Stem Cells as In Vitro Model of Parkinson's Disease

Progress in understanding neurodegenerative cell biology in Parkinson's disease (PD) has been hampered by a lack of predictive and relevant cellular models. In addition, the lack of an adequate in vitro human neuron cell-based model has been an obstacle for the uncover of new drugs for treating PD. The ability to generate induced pluripotent stem cells (iPSCs) from PD patients and a refined capacity to differentiate these iPSCs into DA neurons, the relevant disease cell type, promises a new paradigm in drug development that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSC that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSC can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling PD “in a dish” and for testing compounds against human disease phenotypes in vitro. We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets, and enhance the probability of clinical success of new drugs

Low Levels of Amyloid Precursor Protein (APP) Promote Neurogenesis and Decrease Gliogenesis in Human Neural Stem Cells

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.This research was supported by a grant from the Spanish Ministry of Science and Innovation (RTI2018-101663-B-100) and grant number PID2021-126715OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. R.C. was supported by an FPU predoctoral contract from Universidad de Alcalá (FPU-UAH).S

Legal Immigration in the Frame of the European Union Common Immigration Policy: From a Secondary Role to a Supervened Importance

El presente trabajo pretende analizar el tratamiento del que ha sido objeto la inmigración legal dentro de la Política Común de Inmigración de la Unión Europea. Desde sus inicios, las Instituciones Europeas se han mostrado partidarias de impulsar la configuración de un marco jurídico para la inmigración legal, en tanto que los Estados miembros se han mantenido reacios a avances significativos. El resultado ha sido la aprobación paulatina de directivas que recogen acuerdos de mínimos, sólo regulan determinadas categorías sectoriales de inmigrantes y que han sido adoptadas según las necesidades de los Estados miembros. Ante esta situación y en un escenario de presión migratoria constante hacia una Unión Europa envejecida y con carencias para cubrir ciertos puestos de trabajo, la adecuada regulación de la inmigración legal se configura como un medio necesario para afrontar dichos retos en el marco de la Agenda Europea de MigraciónThis paper aims to analyze the treatment which has been given to legal immigration in the frame of the European Union Common Immigration Policy. Since the early steps of such policy, the European Institutions have shown in favour of promoting a common legal framework for labour immigration, while Member States have been opposed to significant progress. The result has been the gradual adoption of a package of directives that contain agreements of minimums, only regulate sector-based categories of immigrants and have been adopted according to Member States’ needs. In view of this situation and in a context of constant migratory pressure towards an aging European Union with sector-specific labour shortages, the suitable regulation of legal immigration is included in the European Agenda on Migration as a necessary means to tackle these challengesS

Los organoides: órganos humanos en miniatura para estudiar enfermedades

Artículo de divulgación publicado en The Conversation España el día 06/04/2022.Para entender cómo funciona el cuerpo humano y cómo se producen las enfermedades y cómo tratarlas hacemos experimentos. Como no se pueden hacer en humanos, recurrimos a células, animales de experimentación y, desde hace poco, a organoides.N

Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells.

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.This work was supported by grants from the Spanish Ministry of Science and Innovation (RTI2018-101663-B-100), MICINN-ISCIII (PI-10/00291 and MPY1412/09), MINECO (SAF2015-71140-R), and Comunidad de Madrid (NEUROSTEMCM consortium; S2010/BMD-2336).S

Molecular effects of polystyrene nanoplastics on human neural stem cells

All Results NPs cells files are available from the Dryad repository (doi:10.5061/dryad.zpc866tf9).Nanoplastics (NPs) have been found in many ecological environments (aquatic, terrestrial, air). Currently, there is great concern about the exposition and impact on animal health, including humans, because of the effects of ingestion and accumulation of these nanomaterials (NMs) in aquatic organisms and their incorporation into the food chain. NPs´ mechanisms of action on humans are currently unknown. In this study, we evaluated the altered molecular mechanisms on human neural stem cell line (hNS1) after 4 days of exposure to 30 nm polystyrene (PS) NPs (0.5, 2.5 and 10 μg/mL). Our results showed that NPs can induce oxidative stress, cellular stress, DNA damage, alterations in inflammatory response, and apoptosis, which could lead to tissue damage and neurodevelopmental diseases.S

Da espiritualidade organizacional ao capital psicológico individual: qual o papel da liderança autêntica?

A pesar de que el valor de la positividad ha sido reconocido desde hace mucho tiempo, sólo recientemente ha sido el objetivo de la investigación y aplicación en el campo del comportamiento organizacional (Luthans, 2002a,b). Diferentes estudios puede encontrarse en los trabajos recientes que buscan medir el impacto de la introducción en el entorno de la Organización de las características mencionadas como espirituales, como un medio de mejorar el desempeño individual. Además, la investigación empírica ha señalado la importancia del fortalecimiento del capital psicológico positivo no sólo para el bienestar de los propios trabajadores, sino también para mejorar los resultados. Recientemente, la crisis económica y el abandono de los modelos de gestión utilizados en muchas compañías, son acontecimientos que ha llevado a un renovado interés en el papel de líderes y, más particularmente, en su responsabilidad de crear entornos organizativos moralmente saludables. En este estudio hemos querido analizar las consecuencias de la percepción de las características de las organizaciones espirituales en la capital psicológico de los trabajadores para identificar el papel de auténtico liderazgo en esta relación. La investigación se realizó sobre 710 los miembros de una organización. La investigación se desarrolla y prueba un modelo conceptual que mediante el modelado de ecuaciones estructurales AMOS, con una muestra de 710 empleados. Los resultados obtenidos revelan que la espiritualidad organizacional y el liderazgo auténtico tienen una influencia mutua de 39,6% y que en la espiritualidad organizacional, cuando está vinculada al auténtico liderazgo, tiene una capacidad predictiva en relación al capital psicológico de 38,44%. Sin embargo, la percepción de características de autenticidad de los líderes no influyen de ninguna manera en el capital psicológico.Despite the value of positivity having long been recognized, it has only recently been the target of research and application in the field of organizational behaviour (Luthans, 2002a,b). Different studies can be found in recent work which seek to measure the impact of the introduction into the organizational environment of characteristics referred to as spiritual, as a means of improving individual performance. Furthermore, empirical research has indicated the importance of strengthening positive psychological capital not only for the well-being of the employees themselves but also to improve results. Recently, the economic crisis and the abandonment of management models used at many companies are events which have led to renewed interest in the role of leaders and, more particularly, in their responsibility to create morally healthy organizational environments. In this study we have sought to analyse the consequences of the perception of the spiritual characteristics of organizations in the psychological capital of workers and to identify the role of authentic leadership in this relationship. Research was conducted into 710 organizational members. The research develops and tests a conceptual model which underwent structural equation modeling using AMOS, with a sample of 710 employees. The results obtained reveal that organizational spirituality and authentic leadership have a mutual influence of 39.6% and that organizational spirituality, when linked to authentic leadership, has a predictive capacity in relation to psychological capital of 38.44%. However, the perception of leaders’ characteristics of authenticity in no way influences the psychological capital.Apesar do valor da positividade há muito ser reconhecido, só recentemente tem sido alvo de pesquisa e de aplicação no campo do comportamento organizacional (Luthans, 2002a,b). Entre a produção recente encontramos diferentes estudos que procuram medir o impacto da introdução, no ambiente organizacional, de caraterísticas designadas como espirituais, como forma de promoção do desempenho individual. Por outro lado, a investigação empírica tem evidenciado a importancia do reforço do capital psicológico positivo, não só para o bem-estar dos próprios trabalhadores, como também para o incremento dos resultados alcançados na sua atividade. Recentemente, a crise económica e a denúncia dos modelos de gestão utilizados em muitas empresas, fizeram renovar o interesse no papel dos líderes e, particularmente, na sua responsabilidade na criação de ambientes organizacionais moralmente saudáveis. Procurámos, neste estudo, analisar os reflexos da perceção das caraterísticas espirituais das organizações no capital psicológico dos trabalhadores e identificar o papel da liderança autêntica nessa relação. A pesquisa desenvolve e testa um modelo concetual submetido a análise por equações estruturais, através do programa AMOS, numa amostra de 710 membros organizacionais. Os resultados obtidos revelam que a espiritualidade organizacional e a liderança autêntica se influenciam mutuamente em 39,6% e que a espiritualidade organizacional, associada à liderança autêntica, apresenta uma capacidade preditiva do capital psicológico de 38,44%. No entanto, a perceção das caraterísticas de autenticidade dos líderes em nada influencia o capital psicológico.peerReviewe

Advances in Alzheimer’s Disease Research: Human Cerebral Organoids

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 technologyThe authors would like to thank to financing entities: i. State R+D+i Program Oriented to the Challenges of Society. Ministry of Science and Innovation (PID2021-126715OB-I00). ii. Strategic Action in Intramural Health (PI22/00055). iii. Ministry of Science and Innovation and Universities, within the program “R&D Projects «Retos Investigación» (RTI2018-101663-B-100).S

SINGLE-CELL sequencing workflow to study cellular composition and cell type specific expression profiles of human Cerebral Organoids

IBRO 11th World Congress of Neuroscience. Granada (Spain). 9-13 September 2023.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.S