- Placenta-derived Mesenchymal-like Stromal Cells are efficacious in reducing lethality in Gastrointestinal Acute Radiation Syndrome (GI-ARS) Mouse Model

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po2-6-31 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO2-6-31

Author(s):

Yoshiyuki Soeda ◽

Racheli Ofir ◽

Noa Sher ◽

Yoshiyuki Suzuki ◽

Zami Aberman ◽

...

Keyword(s):

Mouse Model ◽

Stromal Cells ◽

Acute Radiation ◽

Acute Radiation Syndrome

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Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

10.21203/rs.3.rs-16132/v4 ◽

2020 ◽

Author(s):

Alison Accarie ◽

Bruno L'homme ◽

Mohamedamine Benadjaoud ◽

Sai Kiang Lim ◽

Chadan Guha ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Intestinal Epithelium ◽

Stromal Cells ◽

Acute Radiation ◽

Whole Body ◽

Mucosal Barrier ◽

Acute Radiation Syndrome ◽

Radiation Induced ◽

Small Intestinal

Abstract Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: HumanMSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24 and 48 hours after lethal whole-body irradiation (10 Grays). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3) and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results: We demonstrated that MSC-derived extracellular vesicles treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Grays whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

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Small extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

10.21203/rs.3.rs-16132/v1 ◽

2020 ◽

Author(s):

Alison Accarie ◽

Bruno L'homme ◽

Mohamedamine Benadjaoud ◽

Sai Kiang Lim ◽

Chadan Guha ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Intestinal Epithelium ◽

Stromal Cells ◽

Acute Radiation ◽

Whole Body ◽

Mucosal Barrier ◽

Acute Radiation Syndrome ◽

Radiation Induced ◽

Small Intestinal

Abstract Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death could rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss and sepsis. In this study, we tested whether small extracellular vesicles/exosomes derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: Human MSC-derived small extracellular vesicles/exosomes were intravenously administered to NUDE mice, 3, 24 and 48 hours after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3) and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of small intestinal epithelium was determined by the quantification of epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using the methods of Kaplan-Meier and Cox. Results: We demonstrated that MSC-derived small extracellular vesicles/exosomes treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and thus increased their survival time. This effect could be attributed to the efficacy of MSC-derived small extracellular vesicles/exosomes in reducing mucosal barrier disruption. We showed that MSC-derived small extracellular vesicles/exosomes improved renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. MSC-derived small extracellular vesicles/exosomes also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions: MSC-derived small extracellular vesicles/exosomes promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived small extracellular vesicles/exosomes could be a treatment modality to limit acute radiation syndrome.

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Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

10.21203/rs.3.rs-16132/v3 ◽

2020 ◽

Author(s):

Alison Accarie ◽

Bruno L'homme ◽

Mohamedamine Benadjaoud ◽

Sai Kiang Lim ◽

Chadan Guha ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Intestinal Epithelium ◽

Stromal Cells ◽

Acute Radiation ◽

Whole Body ◽

Mucosal Barrier ◽

Acute Radiation Syndrome ◽

Radiation Induced ◽

Small Intestinal

Abstract Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24 and 48 hours after lethal whole-body irradiation (10 Grays). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3) and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results: We demonstrated that MSC-derived extracellular vesicles treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Grays whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium.Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

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Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase–expressing umbilical cord mesenchymal stromal cells

Cytotherapy ◽

10.1016/j.jcyt.2014.11.011 ◽

2015 ◽

Vol 17 (4) ◽

pp. 403-417 ◽

Cited By ~ 10

Author(s):

Jingyi Gan ◽

Fanwei Meng ◽

Xin Zhou ◽

Chan Li ◽

Yixin He ◽

...

Keyword(s):

Superoxide Dismutase ◽

Umbilical Cord ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Acute Radiation ◽

Acute Radiation Syndrome ◽

Hematopoietic Recovery

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Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.

10.21203/rs.3.rs-16132/v2 ◽

2020 ◽

Author(s):

Alison Accarie ◽

Bruno L'homme ◽

Mohamedamine Benadjaoud ◽

Sai Kiang Lim ◽

Chadan Guha ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Intestinal Epithelium ◽

Stromal Cells ◽

Acute Radiation ◽

Whole Body ◽

Mucosal Barrier ◽

Acute Radiation Syndrome ◽

Radiation Induced ◽

Small Intestinal

Abstract Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24 and 48 hours after lethal whole-body irradiation (10 Grays). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3) and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results: We demonstrated that MSC-derived extracellular vesicles treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Grays whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

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