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

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Abstract

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.

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High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources

Reka Haraszti, Marie Cecile Didiot, Ellen Sapp … (2016)

Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are explored for use in diagnostics, therapeutics and drug delivery. However, little is known about the relationship of protein and lipid composition of EVs and their source cells. Here, we report high-resolution lipidomic and proteomic analyses of exosomes and MVs derived by differential ultracentrifugation from 3 different cell types: U87 glioblastoma cells, Huh7 hepatocellular carcinoma cells and human bone marrow-derived mesenchymal stem cells (MSCs). We identified 3,532 proteins and 1,961 lipid species in the screen. Exosomes differed from MVs in several different areas: (a) The protein patterns of exosomes were more likely different from their cells of origin than were the protein patterns of MVs; (b) The proteomes of U87 and Huh7 exosomes were similar to each other but different from the proteomes of MSC exosomes, whereas the lipidomes of Huh7 and MSC exosomes were similar to each other but different from the lipidomes of U87 exosomes; (c) exosomes exhibited proteins of extracellular matrix, heparin-binding, receptors, immune response and cell adhesion functions, whereas MVs were enriched in endoplasmic reticulum, proteasome and mitochondrial proteins. Exosomes and MVs also differed in their types of lipid contents. Enrichment in glycolipids and free fatty acids characterized exosomes, whereas enrichment in ceramides and sphingomyelins characterized MVs. Furthermore, Huh7 and MSC exosomes were specifically enriched in cardiolipins; U87 exosomes were enriched in sphingomyelins. This study comprehensively analyses the protein and lipid composition of exosomes, MVs and source cells in 3 different cell types.

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Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

Paul W Armstrong, Burkert M. Pieske, Kevin J Anstrom … (2020)

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Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.

G M Felker, R E Thompson, J M Hare … (2000)

Previous studies of the prognosis of patients with heart failure due to cardiomyopathy categorized patients according to whether they had ischemic or nonischemic disease. The prognostic value of identifying more specific underlying causes of cardiomyopathy is unknown. We evaluated the outcomes of 1230 patients with cardiomyopathy. The patients were grouped into the following categories according to underlying cause: idiopathic cardiomyopathy (616 patients), peripartum cardiomyopathy (51); and cardiomyopathy due to myocarditis (111), ischemic heart disease (91), infiltrative myocardial disease (59), hypertension (49), human immunodeficiency virus (HIV) infection (45), connective-tissue disease (39), substance abuse (37), therapy with doxorubicin (15), and other causes (117). Cox proportional-hazards analysis was used to assess the association between the underlying cause of cardiomyopathy and survival. During a mean follow-up of 4.4 years, 417 patients died and 57 underwent cardiac transplantation. As compared with the patients with idiopathic cardiomyopathy, the patients with peripartum cardiomyopathy had better survival (adjusted hazard ratio for death, 0.31; 95 percent confidence interval, 0.09 to 0.98), and survival was significantly worse among the patients with cardiomyopathy due to infiltrative myocardial disease (adjusted hazard ratio, 4.40; 95 percent confidence interval, 3.04 to 6.39), HIV infection (adjusted hazard ratio, 5.86; 95 percent confidence interval, 3.92 to 8.77), therapy with doxorubicin (adjusted hazard ratio, 3.46; 95 percent confidence interval, 1.67 to 7.18), and ischemic heart disease (adjusted hazard ratio, 1.52; 95 percent confidence interval, 1.07 to 2.17). The underlying cause of heart failure has prognostic value in patients with unexplained cardiomyopathy. Patients with peripartum cardiomyopathy appear to have a better prognosis than those with other forms of cardiomyopathy. Patients with cardiomyopathy due to infiltrative myocardial diseases, HIV infection, or doxorubicin therapy have an especially poor prognosis.

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Author and article information

Contributors

Connor G. O’Brien: @coobrien

Phillip C. Yang

Journal

Journal ID (nlm-ta): JACC CardioOncol

Journal ID (iso-abbrev): JACC CardioOncol

Title: JACC: CardioOncology

Publisher: Elsevier

ISSN (Electronic): 2666-0873

Publication date PMC-release: 27 July 2021

Publication date Collection: September 2021

Publication date (Electronic): 27 July 2021

Volume: 3

Issue: 3

Pages: 428-440

Affiliations

[a ]Department of Medicine, Division of Cardiology, University California San Francisco School of Medicine, San Francisco, California, USA

[b ]Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA

[c ]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

[d ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA

[e ]Department of Geriatric Cardiovascular Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China

[f ]Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

[g ]Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, California, USA

[h ]Department of Materials Science and Engineering, Stanford University, Stanford, California, USA

[i ]Department of Pediatrics (Infectious Diseases), Stanford University School of Medicine, Stanford, California, USA

[j ]Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA

[k ]Department of Electrical Engineering (by courtesy), Stanford, California, USA

Author notes

[∗ ] Address for correspondence: Dr Phillip C. Yang, Division of Cardiovascular Medicine, Department of Medicine, Stanford University, 240 Pasteur Drive, BMI 3053, Stanford, California 94304, USA. phillip@ 123456stanford.edu

[∗]

Drs O’Brien and Ozen contributed equally to this work.

Article

Publisher Item ID: S2666-0873(21)00146-0

DOI: 10.1016/j.jaccao.2021.05.006

PMC ID: 8463733

PubMed ID: 34604804

SO-VID: 4ca7ca96-a921-44d6-93e4-8ae327e8ff34

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 27 September 2020

Date revision received : 29 April 2021

Date accepted : 11 May 2021

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

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Abstract

Background

Objectives

Methods

Results

Conclusions

Central Illustration

Related collections

Bacterial extracellular vesicles

Most cited references 30

High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources

Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.

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Cited by 33

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