Person:
Coronel Lopez, Raquel

First Name

Raquel

Last Name

Coronel Lopez

Institution

ISCIII

Centrre

ISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)

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Now showing 1 - 10 of 17

Impact of environmental neurotoxic: current methods and usefulness of human stem cells.
(Elsevier, 2020-12) Rosca, Andreea; Coronel Lopez, Raquel; Moreno, Miryam; Gonzalez-Martin-Niño, Rosa Maria; Oniga, Andreea; Martin, Alberto; López-Alonso, Victoria; González-Caballero, MCarmen; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)
The development of central nervous system is a highly coordinated and complex process. Any alteration of this process can lead to disturbances in the structure and function of the brain, which can cause deficits in neurological development, resulting in neurodevelopmental disorders, including, for example, autism or attention-deficit hyperactivity disorder. Exposure to certain chemicals during the fetal period and childhood is known to cause developmental neurotoxicity and has serious consequences that persist into adult life. For regulatory purposes, determination of the potential for developmental neurotoxicity is performed according the OECD Guideline 426, in which the test substance is administered to animals during gestation and lactation. However, these animal models are expensive, long-time consuming and may not reflect the physiology in humans; that makes it an unsustainable model to test the large amount of existing chemical products, hence alternative models to the use of animals are needed. One of the most promising methods is based on the use of stem cell technology. Stem cells are undifferentiated cells with the ability to self-renew and differentiate into more specialized cell types. Because of these properties, these cells have gained increased attention as possible therapeutic agents or as disease models. Here, we provide an overview of the current models both animal and cellular, available to study developmental neurotoxicity and review in more detail the usefulness of human stem cells, their properties and how they are becoming an alternative to evaluate and study the mechanisms of action of different environmental toxicants.
Background levels and brain organoid impact of RF field exposure in a healthcare environment
(Frontiers Media, 2024-03) Hernández, José A.; Rosca, Andreea; Suárez, Samuel; Coronel Lopez, Raquel; Suarez, Oscar J.; Peran-Ramos, Paula; Marina-Boillos, Pablo; Rabassa, Luis E.; Mateos-Martínez, Patricia; Liste-Noya, Isabel; López-Alonso, Victoria; Torres-Ruiz, Mónica; Febles, Victor M.; Ramos-Gonzalez, Maria Victoria; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Agencia Estatal de Investigación (España)
Introduction: This study is an introduction to the empirical and impact evaluation of radiofrequency electromagnetic field (RF-EMF) radiation exposure in a healthcare environment, focusing on an indoor microenvironment. It explores the expression of various genes associated with cellular responses, cell proliferation, senescence, and apoptotic cell death. The assessment analyzes current personal mobile communications (2G-5G FR1), providing a clear understanding of RF-EMF exposure and compliance with regulatory limits. Methods: The signals from different wireless communication systems at Hospital Universitario de Canarias (HUC) in Tenerife, Canary Islands, Spain, were examined in 11 locations. Four measurement campaigns were performed with frequencyselective exposimeters (PEMs) and an EME Spy 200 MVG, and experimental electric field values were compared as a long-term exposition. The frequency with the highest contribution (2.174 V/m) observed (1840 MHz) in UMTS was selected for biological effects evaluation. Results: The study focuses on four locations with the highest exposure to communication systems (downlinks), analyzing the results to verify compliance with regulations that ensure the safety of patients, the general public, and healthcare workers. LTE B20 (DL), GSM+UMTS 900 (DL), GSM 1800 (DL), UMTS 2100 (DL), and LTE B7 (DL) exhibited relatively higher E/m values throughout the campaigns, and these values consistently remained below the ICNIRP reference levels, signifying a consistently low level of exposure. In addition, this work presents the biological effects on neural stem cells (NSCs) using 3D brain organoids (BOs) exposed to RF signals in a validated and commercial experimental setting: the Gigahertz Transverse Electromagnetic cell (GTEM). The GTEM allows for the creation of homogeneous field electromagnetic fields in a small, enclosed setting and guarantees exposure conditions in a wide range of frequencies. BOs are an in vitro 3D cell-culture technology that reproduces the cellular composition and structure of the developing brain. Analyzing the expression of several genes associated with cellular responses, cell proliferation, senescence, and apoptotic cell death,wefound that exposure of BOs at 1840MHzdid not affectmRNAexpression in brain genes related to apoptosis or senescence. However, a decrease in gene expression for cell proliferation and cell activity markers was observed during the differentiation stage of BOs. Discussion: The discussion emphasizes the coexistence and evolution of various heterogeneous networks and services throughout the four measurement campaigns. Across all measured results, the levels of the obtained E-field were consistently well below the exposure limits set by internationally accepted standards and guidelines. These obtained values have been established in order to consider their potential effects on cell proliferation and cell activity, especially in differentiating biological organisms. Consequently, the results obtained and the methodology presented could serve as a foundational framework for establishing the basis of RF-EMF assessment in future heterogeneous 5G developments, particularly in the millimeter wave (mmWave) frequency range, where the forecast is for massive high-node density networks.
Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells.
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-09-02) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)
Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer's disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.
Physiological and pathological effects of amyloid-β species in neural stem cell biology
(Medknow Publications, 2019-12) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; Monteagudo, Maria; Zambrano, Alberto; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)
Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer's disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer's disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer's disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer's disease.
RNA-SEQ analysis reveals the implication of Amyloid Precursor Protein (APP) in cell fate specification of human neural Stem Cells by several Signaling Pathways. IBRO Neuroscience Reports
(Elsevier, 2023) Coronel Lopez, Raquel; Rosca, Andreea; González-Sastre, Rosa; Mateos-Martínez, Patricia; Gallego, Marta Ines; Liste-Noya, Isabel; López-Alonso, Victoria
Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) in Alzheimer's disease (AD), being the aggregation of β-amyloid (Aβ) peptide a central event. However, many authors consider that alterations in physiological functions of APP are likely to play a key role in AD pathogenesis. APP is a glycoprotein expressed ubiquitously in a wide variety of tissues, being especially abundant in the brain. The APP expression is detected at early stages of nervous system development, as well as in adult brain, suggesting that this protein plays a key and important role at various stages of life. Previous studies in our laboratory revealed that APP playing an important role on differentiation of human neural stem cells (hNSCs), favoring glial differentiation (gliogenesis), and preventing the differentiation of them towards neuronal phenotype (neurogenesis). In that case, we proposed to the APP/AICD/GSK-3β system as a possible molecular mechanism involved in the observed effects. However, given the multifunctionality of APP, we think that other molecular mechanisms could also be implicated. In the present study, we have evaluated the effects of APP overexpression in hNSCs at a global level by a transcriptomic analysis using the massive RNA sequencing (RNA-seq) technology. Specifically, we have focused on differentially expressed genes (DEGs) that are related to neuronal and glial differentiation processes, as well as on groups of DEGs associated with different signaling pathways, to find a possible interaction between them and APP. Our data indicate a differential expression in genes related to gliogenesis and neurogenesis processes, as well as in the pathways of Notch signaling, Wnt signaling, PI3K-AKT signaling, and JAK-STAT signaling, among other. The knowledge of physiological functions of APP, as well as the possible signaling pathways that could be implicated, are essential to advance the understanding of the pathogenesis of AD.
Neurogenesis Is Increased in Human Neural Stem Cells by Aβ40 Peptide
(Multidisciplinary Digital Publishing Institute (MDPI), 2022-05-22) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; Martin, Alberto; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)
Amyloid-β 40 peptides [Aβ1-40 (Aβ40)] are present within amyloid plaques in the brains of patients with Alzheimer's disease (AD). Even though Aβ peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological function of these Aβ peptides remains poorly understood, and the existing data are sometimes controversial. Here, we analyze and compare the effects of monomeric Aβ40 on the biology of differentiating human neural stem cells (human NSCs). For that purpose, we used a model of human NSCs called hNS1. Our data demonstrated that Aβ40 at high concentrations provokes apoptotic cellular death and the damage of DNA in human NSCs while also increasing the proliferation and favors neurogenesis by raising the percentage of proliferating neuronal precursors. These effects can be mediated, at least in part, by β-catenin. These results provide evidence of how Aβ modulate/regulate human NSC proliferation and differentiation, suggesting Aβ40 may be a pro-neurogenic factor. Our data could contribute to a better understanding of the molecular mechanisms involved in AD pathology and to the development of human NSC-based therapies for AD treatment, since these results could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.
SINGLE-CELL sequencing workflow to study cellular composition and cell type specific expression profiles of human Cerebral Organoids
(Elsevier, 2023) González-Sastre, Rosa; Coronel Lopez, Raquel; Mateos-Martínez, Patricia; Jimenez Sancho, Maria Pilar; Rosca, Andreea; Maeso, Laura; Martín Benito, Sabela; Zaballos, Ángel; Liste-Noya, Isabel; López-Alonso, Victoria
Human cerebral organoid culture is a technology with immense potential in the areas of developmental neurobiology and neurodegeneration for example to study cell types, mechanisms involved, to discover of new biomarkers, to propose specific therapeutic strategies or to study the effects of compound-induced toxicity. Single-cell RNA sequencing (scRNA-seq) is a promising technology that will help to define the identity of the cerebral organoids and to understand cellular composition and cell type specific expression profiles. Standardization of workflows to do the scRNA-seq analysis is an important means to improve the use of this technology. We present the workflow and results of the scRNA-seq performed for cerebral organoids generated from the AND-2 cell line of human embryonic stem cells (hESCs). Dissociated cerebral organoid samples were loaded on the 10X Chromium and single cell libraries were prepared according to 10X Genomics standard procedures and sequenced on the Novaseq sequencer (Illumina).The data were checked and aligned to the GRCh38 human reference genome with CellRanger v6.0.2 and analyzed with Seurat v4.0. After quality filtering and data normalization with the SCTransform function, we performed Principal component analysis (PCA) using the highly variable genes, built a Shared Nearest Neighbor (SNN) graph using the Louvain method. To visualize data, Uniform Manifold Approximation and Projection (UMAP) dimensional reduction was performed. The identities of the cell clusters were assigned using the expression of genes specific of each cell type. We annotate in the AND2 cerebral organoids clusters for intermediate progenitor cells, astrocytes, oligodendrocyte precursor cells, excitatory neurons, inhibitory neurons, and mesodermal cells. We find also some cells in these organoids with expression of endothelial and microglial gene markers. Enrichment analysis of the highly variable differentially expressed genes (DEGs) was utilized to characterize the assigned cell types with Gene Ontology (GO), PanglaoDB and Cellmarker databases.
Low Levels of Amyloid Precursor Protein (APP) Promote Neurogenesis and Decrease Gliogenesis in Human Neural Stem Cells
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-09-27) Coronel Lopez, Raquel; López-Alonso, Victoria; Gallego, Marta Ines; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Agencia Estatal de Investigación (España); University of Alcalá (España)
Amyloid precursor protein (APP) has been widely studied due to its association with Alzheimer's disease (AD). However, the physiological functions of APP are still largely unexplored. APP is a transmembrane glycoprotein whose expression in humans is abundant in the central nervous system. Specifically, several studies have revealed the high expression of APP during brain development. Previous studies in our laboratory revealed that a transient increase in APP expression induces early cell cycle exit of human neural stem cells (hNSCs) and directs their differentiation towards glial cells (gliogenesis) while decreasing their differentiation towards neurons (neurogenesis). In the present study, we have evaluated the intrinsic cellular effects of APP down-expression (using siRNA) on cell death, cell proliferation, and cell fate specification of hNSCs. Our data indicate that APP silencing causes cellular effects opposite to those obtained in previous APP overexpression assays, inducing cell proliferation in hNS1 cells (a model line of hNSCs) and favoring neurogenesis instead of gliogenesis in these cells. In addition, we have analyzed the gene and protein expression levels of β-Catenin as a possible molecule involved in these cellular effects. These data could help to understand the biological role of APP, which is necessary to deepen the knowledge of AD.
Advances in Alzheimer’s Disease Research: Human Cerebral Organoids
(Biomedgrid, 2023) Mateos-Martínez, Patricia; González-Sastre, Rosa; Coronel Lopez, Raquel; Rosca, Andreea; Martín Benito, Sabela; Bernabeu-Zornoza, Adela; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España)
Alzheimer’s disease (AD) is the main neurodegenerative disorder in old age, causing memory impairment and dependency. The histopathology of AD is characterized by the presence of amyloid plaques and neurofibrillary tangles formed by Aβ peptide and hyperphosphorylated Tau, respectively. There is still no cure or effective treatment for AD. This could be due, in part, to the lack of suitable research models since animal models do not recapitulate the full physiological complexity of the human brain. With the development of induced pluripotent stem cells (iPSCs), these limitations could be overcome. Even so, the bi-dimensional (2D) culture models still do not allow to recapitulate all types of brain cells and do not show a three-dimensional (3D) arrangement. Since obtaining 3D cultures called organoids, a new opportunity arises to overcome the limitations of previous models. Human Cerebral Organoids (hCOs) represent a pioneering model, in which part of the complexity of the human brain is present. For this reason, they are fast becoming a very remarkable model for the study of the evolution of the molecular and cellular pathology of AD. This review provides a brief overview of AD research, focusing on the most recent advances achieved through the development of stem cell and cerebral organoid technology
Role of Amyloid Precursor Protein (APP) and Its Derivatives in the Biology and Cell Fate Specification of Neural Stem Cells
(Springer, 2018-09) Coronel Lopez, Raquel; Bernabeu-Zornoza, Adela; Palmer, Charlotte; Muñiz-Moreno, Mar; Zambrano, Alberto; Cano, Eva; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)
Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (η-secretase, δ-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPα (sAPPα), soluble APPβ (sAPPβ), β-amyloid (Aβ) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described.