scholarly journals Epilepsy Research Now in 3D: Harnessing the Power of Brain Organoids in Epilepsy

2022 ◽  
pp. 153575972110703
Author(s):  
Christina Gross
Keyword(s):  
Pluripotent Stem Cells ◽  
Network Formation ◽  
Neurological Diseases ◽  
Extracellular Recording ◽  
Brain Network ◽  
Calcium Sensor ◽  
Brain Growth ◽  
Anatomical Changes ◽  
Intact Brain ◽  
Induced Pluripotent

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

scholarly journals Identification of neural oscillations and epileptiform changes in human brain organoids

2019 ◽  
Author(s):  
Ranmal A. Samarasinghe ◽  
Osvaldo A. Miranda ◽  
Simon Mitchell ◽  
Isabella Ferando ◽  
Momoko Watanabe ◽  
...  
Keyword(s):  
Neural Network ◽  
Human Brain ◽  
Network Architecture ◽  
Network Formation ◽  
Neurological Diseases ◽  
Extracellular Recording ◽  
Brain Network ◽  
Network Activity ◽  
Intact Brain ◽  
Oscillatory Network

ABSTRACTHuman brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-α. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

scholarly journals Identification of Molecular Signatures in Neural Differentiation and Neurological Diseases Using Digital Color-Coded Molecular Barcoding

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Debora Salerno ◽  
Alessandro Rosa
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neural Differentiation ◽  
Disease Modeling ◽  
Neurological Diseases ◽  
Embryonic Stem ◽  
Molecular Signatures ◽  
Molecular Barcoding ◽  
Induced Pluripotent

Human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells, represent powerful tools for disease modeling and for therapeutic applications. PSCs are particularly useful for the study of development and diseases of the nervous system. However, generating in vitro models that recapitulate the architecture and the full variety of subtypes of cells that make the complexity of our brain remains a challenge. In order to fully exploit the potential of PSCs, advanced methods that facilitate the identification of molecular signatures in neural differentiation and neurological diseases are highly demanded. Here, we review the literature on the development and application of digital color-coded molecular barcoding as a potential tool for standardizing PSC research and applications in neuroscience. We will also describe relevant examples of the use of this technique for the characterization of the heterogeneous composition of the brain tumor glioblastoma multiforme.

scholarly journals Ngn2 induces diverse neuronal lineages from human pluripotency

2020 ◽  
Author(s):  
Hsiu-Chuan Lin ◽  
Zhisong He ◽  
Sebastian Ebert ◽  
Maria Schörnig ◽  
Malgorzata Santel ◽  
...  
Keyword(s):  
Nervous System ◽  
Pluripotent Stem Cells ◽  
Time Course ◽  
Neurological Diseases ◽  
Molecular Heterogeneity ◽  
Neuron Type ◽  
Functional Maturation ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
Two Populations

Human neurons engineered from induced pluripotent stem cells (iPSCs) through Neurogenin 2 (Ngn2) overexpression are widely used to study neuronal differentiation mechanisms and to model neurological diseases. However, the differentiation paths and heterogeneity of emerged neurons have not been fully explored. Here we used single-cell transcriptomics to dissect the cell states that emerge during Ngn2 overexpression across a time course from pluripotency to neuron functional maturation. We find a substantial molecular heterogeneity in the neuron types generated, with at least two populations that express genes associated with neurons of the peripheral nervous system. Neuron heterogeneity is observed across multiple iPSC clones and lines from different individuals. We find that neuron fate acquisition is sensitive to Ngn2 expression level and the duration of Ngn2 forced expression. Our data reveals that Ngn2 dosage can regulate neuron fate acquisition, and that Ngn2-iN heterogeneity can confound results that are sensitive to neuron type.

Nuclear reprogramming and induced pluripotency

2019 ◽  
pp. 205-212
Author(s):  
John C. Lucchesi
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Late Onset ◽  
Neurological Diseases ◽  
Embryonic Stem ◽  
Induced Pluripotency ◽  
Differentiated Cells ◽  
Induced Pluripotent ◽  
Bivalent Promoter

Four core transcription factors known to maintain the pluripotent state in embryonic stem cells (ESCs)—Oct4, Sox2, Klf4 and c-Myc—were used to induce pluripotent stem cells in adult-derived fibroblasts. Induced pluripotent stem cells (iPSCs), like ESCs, have less condensed and more transcriptionally active chromatin than differentiated cells. The number of genes with bivalent promoter marks increases during reprogramming, reflecting the switch of differentiation-specific active genes to an inactive, but poised, status. The levels of DNA methyl transferases and demethylases are increased, underlying the changes in the pattern of DNA methylation that occur late during reprogramming. The potential therapeutic applications of iPSCs include reprogramming a patient’s own cells to avoid the problem of rejection following injection to restore tissue or organ function. iPSCs derived from individuals at risk of developing late-onset neurological diseases could be differentiated in culture to predict the future occurrence of the disease. Caveats involve the fact that long-term culturing often results in genomic mutations that may, by chance, involve tumor suppressors or oncogenes.

scholarly journals Modelling Neurotropic Flavivirus Infection in Human Induced Pluripotent Stem Cell-Derived Systems

2019 ◽  
Vol 20 (21) ◽  
pp. 5404 ◽  
Author(s):  
Giovanna Desole ◽  
Alessandro Sinigaglia ◽  
Silvia Riccetti ◽  
Giulia Masi ◽  
Monia Pacenti ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Viral Infections ◽  
Neurological Diseases ◽  
Induced Pluripotent Stem Cell ◽  
Immune Response Gene ◽  
Patient Specific ◽  
Lower Efficiency ◽  
Massive Cell Death ◽  
Induced Pluripotent

Generation of human induced pluripotent stem cells (hiPSCs) and their differentiation into a variety of cells and organoids have allowed setting up versatile, non-invasive, ethically sustainable, and patient-specific models for the investigation of the mechanisms of human diseases, including viral infections and host–pathogen interactions. In this study, we investigated and compared the infectivity and replication kinetics in hiPSCs, hiPSC-derived neural stem cells (NSCs) and undifferentiated neurons, and the effect of viral infection on host innate antiviral responses of representative flaviviruses associated with diverse neurological diseases, i.e., Zika virus (ZIKV), West Nile virus (WNV), and dengue virus (DENV). In addition, we exploited hiPSCs to model ZIKV infection in the embryo and during neurogenesis. The results of this study confirmed the tropism of ZIKV for NSCs, but showed that WNV replicated in these cells with much higher efficiency than ZIKV and DENV, inducing massive cell death. Although with lower efficiency, all flaviviruses could also infect pluripotent stem cells and neurons, inducing similar patterns of antiviral innate immune response gene expression. While showing the usefulness of hiPSC-based infection models, these findings suggest that additional virus-specific mechanisms, beyond neural tropism, are responsible for the peculiarities of disease phenotype in humans.

scholarly journals Integrative Research of Induction of Pluripotent Stem Cells

2017 ◽  
Vol 4 (3-4) ◽  
pp. 115-124 ◽  
Author(s):  
Penglin Gao ◽  
Chuanhe Sun ◽  
Weilong Liao ◽  
Wenfei Jiang ◽  
Te Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Viral Vector ◽  
Neurological Diseases ◽  
Embryonic Stem ◽  
Basic Research ◽  
Model Systems ◽  
Suitable Model ◽  
Integrative Research ◽  
Induced Pluripotent

Since the Japanese scientist Shinya Yamanaka used a viral vector to transfer the combination of 4 factors into differentiated somatic cells and reprogramed them to obtain similar embryonic stem cells and induced pluripotent stem cells (iPSCs), it provided one integrative method for studying many medical fields. Patient-derived iPSCs have provided an opportunity to study human diseases for which no suitable model systems are available. iPSC technology has since become a major breakthrough in the field of stem cell research. With the continuous development of iPSC technology and the continuous improvement of technical levels, excellent advances have become more and more common in the basic research and medical fields of life sciences. This article reviews the development history, clinical application, and problems and prospects of iPSC, and focuses on the application of iPSC in neurological diseases.

scholarly journals Induced Pluripotent Stem Cells to Model and Treat Neurogenetic Disorders

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Hansen Wang ◽  
Laurie C. Doering
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neurological Diseases ◽  
Cellular Reprogramming ◽  
Cell Populations ◽  
Therapeutic Implications ◽  
Skin Biopsies ◽  
Neurogenetic Disorders ◽  
Induced Pluripotent

Remarkable advances in cellular reprogramming have made it possible to generate pluripotent stem cells from somatic cells, such as fibroblasts obtained from human skin biopsies. As a result, human diseases can now be investigated in relevant cell populations derived from induced pluripotent stem cells (iPSCs) of patients. The rapid growth of iPSC technology has turned these cells into multipurpose basic and clinical research tools. In this paper, we highlight the roles of iPSC technology that are helping us to understand and potentially treat neurological diseases. Recent studies using iPSCs to model various neurogenetic disorders are summarized, and we discuss the therapeutic implications of iPSCs, including drug screening and cell therapy for neurogenetic disorders. Although iPSCs have been used in animal models with promising results to treat neurogenetic disorders, there are still many issues associated with reprogramming that must be addressed before iPSC technology can be fully exploited with translation to the clinic.

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