Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity

Milano, Giuseppina; Biemmi, Vanessa; Lazzarini, Edoardo; Balbi, Carolina; Ciullo, Alessandra; Bolis, Sara; Ameri, Pietro; Silvestre, Dario Di; Mauri, Pierluigi; Barile, Lucio; Vassalli, Giuseppe

doi:10.1093/cvr/cvz108

Cited by 106 publications

(112 citation statements)

References 38 publications

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“…Moreover, miR-146a knock-out mice showed larger infarcts compared to wild-type mice; injection of a miR-146a mimic at the time of MI rescued the level of ejection fraction similarly to wild-type animals, suggesting a mechanism of action for the cardioprotective effect mediated by CDC-EVs [90]. A similar effect has also been reported in a preclinical model of cancer drug-induced cardiotoxicity [157]. Indeed, human CPC-EVs were able to significantly decrease reactive oxygen species (ROS) production in cardiomyocytes following Doxorubicin/trastuzumab treatment in vitro.…”

Section: A Role For Cpc-derived Evssupporting

confidence: 68%

“…CPC-EVs prevented Doxorubicin-derived induction of Traf6, Smad4, Irak1, Nox4 and Mpo gene expression; this effect was abolished when miRNA146a-5p was knocked down via loading of a specific siRNA into the EV-producing cells. Moreover, in vivo intravenous administration of EVs significantly preserved cardiac function during Doxorubicin/trastuzumab treatment [157]. Additional studies have also identified Y RNA fragment inside CDC-EVs [158].…”

Section: A Role For Cpc-derived Evsmentioning

confidence: 91%

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Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

Balbi

Costa

Barile

2020

Cells

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Ischaemic cardiac disease is associated with a loss of cardiomyocytes and an intrinsic lack of myocardial renewal. Recent work has shown that the heart retains limited cardiomyocyte proliferation, which remains inefficient when facing pathological conditions. While broadly active in the neonatal mammalian heart, this mechanism becomes quiescent soon after birth, suggesting loss of regenerative potential with maturation into adulthood. A key question is whether this temporary regenerative window can be enhanced via appropriate stimulation and further extended. Recently the search for novel therapeutic approaches for heart disease has centred on stem cell biology. The "paracrine effect" has been proposed as a promising strategy to boost endogenous reparative and regenerative mechanisms from within the cardiac tissue by exploiting the modulatory potential of soluble stem cell-secreted factors. As such, growing interest has been specifically addressed towards stem/progenitor cell-secreted extracellular vesicles (EVs), which can be easily isolated in vitro from cell-conditioned medium. This review will provide a comprehensive overview of the current paradigm on cardiac repair and regeneration, with a specific focus on the role and mechanism(s) of paracrine action of EVs from cardiac stromal progenitors as compared to exogenous stem cells in order to discuss the optimal choice for future therapy. In addition, the challenges to overcoming translational EV biology from bench to bedside for future cardiac regenerative medicine will be discussed.

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Section: A Role For Cpc-derived Evssupporting

confidence: 68%

Section: A Role For Cpc-derived Evsmentioning

confidence: 91%

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

Balbi

Costa

Barile

2020

Cells

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“…A spectrum of stem cells has been searched for treating myocardial disease, including skeletal myoblasts, bone marrowderived cells, induced pluripotent stem cells, endothelial progenitor cells, and cardiac progenitor cells [2]. Researchers and clinicians are also researching alternative options, including cell-free approaches, a new candidate that possesses the benefit of cell therapy without the need for cell transplantation [36,37]. MSCs appear to be a good candidate in light of their immunosuppressive properties and paracrine ability [38,39].…”

Section: Discussionmentioning

confidence: 99%

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

2020

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Aims: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIFpretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosome MIF), and delivered to cardiomyocytes subjected to H 2 O 2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. Exosome MIF protected cardiomyocytes from H 2 O 2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosome MIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosome MIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosome MIF inhibited H 2 O 2-induced apoptosis through modulating oxidative stress. Conclusions: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosome MIF in protecting cardiomyocytes from apoptosis.

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“…Interestingly, it has been shown that treatment with exosomes of cardiac mesenchymal progenitor cells injected systemically in a mouse model of cardiotoxicity obtained with DOX/trastuzumab treatment was able to decrease ROS and inflammation and LV dysfunction. The vesicles were highly enriched in miR-146a compared with human dermal fibroblast exosomes, a miRNA that plays a cardioprotective role [167].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

Pellegrini

Sileno

D'agostino

et al. 2020

Cancers

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Cancer treatment has made significant progress in the cure of different types of tumors. Nevertheless, its clinical use is limited by unwanted cardiotoxicity. Aside from the conventional chemotherapy approaches, even the most newly developed, i.e., molecularly targeted therapy and immunotherapy, exhibit a similar frequency and severity of toxicities that range from subclinical ventricular dysfunction to severe cardiomyopathy and, ultimately, congestive heart failure. Specific mechanisms leading to cardiotoxicity still remain to be elucidated. For instance, oxidative stress and DNA damage are considered key players in mediating cardiotoxicity in different treatments. microRNAs (miRNAs) act as key regulators in cell proliferation, cell death, apoptosis, and cell differentiation. Their dysregulation has been associated with adverse cardiac remodeling and toxicity. This review provides an overview of the cardiotoxicity induced by different oncologic treatments and potential miRNAs involved in this effect that could be used as possible therapeutic targets.Cancers 2020, 12, 704 2 of 24 circulating miRNAs have been used as excellent biomarkers in different studies and can be used as biomarkers for cardiovascular diseases (CVDs) [5]. Moreover, miRNA deregulation is often associated with tumor progression, and many anticancer treatments affect miRNA expression. In this review we aimed to discuss relevant miRNAs modulated by therapies for cancer that have been demonstrated to be involved in CVD. In the following paragraphs, we provide an overview of the most important anticancer treatments that are known to induce cardiotoxicity. Anticancer Treatment and CardiotoxicityAnticancer treatment has accomplished remarkable progress in the last century resulting in improved quality of life and survival rates of cancer patients. These advances in cancer treatment, however, have been often accompanied by therapy-related complications, including secondary side effects on the whole organism [6].The most commonly used cancer therapeutics in modern medicine include the traditional surgery, radiotherapy, and conventional chemotherapy approaches; moreover, two new therapeutic modalities have been introduced in recent decades, namely molecularly targeted therapy and immunotherapy [7], as summarized in Figure 1. Traditional chemotherapy agents consist of non-specific cytotoxic treatments (e.g., alkylating agents and antimetabolites) that rapidly eliminate replicating cells, including not only tumor cells but also normal tissue cells, with a broad range of side effects that significantly limit their applications in cancer therapy. In contrast to conventional systemic chemotherapy, molecularly targeted cancer therapies, using novel drugs aimed at the inhibition of intracellular signaling pathways fundamental for cancer proliferation or differentiation (e.g., monoclonal antibodies and low molecular weight protein-kinase inhibitors), are thought to be cancer-specific, with fewer associated adverse effects on normal cells [8]. Lastly, immunother...

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Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity

Cited by 106 publications

References 38 publications

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

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