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Article

Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis

1
Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
2
Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(12), 450; https://doi.org/10.3390/ph13120450
Received: 21 October 2020 / Revised: 30 November 2020 / Accepted: 4 December 2020 / Published: 9 December 2020
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos. View Full-Text
Keywords: atrophy; embryonic stem cells; exosomes; inflammation; macrophage; muscle toxicity atrophy; embryonic stem cells; exosomes; inflammation; macrophage; muscle toxicity
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MDPI and ACS Style

Dessouki, F.B.A.; Kukreja, R.C.; Singla, D.K. Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis. Pharmaceuticals 2020, 13, 450. https://doi.org/10.3390/ph13120450

AMA Style

Dessouki FBA, Kukreja RC, Singla DK. Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis. Pharmaceuticals. 2020; 13(12):450. https://doi.org/10.3390/ph13120450

Chicago/Turabian Style

Dessouki, Fatima B.A., Rakesh C. Kukreja, and Dinender K. Singla. 2020. "Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis" Pharmaceuticals 13, no. 12: 450. https://doi.org/10.3390/ph13120450

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