Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic

Tiffani C. Chance; Xiaowu Wu; Jeffrey D. Keesee; Josue Garcia-Marcano; Christi L. Salgado; Bin Liu; Jennifer J. Moseley; Kiel A. Peck; Luis R. Borlado; Nadia A. Atai; Stephen J. Gould; Linda S. Marban; Andrew P. Cap; Christopher R. Rathbone; James A. Bynum

doi:10.1097/TA.0000000000003218

Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic

Tiffani C. Chance, Xiaowu Wu, Jeffrey D. Keesee, Josue Garcia-Marcano, Christi L. Salgado, Bin Liu, Jennifer J. Moseley, Kiel A. Peck, Luis R. Borlado, Nadia A. Atai, Stephen J. Gould, Linda S. Marban, Andrew P. Cap, Christopher R. Rathbone, James A. Bynum

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined. METHODS: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock. RESULTS: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy. CONCLUSION: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.

Original language	English (US)
Pages (from-to)	S81-S88
Journal	Journal of Trauma and Acute Care Surgery
Volume	91
Issue number	2
DOIs	https://doi.org/10.1097/TA.0000000000003218
State	Published - Aug 2021

Keywords

Cardiosphere-derived cells
coagulation
extracellular vesicles
rat
shock

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine
Surgery

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10.1097/TA.0000000000003218

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Chance, T. C., Wu, X., Keesee, J. D., Garcia-Marcano, J., Salgado, C. L., Liu, B., Moseley, J. J., Peck, K. A., Borlado, L. R., Atai, N. A., Gould, S. J., Marban, L. S., Cap, A. P., Rathbone, C. R., & Bynum, J. A. (2021). Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic. Journal of Trauma and Acute Care Surgery, 91(2), S81-S88. https://doi.org/10.1097/TA.0000000000003218

Chance, TC, Wu, X, Keesee, JD, Garcia-Marcano, J, Salgado, CL, Liu, B, Moseley, JJ, Peck, KA, Borlado, LR, Atai, NA, Gould, SJ, Marban, LS, Cap, AP, Rathbone, CR & Bynum, JA 2021, 'Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic', Journal of Trauma and Acute Care Surgery, vol. 91, no. 2, pp. S81-S88. https://doi.org/10.1097/TA.0000000000003218

@article{20297124350648c584e0b8d6cc78f42b,

title = "Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic",

abstract = "BACKGROUND: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined. METHODS: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock. RESULTS: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy. CONCLUSION: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.",

keywords = "Cardiosphere-derived cells, coagulation, extracellular vesicles, rat, shock",

author = "Chance, {Tiffani C.} and Xiaowu Wu and Keesee, {Jeffrey D.} and Josue Garcia-Marcano and Salgado, {Christi L.} and Bin Liu and Moseley, {Jennifer J.} and Peck, {Kiel A.} and Borlado, {Luis R.} and Atai, {Nadia A.} and Gould, {Stephen J.} and Marban, {Linda S.} and Cap, {Andrew P.} and Rathbone, {Christopher R.} and Bynum, {James A.}",

note = "Funding Information: This research was supported in part by an appointment to the Student Research Participant Program at the US Army Institute of Surgical Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and United States Army Medical Research and Development Command (USAMRDC). Funding Information: The authors declare no conflicts of interest. The studies presented here were funded by the US Army Medical Research and Material Command Combat Casualty Care Research Program. The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Army Medical Department, Department of the Army, Department of Defense, or the US Government. Publisher Copyright: Copyright {\textcopyright} 2021 Wolters Kluwer Health, Inc. All rights reserved.",

year = "2021",

month = aug,

doi = "10.1097/TA.0000000000003218",

language = "English (US)",

volume = "91",

pages = "S81--S88",

journal = "Journal of Trauma and Acute Care Surgery",

issn = "2163-0755",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

TY - JOUR

T1 - Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic

AU - Chance, Tiffani C.

AU - Wu, Xiaowu

AU - Keesee, Jeffrey D.

AU - Garcia-Marcano, Josue

AU - Salgado, Christi L.

AU - Liu, Bin

AU - Moseley, Jennifer J.

AU - Peck, Kiel A.

AU - Borlado, Luis R.

AU - Atai, Nadia A.

AU - Gould, Stephen J.

AU - Marban, Linda S.

AU - Cap, Andrew P.

AU - Rathbone, Christopher R.

AU - Bynum, James A.

N1 - Funding Information: This research was supported in part by an appointment to the Student Research Participant Program at the US Army Institute of Surgical Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and United States Army Medical Research and Development Command (USAMRDC). Funding Information: The authors declare no conflicts of interest. The studies presented here were funded by the US Army Medical Research and Material Command Combat Casualty Care Research Program. The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Army Medical Department, Department of the Army, Department of Defense, or the US Government. Publisher Copyright: Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

PY - 2021/8

Y1 - 2021/8

N2 - BACKGROUND: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined. METHODS: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock. RESULTS: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy. CONCLUSION: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.

AB - BACKGROUND: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined. METHODS: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock. RESULTS: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy. CONCLUSION: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.

KW - Cardiosphere-derived cells

KW - coagulation

KW - extracellular vesicles

KW - rat

KW - shock

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Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic

Abstract

Keywords

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