Pilar Sepulveda

• PhD
• Principal Investigator at Hospital Universitari i Politècnic la Fe

Skin represents the main barrier against the external environment, but also plays a role in human relations, as one of the prime determinants of beauty, resulting in a high consumer demand for skincare-related pharmaceutical products. Given the importance of skin aging in both medical and social spheres, the present research aims to characterize mi...

Background/aims Extracellular vesicles (EVs) derived from dental pulp mesenchymal stem cells (DP-MSCs) are a promising therapeutic option for the treatment of myocardial ischemia. The aim of this study is to determine whether MSC-EVs could promote a pro-resolving environment in the heart by modulating macrophage populations. Methods EVs derived fr...

Background Skin represents the main barrier against the external environment, but also plays a role in human relations, as one of the prime determinants of beauty, resulting in a high consumer demand for skincare-related pharmaceutical products. Given the importance of skin aging in both medical and social spheres, the present research aims to char...

Background/aims: Extracellular vesicles (EVs) derived from dental pulp mesenchymal stem cells (DP-MSCs) are a promising therapeutic option for the treatment of myocardial ischemia. The aim of this study was to determine whether MSC-EVs could promote a pro-resolving environment in the heart by modulating macrophage populations. Methods: EVs derived...

Introduction Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. Identifying these...

Despite atrial fibrillation (AF) being a common, clinically important, and economically significant public health problem, the initiation mechanisms of atrial remodeling during AF is still unclear. Furthermore, really few experimental models have the power to investigate these mechanisms in a human invitro two-dimensional (2D) monolayer of atrial c...

Despite improvements in cancer survival, cancer therapy–related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Glo...

Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. We isolated HM sEVs from HM sam...

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better unders...

Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-β1) exp...

Carbon black nanomaterial (CB-NM), as an industrial product with a large number of applications, poses a high risk of exposure, and its impact on health needs to be assessed. The most common testing platform for engineered (E)NMs is in vitro toxicity assessment, which requires prior ENM dispersion, stabilization, and characterization in cell cultur...

The data currently described was generated within the EU/FP7 HeCaToS project (Hepatic and Cardiac Toxicity Systems modeling). The project aimed to develop an in silico prediction system to contribute to drug safety assessment for humans. For this purpose, multi-omics data of repeated dose toxicity were obtained for 10 hepatotoxic and 10 cardiotoxic...

Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We assessed clinical data from patients with breast cancer receiving anthracyclines and searched for discriminating microRNAs between patients that developed cardi...

Extracellular vesicles (EVs) are secreted by cells and can be found in biological fluids (e.g., blood, saliva, urine, cerebrospinal fluid, and milk). EV isolation needs to be optimized carefully depending on the type of biofluid and tissue. Human milk (HM) is known to be a rich source of EVs, and they are thought to be partially responsible for the...

Impaired wound healing in patients with type 2 diabetes (DM2) is characterized by chronic inflammation, which delays wound closure. Specialized pro-resolving lipid mediators (SPMs) are bioactive molecules produced from essential polyunsaturated fatty acids (PUFAs), principally omega-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SPMs...

Aberrant Notch signaling is implicated in breast cancer progression, and recent studies have demonstrated links between the Notch pathway components Notch1 and Notch1 intracellular domain (N1ICD) with poor clinical outcomes. Growing evidence suggests that Notch signaling can be regulated by small extracellular vesicles (SEVs). Here, we used breast...

Many anticancer agents used in clinics induce premature senescence in healthy tissues generating accelerated aging processes and adverse side-effects in patients. Cardiotoxicity is a well-known limiting factor of anticancer treatment with doxorubicin (DOX), a very effective anthracycline widely used as antitumoral therapy in clinical practice, that...

Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-...

MSCs products as well as their derived extracellular vesicles, are currently being explored as advanced biologics in cell-based therapies with high expectations for their clinical use in the next few years. In recent years, various strategies designed for improving the therapeutic potential of mesenchymal stromal cells (MSCs), including pre-conditi...

Research on cardiac progenitor cell populations has generated expectations about their potential for cardiac regeneration capacity after acute myocardial infarction and during physiological aging; however, the endogenous capacity of the adult mammalian heart is limited. The modest efficacy of exogenous cell-based treatments can guide the developmen...

[This corrects the article DOI: 10.1155/2020/8872009.].

The dextro-transposition of the great arteries (d-TGA) is one of the most common congenital heart diseases. To identify biological processes that could be related to the development of d-TGA, we established induced pluripotent stem cell (iPSC) lines from two patients with d-TGA and from two healthy subjects (as controls) and differentiated them int...

Background Poor graft function or graft failure after allogeneic stem cell transplantation is an unmet medical need, in which mesenchymal stromal cells (MSC) constitute an attractive potential therapeutic approach. Hypoxia-inducible factor-1α (HIF-1α) overexpression in MSC (HIF-MSC) potentiates the angiogenic and immunomodulatory properties of thes...

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-...

The endorsement of functional features such as biocompatibility, mechanical integrity, or electrical conductivity to tissue engineering (TE) scaffolds is essential to stimulate cell adhesion and proliferation. In this study, electrospun nanofibers based on polycaprolactone (PCL) and gelatin (Ge) (ratios 60/40, 50/50, and 40/60), and polyaniline (PA...

Introduction Management of donor site morbidity in the setting of split thickness skin graft (STSG) is of crucial importance with no superior wound dressing described to date and the growing need of decreasing epithelializing time. The purpose of the study was to compare the standard of care using a hydrocolloid dressing to platelet rich plasma (PR...

Exosomes are nanosized vesicles containing specific cargos of DNA, RNA, proteins, metabolites, and intracellular and membrane lipids. Exosome isolation needs to be optimized carefully depending on the type of biofluid and tissue and the retrieved exosomes need to be characterized. The main objective of this study was to determine the feasibility of...

Recent studies show that microvascular injury consists of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). In patients with reperfused ST-segment elevation myocardial infarction (STEMI) quantitative assessment of IMH with T2* cardiovascular magnetic resonance imaging (CMR) appears to be useful in evaluation of microvascular dam...

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracel...

While coronary angioplasty represents an effective treatment option following acute myocardial infarction, the reperfusion of the occluded coronary artery can prompt ischemia–reperfusion (I/R) injury that significantly impacts patient outcomes. As ω‐3 polyunsaturated fatty acids (PUFAs) have proven, yet limited cardioprotective abilities, an optimi...

Interleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of hematological and immune responses. IL-6 is secreted chiefly by stromal cells, but little is known about its precise role in the homeostasis of human mesenchymal stromal cells (hMSCs) and the role it may play in hMSC-mediated immunoregulation. We studied the role of IL-6 in...

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin‐1 (FBN1) gene, and cardiovascular involvement is the leading cause of mortality. We sought to examine the genotype/phenotype realtionship in 61 consecutive patients with a phenotype and genotype compatible with MFS. The FBN1 gene was analyzed by mass...

Human bone marrow mesenchymal stem cells (BM-MSCs) and cardiac progenitor/stem cells (CPCs) have been extensively studied as a potential therapeutic treatment for myocardial infarction (MI). Previous reports suggest that lower doses of CPCs are needed to improve cardiac function relative to their bone marrow counterparts. Here, we confirmed this ob...

Critical surgical and medical advances have shifted the focus of congenital heart disease (CHD) patients from survival to achievement of a greater health-related quality of life (HRQoL). HRQoL is influenced, amongst other factors, by aerobic capacity and respiratory muscle strength, both of which are reduced in CHD patients. This study evaluates th...

During the course of evolution, prokaryote and eukaryote cells have developed elegant and to some extent analogous strategies to communicate with each other and to adapt to their surrounding environment. Eukaryotic cells communicate with each other through direct interaction via juxtracrine signaling and/or by secreting soluble factors. These secre...

Classically clinical evaluation of patients with aortic stenosis (AS) is made using clinical and echocardiographic parameters but recently new imaging techniques as cardiovascular magnetic resonance (CMR ) are being used increasingly in this clinical setting. We aim to assess utility and prognostic value of aortic valve area (AVA) by CMR in patient...

Nanofibrous scaffolds composed of polycaprolactone (PCL) and gelatin (Ge) were obtained through a hydrolytic assisted electrospinning process. The PCL-to-Ge proportion (100/0 to 20/80), as well as the dissolution time (24, 48, 72, 96, 120 h) into a 1:1 formic/acetic acid solvent before electrospinning were modified to obtain the different samples....

In the setting of STEMI, microvascular injury consists of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). We aimed to investigate prognostic value and clinical predictors of MR T2* w analysis of IMH in this setting. Methods A single center observational cohort study was performed in patients with reperfused STEMI with CMR exa...

Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. T...

Regulation of circulating free fatty acid (FFA) levels and delivery is crucial to maintain tissue homeostasis. Exosomes are nanomembranous vesicles that are released from diverse cell types and mediate intercellular communication by delivering bioactive molecules. Here, we sought to investigate the uptake of FFAs by circulating exosomes, the delive...

Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) a...

(A) Representative western blot images of proteins extracted from AC10 cell cultures in normoxia or hypoxia (2% O2). Lanes were loaded with equal amounts of protein and incubated with a hypoxia inducible factor-1 antibody. Signals were quantified by densitometry (n = 3). (B) Quantification of viable AC10 by CCK8 after different culture conditions u...

Cell proliferation assay of AC10, fibroblasts and human umbilical cord vein cells (HUVEC). Representative example of cell proliferation measured by CCK-8 assay after 48 h of culture in presence of Nx and Hx CM-EVs. Results are presented in arbitrary units (n = 3).

Protein identification in cardiomyocyte-derived extracellular vesicles in hypoxia.

Protein identification in cardiomyocyte-derived extracellular vesicles in normoxia.

Gene ontology biological processes for proteins identified in extracellular vesicles derived in hypoxia.

Tube formation assay of human coronary artery endothelial cells (HCAEC). (A) Representative images of tube formation after 6 h of culture in the presence of normoxia (Nx) or hypoxia (Hx) cardiomyocyte-derived extracellular vesicles. (B) Quantification of total loops, tube length, total tubes and number of branching points from images taken after 6...

Gene ontology biological processes for proteins identified in extracellular vesicles derived in normoxia.

BACKGROUND The incidence of cardiotoxicity in patients receiving treatment for breast cancer is unknown. There is not enough evidence about early detection and appropriate management of cardiotoxicity. The aim of this study is to identify early markers of risk of cardiac toxicity. MATERIAL AND METHOD Prospective study was conducted between 2014 and...

Monitoring and understanding the in vitro behaviour of polyester based scaffolds both comprising the study of the hydrolytic degradation and the cell seeding viability is essential to ensure the desired functionality, according to a given biomedical purpose. As a model case to compare the performance of techniques to monitor the in vitro behaviour,...

During the course of evolution, prokaryote and eukaryote cells have developed elegant and to some extent analogous strategies to communicate with each other and to adapt to their surrounding environment. Eukaryotic cells communicate with each other through direct interaction via juxtracrine signaling and/or by secreting soluble factors. These secre...

Background Human dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as other MSCs. Hypoxia-preconditioning and hypoxia-inducible factor 1 (HIF-1) alpha overexpression significantly improves MSC therapeutics, but the m...

Background Human dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as in other MSCs. Hypoxia-preconditioning and hypoxia inducible factor 1 alpha (HIF-1 alpha) overexpression significantly improve MSC therapeutics, b...

Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1α) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms...

Background Cardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac cel...

Supporting Information.

Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in trans...

Cardiosphere-derived cell (CDC) infusion into damaged myocardium has shown some reparative effect; this could be improved by better selection of patients and cell subtype. CDCs isolated from patients with ischemic heart disease are able to support vessel formation in vitro but this ability varies between patients. The primary aim of our study was t...

Human dermo-epidermal skin equivalents (DE) comprising in vitro expanded autologous keratinocytes and fibroblasts are a good option for massive burn treatment. However, the lengthy expansion time required to obtain sufficient surface to cover an extensive burn together with the challenging surgical procedure limits their clinical use. The integrati...

γδ T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human γδ T lymphocytes express a Vγ9Vδ2+ (Vδ2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFNγ, produced by Vδ2+ cells, activates mesenchymal stem cell (MSC)-mediated im...

Total PBMCs were activated and cultured in the presence or absence of MSCs. Addition of 1-MT alone reduces significantly the expansion of Vδ2+ cells even in the absence of MSCs while addition of vehicle has no influence on the percentage of Vδ2+ cells. Results show the means ± S.D. of triplicate samples. (TIF)

Background: Cardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac ce...

Aims: Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship, which is essential for maintaining the metabolic requirements of the heart. Little is known about the mechanisms that regulate nutrient flow from ECs to associated CMs, especially in situations of acute stress when local active processes are required t...

Introduction and objectives: Animal models are a useful tool for the evaluation of disease mechanisms and also for technologies for diagnosis and treatment. In this study we performed a descriptive analysis of the functional and structural cardiac changes occurred as a result of acute coronary occlusion in pigs and its evolution during 5 weeks. M...

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. Little is known about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulat...

Introducción: La elección la solución cardiopléjica óptima sigue siendo motivo de debate en la actualidad. La cardioplejía Del Nido (diseñada originariamente para la población pediátrica) está ganando popularidad en el campo de la cirugía cardiaca del adulto. Métodos: Serie consecutiva de 30 pacientes que recibieron cardioplejía Del Nido como estra...

A number of metabolites have signaling properties by acting through G protein-coupled receptors. Succinate, a Kreb's cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Suncr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the...

Background The amount of epicardial adipose tissue (EAT) has been associated with the presence of atherosclerotic disease but its role in assessing the risk of obstructive coronary artery disease (CAD) and its relationship with other cardiovascular risk factors is not fully established. We hypothesized that EAT quantified by cardiac magnetic resona...

Polymer Therapeutics can be considered among the first and most successful polymeric nanomedicines and comprises a variety of complex macromolecular systems, whose common feature is the presence of a rationally designed covalent chemical bond between a water-soluble polymeric carrier and the bioactive molecule(s). Polymer–drug conjugate concept was...

Purpose: 3D echocardiography (3DE) enables fast 3D acquisition but subsequent manual navigation to find 2D diagnostic planes can be time consuming. We have developed and validated an automated machine learning-based technique to find apical 2-, 3- and 4-chamber (A2C, A3C, A4C) views that enables fast volume navigation and analysis. Methods: 3DE vol...

miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidativ...

The development of biomaterials for myocardial tissue engineering requires a careful assessment of their performance with regards to functionality and biocompatibility, including the immune response. poly(3-hydroxybutyrate) (PHB), poly(e-caprolactone) (PCL), silk, poly-lactic acid (PLA), and polyamide (PA) scaffolds were generated by electrospinnin...

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR st...

Cardiac progenitor cells (CPCs) from adult myocardium offer an alternative cell therapy approach for ischaemic heart disease. Improved clinical performance of CPCs in clinical trials requires a comprehensive definition of their biology and specific interactions with the environment. In this work we characterize specific human CPC surface markers an...

Cardiac progenitor cells (CPCs) from adult myocardium offer an alternative cell therapy approach for ischaemic heart disease. Improved clinical performance of CPCs in clinical trials requires a comprehensive definition of their biology and specific interactions with the environment. In this work we characterize specific human CPC surface markers an...

Rationale: Transplantation of allogeneic cardiac stem/progenitor cells (CPC) in experimental myocardial infarction promoted cardiac regeneration and improved heart function. Although this has enhanced prospects of using allogeneic CPC for cardiac repair, the mechanisms regulating the behavior of these allogeneic cells, which are central to clinica...

Mesenchymal stem cells (MSC) are effective in treating myocardial infarction (MI) and previous reports demonstrated that hypoxia improves MSC self-renewal and therapeutics. Considering that hypoxia-inducible factor-1 alpha (HIF-1α) is a master regulator of the adaptative response to hypoxia, we hypothesized that HIF-1α overexpression in MSC could m...

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and se...

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytoki...

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and se...

The biology of the α subunits of the hypoxia-inducible factors (HIFα) has expanded in the past years from their original role in angiogenesis to their nowadays position in the self-renewal and differentiation of stem cells. Hypoxia is a physiological condition in different tissues-including tumors-and, may cause stem cells in the onset of genomic i...