Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury: Insights Into the SENECA Trial.

Autor:	O'Brien CG; Department of Medicine, Division of Cardiology, University California San Francisco School of Medicine, San Francisco, California, USA., Ozen MO; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Bio-Acoustic MEMS in Medicine BAMM Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Stanford University, Palo Alto, California, USA., Ikeda G; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Vaskova E; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Jung JH; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Bayardo N; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Santoso MR; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Shi L; Department of Geriatric Cardiovascular Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China., Wahlquist C; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Jiang Z; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, California, USA., Jung Y; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, California, USA., Zeng Y; Department of Materials Science and Engineering, Stanford University, Stanford, California, USA., Egan E; Department of Pediatrics (Infectious Diseases), Stanford University School of Medicine, Stanford, California, USA., Sinclair R; Department of Materials Science and Engineering, Stanford University, Stanford, California, USA., Gee A; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA., Witteles R; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Mercola M; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA., Svensson KJ; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, California, USA., Demirci U; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Bio-Acoustic MEMS in Medicine BAMM Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Stanford University, Palo Alto, California, USA.; Department of Electrical Engineering (by courtesy), Stanford, California, USA., Yang PC; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
Jazyk:	angličtina
Zdroj:	JACC. CardioOncology [JACC CardioOncol] 2021 Jul 27; Vol. 3 (3), pp. 428-440. Date of Electronic Publication: 2021 Jul 27 (Print Publication: 2021).
DOI:	10.1016/j.jaccao.2021.05.006
Abstrakt:	Background: Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification. Objectives: The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients. Methods: Patient-specific iCMs were injured with 1 μmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system. Results: iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy. Conclusions: L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs. Competing Interests: Funding for this project was provided by the F-32 Ruth L Kirschstein National Research Service Award and the K-24 Midcareer Investigator Award in Patient Oriented Research from the National Institutes of Health (NIH); and by the Cardiovascular Cell Therapy Research Network (CCTRN) via the UM1 award entitled Regional Clinical Centers for the Cardiovascular Cell Therapy Research Network, University of Texas Health Science Center. The Cardiac Cell Therapy Research Network provided support under the cooperative NIH-sponsored 5UM1HL11345604, 5UM1HL087318-0, and K24HL130553 (all to Dr Yang). Additional project support was provided by an NIH R00 grant (DK111916), Jacob Churg Foundation, McCormick and Gabilan Award, and NIH P30 grant (DK116074) (all to Dr Svensson); NIH F-32 Award (5F32HL139046-02 to Dr O’Brien); and American Heart Association (18CDA34070040 to Dr Wahlquist, 18POST34080005 to Dr Jung, and 20POST35120540 to Dr Ikeda). Dr Gee is a member of the SENECA trial team. Dr Witteles is an associate editor of JACC: CardioOncology. Dr Demirci is a founder of and has an equity interest in DxNow Inc, a company that is developing microfluidic IVF tools and imaging technologies; Koek Biotech, a company that is developing microfluidic technologies for clinical solutions; Levitas Inc, a company focusing on developing microfluidic sorters using magnetic levitation; and Hillel Inc, a company bringing microfluidic cell phone tools to home settings; these interests were viewed and managed in accordance with the conflict of interest policies. Dr Yang is a consultant for Terumo Corporation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. (© 2021 The Authors.)
Databáze:	MEDLINE
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