Jorge Sanz‐Ros

Hospital Universitari i Politècnic La Fe

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Cristina Mas‐Bargues

Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable

Consuelo Borrás

Universitat de València

José Viña

Universitat de València

Mar Dromant

Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable

Marta Inglés

Universitat de València

Nekane Romero-García

Hospital Clínico Universitario de Valencia

Lucía Gimeno-Mallench

Universidad Cardenal Herrera CEU

Aurora Román-Domínguez

Universitat de València

Javier Huete-Acevedo

Universitat de València

Juan Gambini

Universitat de València

Cooperative Institutions

Universitat de València

Centro de Investigación Biomédica en Red

INCLIVA Health Research Institute

Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable

Instituto de Salud Carlos III

Hospital Universitari i Politècnic La Fe

Centre for Biomedical Network Research on Rare Diseases

Hospital Clínico Universitario de Valencia

Centro de Investigación en Red en Enfermedades Cardiovasculares

Stanford University

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Extracellular Vesicles as Therapeutic Resources in the Clinical Environment

International Journal of Molecular Sciences (2023)

Jorge Sanz‐Ros Cristina Mas‐Bargues Nekane Romero-García Javier Huete-Acevedo Mar Dromant

The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge on different key points regarding the use of EVs in a clinical setting. These points are related to cell sources of EVs, isolation, storage, and delivery methods, as well as modifications to the releasing cells for improved production of EVs. Finally, we will depict the application of EVs therapies in clinical trials, considering the impact of the COVID-19 pandemic on the development of these therapies, pointing out that although it is a promising therapy for human diseases, we are still in the initial phase of its application to patients.

Extracellular Vesicles

Extracellular vesicles

Isolation

Pandemic

10.3390/ijms24032344

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Citations (51)

BCL-xL, a mitochondrial protein involved in successful aging and frailty prevention

Free Radical Biology and Medicine (2023)

Cristina Mas‐Bargues Jorge Sanz‐Ros Nekane Romero-García Javier Huete-Acevedo Mar Dromant

10.1016/j.freeradbiomed.2023.03.185

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Citations (0)

Role of Redox Homeostasis in the Communication Between Brain and Liver Through Extracellular Vesicles

Antioxidants (2024)

Javier Huete-Acevedo Cristina Mas‐Bargues Marta Arnal-Forné Sandra Atencia-Rabadán Jorge Sanz‐Ros

Extracellular vesicles (EVs) are small, membrane-bound particles secreted by cells into the extracellular environment, playing an increasingly recognized role in inter-organ communication and the regulation of various physiological processes. Regarding the redox homeostasis context, EVs play a pivotal role in propagating and mitigating oxidative stress signals across different organs. Cells under oxidative stress release EVs containing signaling molecules that can influence the redox status of distant cells and tissues. EVs are starting to be recognized as contributors to brain-liver communication. Therefore, in this review, we show how redox imbalance can affect the release of EVs in the brain and liver. We propose EVs as mediators of redox homeostasis in the brain-liver axis.

Homeostasis

Extracellular Vesicles

10.3390/antiox13121493

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Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice.

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Jorge Sanz‐Ros Javier Huete-Acevedo Cristina Mas‐Bargues Nekane Romero García Mar Dromant

Background: Aging is a process characterized by a progressive decline in physiological functions. This decline contributes to an increased risk of various age-related diseases, including conditions such as heart failure or aortic stenosis. Recent advances have highlighted the potential of stem cell therapies in mitigating the adverse effects of aging. The mechanisms underlying the therapeutic effects of these cells appear to be largely paracrine, including the exchange of different molecules via extracellular vesicles (EVs). This work aims to investigate the potential of sEVs derived from young adipose-derived stem cells (ADSC-sEVs) in restoring structural, molecular, and functional changes associated with aging in the heart. Methods: Aged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls, young mice were also included to identify specific changes associated with aging. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. Additionally, a comprehensive metabolomic analysis was performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status. Results: Administration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including reductions in oxidative stress, inflammation, and cellular senescence. We also report on age-related changes reversal in myocardial structure and function, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile. Conclusions: These results denote the potential of ADSC-sEVs as a novel, non-invasive therapeutic strategy to mitigate cardiac aging-associated functional decline.

Senescence

Extracellular vesicles

Stem Cell Therapy

10.1101/2024.06.06.597840

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Drosophila melanogaster overexpression FAS live longer

Free Radical Biology and Medicine (2018)

Lucía Gimeno-Mallench Vladimir I. Klichko Svetlana N. Radyuk Cristina Mas‐Bargues Marta Inglés

Fas ligand

Melanogaster

10.1016/j.freeradbiomed.2018.04.380

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The Potential Use of Mitochondrial Extracellular Vesicles as Biomarkers or Therapeutical Tools

International Journal of Molecular Sciences (2023)

Jorge Sanz‐Ros Cristina Mas‐Bargues Nekane Romero-García Javier Huete-Acevedo Mar Dromant

The mitochondria play a crucial role in cellular metabolism, reactive oxygen species (ROS) production, and apoptosis. Aberrant mitochondria can cause severe damage to the cells, which have established a tight quality control for the mitochondria. This process avoids the accumulation of damaged mitochondria and can lead to the release of mitochondrial constituents to the extracellular milieu through mitochondrial extracellular vesicles (MitoEVs). These MitoEVs carry mtDNA, rRNA, tRNA, and protein complexes of the respiratory chain, and the largest MitoEVs can even transport whole mitochondria. Macrophages ultimately engulf these MitoEVs to undergo outsourced mitophagy. Recently, it has been reported that MitoEVs can also contain healthy mitochondria, whose function seems to be the rescue of stressed cells by restoring the loss of mitochondrial function. This mitochondrial transfer has opened the field of their use as potential disease biomarkers and therapeutic tools. This review describes this new EVs-mediated transfer of the mitochondria and the current application of MitoEVs in the clinical environment.

Organelle

Mitochondrial respiratory chain

10.3390/ijms24087005

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Citations (16)

Small extracellular vesicles from senescent stem cells trigger adaptive mechanisms in young stem cells by increasing antioxidant enzyme expression

Free Radical Biology and Medicine (2023)

Cristina Mas‐Bargues Jorge Sanz‐Ros Nekane Romero-García Javier Huete-Acevedo Mar Dromant

Extracellular Vesicles

10.1016/j.freeradbiomed.2023.03.153

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Citations (1)

Small extracellular vesicles from young mice prevent frailty, improve healthspan and decrease epigenetic age in old mice

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Jorge Sanz‐Ros Cristina Mas‐Bargues Daniel Monleón Juozas Gordevičius Robert T. Brooke

Summary Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

Senescence

Extracellular Vesicles

10.1101/2021.07.29.454302

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Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine

International Journal of Molecular Sciences (2019)

Cristina Mas‐Bargues Jorge Sanz‐Ros Aurora Román-Domínguez Marta Inglés Lucía Gimeno-Mallench

The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of these factors is oxygen concentration, which has been closely linked to the maintenance of stemness. The widely used environmental 21% O2 concentration represents a hyperoxic non-physiological condition, which can impair stem cell behaviour by many mechanisms. The goal of this review is to understand these mechanisms underlying the oxygen signalling pathways and their negatively-associated consequences. This may provide a rationale for culturing stem cells under physiological oxygen concentration for stem cell therapy success, in the field of tissue engineering and regenerative medicine.

Regenerative Medicine

10.3390/ijms20051195

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Citations (175)

Small extracellular vesicles from senescent stem cells trigger adaptive mechanisms in young stem cells by increasing antioxidant enzyme expression

Redox Biology (2023)

Cristina Mas‐Bargues Jorge Sanz‐Ros Nekane Romero-García Javier Huete-Acevedo Mar Dromant

Extracellular vesicles' biogenesis, shedding, and uptake are redox-sensitive. Indeed, oxidative stress conditions influence extracellular vesicles' release and content, which can modulate the redox status of the receiving cells. In this study, we aimed to assess the effect of extracellular vesicles from human dental pulp stem cells cultured under 21% O2 (senescent stem cells) on human dental pulp stem cells cultured under 3% O2 (young stem cells). Extracellular vesicles were isolated by ultracentrifugation from senescent stem cells and prepared for the treatment of young stem cells at a final concentration of 10 μg/mL. Cells were analyzed for antioxidant gene expression, mitochondrial bioenergetic parameters, ROS production, culture kinetics, and apoptosis. The results show that extracellular vesicles from senescent stem cells induce overexpression of antioxidant genes (MnSOD, CAT, and GPx) in young stem cells, which show an increased non-mitochondrial oxygen consumption, accompanied by reduced maximal respiration and spare respiratory capacity without altering mitochondrial membrane potential. This is accompanied by improved cell proliferation, viability, and migration rates and a reduction of apoptosis. In conclusion, extracellular vesicles from senescent stem cells trigger an adaptive response in young stem cells which improves their antioxidant defenses and their proliferation, migration, and survival rates. This suggests that extracellular vesicles can modulate the cells' microenvironment and the balance between proliferation and senescence.

Extracellular vesicles

10.1016/j.redox.2023.102668

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Citations (10)