Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury

O’Brien, Connor; Özen, Mehmet Özgün; Ikeda, Gentaro; Vaskova, Evgeniya; Jung, Ji Hye; Bayardo, Nathan; Santoso, Michelle; Shi, Liye; Wahlquist, Christine; Jiang, Zewen; Jung, Yunshin; Zeng, Yitian; Egan, Elizabeth S.; Sinclair, Robert; Gee, Adrian P.; Witteles, Ronald; Mercola, Mark; Svensson, Katrin J.; Demirci, Utkan; Yang, Phillip C.

doi:10.1016/j.jaccao.2021.05.006

Cited by 59 publications

(45 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the transport of mitochondria from a healthy cell can potentially replace damaged mitochondria to rescue mitochondrial function [164,165]. Consistent with this, hPSC-cardiomyocytes have been shown to take up exogenous mitochondria and incorporate them into the existing mitochondrial network, resulting in improved contractility, calcium flux, and ATP production when challenged with DOX [166,167]. The transplantation of stem cells, including mesenchymal stem cells (MSCs), hPSCs, and their derivatives, have become a focus of research as sources of healthy mitochondria to treat tissue injury via mitochondrial transfer [168].…”

Section: Mitochondrial Transplantationmentioning

confidence: 68%

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Leung

Poon

2022

IJMS

View full text Add to dashboard Cite

Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades of research, treatment options remain limited. The mitochondria is commonly considered to be the main target of doxorubicin and mitochondrial dysfunction is the hallmark of doxorubicin-induced cardiotoxicity. Here, we review the pathogenic mechanisms of doxorubicin-induced cardiotoxicity and present an update on cardioprotective strategies for this disorder. Specifically, we focus on strategies that can protect the mitochondria and cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, and mitochondrial transfer. We also discuss the shortcomings of existing models of doxorubicin-induced cardiotoxicity and explore advances in the use of human pluripotent stem cell derived cardiomyocytes as a platform to facilitate the identification of novel treatments against this disorder.

show abstract

Section: Mitochondrial Transplantationmentioning

confidence: 68%

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Leung

Poon

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…1B ). EVs were then isolated using two orthogonal approaches: affinity-based (exoRNeasy) and nanofiltration-based (ExoTIC: Exosome Total Isolation Chip) 20–23 . Each EV isolation method captured distinct EV populations, as determined by nanoparticle tracking analysis (NTA) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Exosome Total Isolation Chip) [20][21][22][23] . Each EV isolation method captured distinct EV populations, as determined by nanoparticle tracking analysis (NTA) (Fig.…”

Section: Kras(g12c) Inhibition Decreases Cell Viability and Ev Sizementioning

confidence: 99%

Extracellular RNA signatures of mutant KRAS(G12C) lung adenocarcinoma cells

Khojah

Reggiardo

Özen

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Extracellular RNAs (exRNAs) are actively secreted from cells in membrane-bound extracellular vesicles (EVs). Diverse classes of RNAs are secreted as exRNAs, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and transposable element RNAs (TE RNAs). However, the full composition and clinical utility of exRNAs secreted in response to oncogenic signaling are unknown. Here we use both affinity- and nanofiltration-based EV isolation approaches to show that mutant KRAS(G12C) signaling results in the secretion of specific lncRNAs, TE RNAs, and mRNAs, some of which are prognostic for lung adenocarcinoma (LUAD) patient survival. We found that inhibition of KRAS(G12C) signaling broadly reprograms the noncoding transcriptome, as evidenced by a substantial increase in TE RNA secretion. KRAS(G12C) inhibition also increased the abundance of secreted lncRNAs and retained intron-containing transcripts, while decreasing the mRNA content of EVs. Oncogenic KRAS(G12C) signaling was required for the secretion of mRNAs from a set of 20 genes that are significantly associated with unfavorable clinical outcomes in LUAD. Our study suggests that both coding and noncoding RNAs that are secreted in EVs may serve as KRAS(G12C)-specific signatures for diagnosing lung cancer.

show abstract

“…In the future, the technique introduced here will stimulate applications in additional research areas, for example, the rejuvenation of cells with low metabolic activity in stem cell therapies [ 4 , 65 , 66 ] or as an alternative strategy in mitochondrial replacement therapy approaches. Beyond, it offers new perspectives to address fundamental questions in cell biology, mechanobiology, and cell engineering.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria transplantation between living cells

Gäbelein

Feng

Sarajlic³

et al. 2022

PLoS Biol

View full text Add to dashboard Cite

Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject, and transplant organelles from and into living cells with subcellular spatial resolution. The technology combines atomic force microscopy, optical microscopy, and nanofluidics to achieve force and volume control with real-time inspection. We developed dedicated probes that allow minimally invasive entry into cells and optimized fluid flow to extract specific organelles. When extracting single or a defined number of mitochondria, their morphology transforms into a pearls-on-a-string phenotype due to locally applied fluidic forces. We show that the induced transition is calcium independent and results in isolated, intact mitochondria. Upon cell-to-cell transplantation, the transferred mitochondria fuse to the host cells mitochondrial network. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed monitoring of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 minutes after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, donor mitochondrial DNA (mtDNA) was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle physiology and homeostasis, but also for therapy, mechanobiology, and synthetic biology.

show abstract

Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury

Cited by 59 publications

References 28 publications

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Extracellular RNA signatures of mutant KRAS(G12C) lung adenocarcinoma cells

Mitochondria transplantation between living cells

Contact Info

Product

Resources

About