scholarly journals Induced Pluripotent Stem Cell (iPSC)-Based Neurodegenerative Disease Models for Phenotype Recapitulation and Drug Screening

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 2000 ◽  
Author(s):  
Chia-Yu Chang ◽  
Hsiao-Chien Ting ◽  
Ching-Ann Liu ◽  
Hong-Lin Su ◽  
Tzyy-Wen Chiou ◽  
...  
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Drug Screening ◽  
Large Scale ◽  
Small Animal ◽  
Induced Pluripotent Stem Cell ◽  
Disease Models ◽  
Therapeutic Drugs ◽  
Induced Pluripotent

Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models

Open Biology ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 180138 ◽  
Author(s):  
Era Taoufik ◽  
Georgia Kouroupi ◽  
Ourania Zygogianni ◽  
Rebecca Matsas
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Pluripotent Stem Cell ◽  
Clinical Symptoms ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Synaptic Dysfunction ◽  
Disease Models ◽  
Cellular Mechanisms ◽  
Induced Pluripotent

Synaptic dysfunction in CNS disorders is the outcome of perturbations in physiological synapse structure and function, and can be either the cause or the consequence in specific pathologies. Accumulating data in the field of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia and bipolar disorder, point to a neurodevelopmental origin of these pathologies. Due to a relatively early onset of behavioural and cognitive symptoms, it is generally acknowledged that mental illness initiates at the synapse level. On the other hand, synaptic dysfunction has been considered as an endpoint incident in neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's, mainly due to the considerably later onset of clinical symptoms and progressive appearance of cognitive deficits. This dichotomy has recently been challenged, particularly since the discovery of cell reprogramming technologies and the generation of induced pluripotent stem cells from patient somatic cells. The creation of ‘disease-in-a-dish’ models for multiple CNS pathologies has revealed unexpected commonalities in the molecular and cellular mechanisms operating in both developmental and degenerative conditions, most of which meet at the synapse level. In this review we discuss synaptic dysfunction in prototype neurodevelopmental and neurodegenerative diseases, emphasizing overlapping features of synaptopathy that have been suggested by studies using induced pluripotent stem-cell-based systems. These valuable disease models have highlighted a potential neurodevelopmental component in classical neurodegenerative diseases that is worth pursuing and investigating further. Moving from demonstration of correlation to understanding mechanistic causality forms the basis for developing novel therapeutics.

scholarly journals Zebrafish and Medaka: Important Animal Models for Human Neurodegenerative Diseases

2021 ◽  
Vol 22 (19) ◽  
pp. 10766
Author(s):  
Jing Wang ◽  
Hong Cao
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Large Scale ◽  
Gene Knockout ◽  
Forward Genetics ◽  
Suitable Model ◽  
Human Beings ◽  
Fast Development ◽  
Human Neurodegenerative Disease

Animal models of human neurodegenerative disease have been investigated for several decades. In recent years, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become popular in pathogenic and therapeutic studies about human neurodegenerative diseases due to their small size, the optical clarity of embryos, their fast development, and their suitability to large-scale therapeutic screening. Following the emergence of a new generation of molecular biological technologies such as reverse and forward genetics, morpholino, transgenesis, and gene knockout, many human neurodegenerative disease models, such as Parkinson’s, Huntington’s, and Alzheimer’s, were constructed in zebrafish and medaka. These studies proved that zebrafish and medaka genes are functionally conserved in relation to their human homologues, so they exhibit similar neurodegenerative phenotypes to human beings. Therefore, fish are a suitable model for the investigation of pathologic mechanisms of neurodegenerative diseases and for the large-scale screening of drugs for potential therapy. In this review, we summarize the studies in modelling human neurodegenerative diseases in zebrafish and medaka in recent years.

scholarly journals Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

2021 ◽  
Vol 22 (5) ◽  
pp. 2659
Author(s):  
Gianluca Costamagna ◽  
Giacomo Pietro Comi ◽  
Stefania Corti
Keyword(s):  
Drug Discovery ◽  
Drug Screening ◽  
Neural Development ◽  
Neurological Disorders ◽  
Large Scale ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Cellular Level ◽  
Complex Data ◽  
Complex Data Sets

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

scholarly journals Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

2021 ◽  
Vol 22 (9) ◽  
pp. 4334
Author(s):  
Katrina Albert ◽  
Jonna Niskanen ◽  
Sara Kälvälä ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Induced Pluripotent Stem Cells ◽  
Glial Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Human Ipscs ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

scholarly journals Large-Scale Production of Human iPSC-Derived Macrophages for Drug Screening

2020 ◽  
Vol 21 (13) ◽  
pp. 4808 ◽  
Author(s):  
Simon Gutbier ◽  
Florian Wanke ◽  
Nadine Dahm ◽  
Anna Rümmelin ◽  
Silke Zimmermann ◽  
...  
Keyword(s):  
Drug Screening ◽  
Large Scale ◽  
Neoplastic Cell ◽  
Leukemic Cells ◽  
High Yield ◽  
Scale Production ◽  
Large Scale Production ◽  
Compound Screening ◽  
Health And Disease ◽  
Induced Pluripotent

Tissue-resident macrophages are key players in inflammatory processes, and their activation and functionality are crucial in health and disease. Numerous diseases are associated with alterations in homeostasis or dysregulation of the innate immune system, including allergic reactions, autoimmune diseases, and cancer. Macrophages are a prime target for drug discovery due to their major regulatory role in health and disease. Currently, the main sources of macrophages used for therapeutic compound screening are primary cells isolated from blood or tissue or immortalized or neoplastic cell lines (e.g., THP-1). Here, we describe an improved method to employ induced pluripotent stem cells (iPSCs) for the high-yield, large-scale production of cells resembling tissue-resident macrophages. For this, iPSC-derived macrophage-like cells are thoroughly characterized to confirm their cell identity and thus their suitability for drug screening purposes. These iPSC-derived macrophages show strong cellular identity with primary macrophages and recapitulate key functional characteristics, including cytokine release, phagocytosis, and chemotaxis. Furthermore, we demonstrate that genetic modifications can be readily introduced at the macrophage-like progenitor stage in order to interrogate drug target-relevant pathways. In summary, this novel method overcomes previous shortcomings with primary and leukemic cells and facilitates large-scale production of genetically modified iPSC-derived macrophages for drug screening applications.

scholarly journals Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms

2020 ◽  
Vol 190 ◽  
pp. 101805 ◽  
Author(s):  
Angélica María Sabogal-Guáqueta ◽  
Alejandro Marmolejo-Garza ◽  
Vítor Passos de Pádua ◽  
Bart Eggen ◽  
Erik Boddeke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent
Sign in / Sign up

Export Citation Format

Share Document