Electrophysiological Effects of Extracellular Vesicles Secreted by Cardiosphere-Derived Cells: Unraveling the Antiarrhythmic Properties of Cell Therapies

Gomez-Cid, L; Moro-Lopez, M; Nava, A; Hernández-Romero, Ismael; Fernández, Ana; Suarez-Sancho, S; Atienza, Felipe; Grigorian-Shamagian, Lilián; Fernández‐Avilés, Francisco

doi:10.3390/pr8080924

Cited by 8 publications

(14 citation statements)

References 45 publications

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“…Different mechanisms, such as immaturity of the electrical phenotypes of the transplanted phenotypes, poor cell-cell coupling and cardiac nerve sprouting, have been proposed as contributors to arrhythmogenic risk after stem cell administration [45]. Despite the proarrhythmic effects that have been attributed to stem cell therapy [46], antiarrhythmic properties have also been reported after mesenchymal stem cell or CDC delivery [47]. In our investigation, however, no statistically significant differences in VT inducibility rates were detected between CON and CDCs-treated animals (both free and encapsulated).…”

Section: Discussionmentioning

confidence: 99%

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model

et al. 2021

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The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.

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Section: Discussionmentioning

confidence: 99%

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model

et al. 2021

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“…For the combined product, EVs isolated from conditioned medium [6,7] were incorporated into the hydrogels (EVs-PEG-cECMH), observing similar gelation kinetics to hydrogels with PEG (Figure 2a). They also presented reduced lag and gelation time (t 1/2 = 13 ± 3 min) and a higher speed of gelation (slope = 0.022 ± 0.009).…”

Section: Lyophylized Cecm Retained Native Ecm Proteins and Sgagsmentioning

confidence: 98%

“…EVs used as therapeutic product were isolated from human CDCs, as previously described [6,7]. Briefly, cardiac biopsies from patients undergoing cardiac surgery were processed to obtain 1-2 mm explants.…”

Section: Edcs Cdcs and Derived Extracellular Vesicle Isolationmentioning

confidence: 99%

“…Some of the challenges seemed to be solved once it was clarified that most of their beneficial effects are caused by paracrine mediators, such as extracellular vesicles (EVs), which possess meaningful advantages as therapeutics vs. their parenteral cells [3,4]. In particular, EVs derived from cardiosphere-derived cells (CDCs) have shown potential to improve cardiac function in infarcted [5] and aged hearts [6], as well as antiarrhythmic effects [7]. However, EV retention at the target site remains as one of their main challenges [8].…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Extracellular Matrix Hydrogel Enriched with Polyethylene Glycol Presents Improved Gelation Time and Increased On-Target Site Retention of Extracellular Vesicles

Gomez-Cid

López-Donaire

Velasco

et al. 2021

IJMS

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Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs–PEG–cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs–PEG–cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.

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“…Some cell products have been characterized for their MoA, but a robust quantification of these effects to compare and identify the most potent cell type for a certain clinical condition, and/or from batch to batch is still lacking [2]. Today is accepted that the cells exert their therapeutic effects mostly through paracrine secretion of soluble factors and/ or extracellular vesicles [16,19,25,26]. Indeed, extracellular vesicles offer the potential to overcome the frailty of cell therapy by conserving their bioactivity regardless of the extremes of handling [27].…”

Section: Disease-targeted and Mechanism Of Action-guided Potency Tests In Cardiovascular Regenerative Medicinementioning

confidence: 99%

The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development

Gomez-Cid

Grigorian-Shamagian

Sanz‐Ruiz

et al. 2021

Stem Cell Rev and Rep

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Biological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action. Graphical Abstract Development of potency assays for cell-based products consists in understanding the pathophysiology of the disease, identifying potential mechanisms of action (MoA) to counteract it and finding the most suitable cell-based product that exhibits these MoA. When applied, the potency assay needs to correlate bioactivity of the product, via a measurement related to the MoA, with treatment efficacy. However, in the cardiovascular field, the process faces several challenges and high requirements.

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Electrophysiological Effects of Extracellular Vesicles Secreted by Cardiosphere-Derived Cells: Unraveling the Antiarrhythmic Properties of Cell Therapies

Cited by 8 publications

References 45 publications

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model

Cardiac Extracellular Matrix Hydrogel Enriched with Polyethylene Glycol Presents Improved Gelation Time and Increased On-Target Site Retention of Extracellular Vesicles

The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development

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