scholarly journals Pre-clinical Investigation of Rett Syndrome Using Human Stem Cell-Based Disease Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Florencia D. Haase ◽  
Bronte Coorey ◽  
Lisa Riley ◽  
Laurence C. Cantrill ◽  
Patrick P. L. Tam ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neural Development ◽  
Clinical Investigation ◽  
Neurodevelopmental Disorder ◽  
Limited Resource ◽  
Cell Types ◽  
Disease Models ◽  
Conventional Animal ◽  
Brain Organoid ◽  
Induced Pluripotent

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, mostly caused by mutations in MECP2. The disorder mainly affects girls and it is associated with severe cognitive and physical disabilities. Modeling RTT in neural and glial cell cultures and brain organoids derived from patient- or mutation-specific human induced pluripotent stem cells (iPSCs) has advanced our understanding of the pathogenesis of RTT, such as disease-causing mechanisms, disease progression, and cellular and molecular pathology enabling the identification of actionable therapeutic targets. Brain organoid models that recapitulate much of the tissue architecture and the complexity of cell types in the developing brain, offer further unprecedented opportunity for elucidating human neural development, without resorting to conventional animal models and the limited resource of human neural tissues. This review focuses on the new knowledge of RTT that has been gleaned from the iPSC-based models as well as limitations of the models and strategies to refine organoid technology in the quest for clinically relevant disease models for RTT and the broader spectrum of neurodevelopmental disorders.

scholarly journals Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

2020 ◽  
Vol 8 ◽  
Author(s):  
Ana Rita Gomes ◽  
Tiago G. Fernandes ◽  
Sandra H. Vaz ◽  
Teresa P. Silva ◽  
Evguenia P. Bekman ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neural Development ◽  
Neurological Disorders ◽  
Neurodevelopmental Disorder ◽  
Cortical Layer ◽  
Patient Specific ◽  
Human Patient ◽  
Personalized Diagnosis ◽  
Induced Pluripotent ◽  
Lower Expression

Engineering brain organoids from human induced pluripotent stem cells (hiPSCs) is a powerful tool for modeling brain development and neurological disorders. Rett syndrome (RTT), a rare neurodevelopmental disorder, can greatly benefit from this technology, since it affects multiple neuronal subtypes in forebrain sub-regions. We have established dorsal and ventral forebrain organoids from control and RTT patient-specific hiPSCs recapitulating 3D organization and functional network complexity. Our data revealed a premature development of the deep-cortical layer, associated to the formation of TBR1 and CTIP2 neurons, and a lower expression of neural progenitor/proliferative cells in female RTT dorsal organoids. Moreover, calcium imaging and electrophysiology analysis demonstrated functional defects of RTT neurons. Additionally, assembly of RTT dorsal and ventral organoids revealed impairments of interneuron’s migration. Overall, our models provide a better understanding of RTT during early stages of neural development, demonstrating a great potential for personalized diagnosis and drug screening.

scholarly journals Exosomes regulate Neurogenesis and Circuit Assembly in a Model of Rett Syndrome

2017 ◽  
Author(s):  
Pranav Sharma ◽  
Pinar Mesci ◽  
Cassiano Carromeu ◽  
Daniel McClatchy ◽  
Lucio Schiapparelli ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neural Development ◽  
Neuronal Development ◽  
Neurodevelopmental Disorder ◽  
The Body ◽  
Neural Cultures ◽  
Induced Pluripotent ◽  
And Function ◽  
Signaling Components ◽  
Promising Avenue

SummaryExosomes are thought to be secreted by all cells in the body and to be involved in intercellular communication. Here, we tested whether neural exosomes regulate the development of neural circuits and whether exosome-mediated signaling may be aberrant in the neurodevelopmental disorder Rett Syndrome (RTT). Quantitative proteomic analysis comparing exosomes from human induced pluripotent stem cells (hiPSC) - derived RTT patient or control neural cultures indicates that control exosomes contain signaling components capable of influencing neuronal development and function, which are lacking in RTT exosomes. Moreover, treatment with control exosomes rescues neuron number, apoptosis, synaptic puncta and synchronized firing phenotypes of MeCP2 knockdown in human primary neurons, indicating that exosomes have the capacity to influence neural development and may be a promising avenue to treat neurodevelopmental disorders like Rett Syndrome.HighlightsExosome proteomics distinguish cargo in RTT vs control hiPSC-derived neural cultures Control but not RTT exosomes increase neurogenesis in human neural cultures hiPSC-derived neural exosomes reverse pathological phenotypes in RTT neural cultures RTT exosomes do not impair neural development

scholarly journals A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells

Cell ◽  
2010 ◽  
Vol 143 (4) ◽  
pp. 527-539 ◽  
Author(s):  
Maria C.N. Marchetto ◽  
Cassiano Carromeu ◽  
Allan Acab ◽  
Diana Yu ◽  
Gene W. Yeo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Rett Syndrome ◽  
Neural Development ◽  
Pluripotent Stem Cells ◽  
Induced Pluripotent

scholarly journals Brain organoid: a 3D technology for investigating cellular composition and interactions in human neurological development and disease models in vitro

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oluwafemi Solomon Agboola ◽  
Xinglin Hu ◽  
Zhiyan Shan ◽  
Yanshuang Wu ◽  
Lei Lei
Keyword(s):  
Human Brain ◽  
Neural Development ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Cellular Interactions ◽  
Neural Lineage ◽  
Brain Physiology ◽  
Brain Organoid

Abstract The study of human brain physiology, including cellular interactions in normal and disease conditions, has been a challenge due to its complexity and unavailability. Induced pluripotent stem cell (iPSC) study is indispensable in the study of the pathophysiology of neurological disorders. Nevertheless, monolayer systems lack the cytoarchitecture necessary for cellular interactions and neurological disease modeling. Brain organoids generated from human pluripotent stem cells supply an ideal environment to model both cellular interactions and pathophysiology of the human brain. This review article discusses the composition and interactions among neural lineage and non-central nervous system cell types in brain organoids, current studies, and future perspectives in brain organoid research. Ultimately, the promise of brain organoids is to unveil previously inaccessible features of neurobiology that emerge from complex cellular interactions and to improve our mechanistic understanding of neural development and diseases. Graphical abstract

scholarly journals Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
James M Mossner ◽  
Renata Batista-Brito ◽  
Rima Pant ◽  
Jessica A Cardin
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Cell Types ◽  
Loss Of Function ◽  
Cortical Function ◽  
Behavioral Phenotypes ◽  
Pathophysiological Role ◽  
And Function ◽  
And Behavior

Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.

scholarly journals Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dorothy P Schafer ◽  
Christopher T Heller ◽  
Georgia Gunner ◽  
Molly Heller ◽  
Christopher Gordon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Neural Circuits ◽  
Neurodevelopmental Disorder ◽  
Cell Types ◽  
Null Mouse ◽  
Causative Role ◽  
Specific Loss ◽  
Synapse Loss ◽  
Circuit Defects

Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder<xref ref-type="bibr" rid="bib19"/><xref ref-type="bibr" rid="bib15"/><xref ref-type="bibr" rid="bib37"/><xref ref-type="bibr" rid="bib47"/>. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role<xref ref-type="bibr" rid="bib67"/>. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.

scholarly journals Urine-derived induced pluripotent/neural stem cells for modeling neurological diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyuan Shi ◽  
Martin Cheung
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neural Development ◽  
Neurological Diseases ◽  
Low Cost ◽  
Invasive Procedure ◽  
Cell Types ◽  
Potential Applications ◽  
Regenerative Medicines ◽  
Induced Pluripotent

AbstractNeurological diseases are mainly modeled using rodents through gene editing, surgery or injury approaches. However, differences between humans and rodents in terms of genetics, neural development, and physiology pose limitations on studying disease pathogenesis in rodent models for neuroscience research. In the past decade, the generation of induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) by reprogramming somatic cells offers a powerful alternative for modeling neurological diseases and for testing regenerative medicines. Among the different somatic cell types, urine-derived stem cells (USCs) are an ideal cell source for iPSC and iNSC reprogramming, as USCs are highly proliferative, multipotent, epithelial in nature, and easier to reprogram than skin fibroblasts. In addition, the use of USCs represents a simple, low-cost and non-invasive procedure for generating iPSCs/iNSCs. This review describes the cellular and molecular properties of USCs, their differentiation potency, different reprogramming methods for the generation of iPSCs/iNSCs, and their potential applications in modeling neurological diseases.

scholarly journals WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome

2021 ◽  
Vol 22 (18) ◽  
pp. 9954
Author(s):  
Florencia Haase ◽  
Brian S. Gloss ◽  
Patrick P. L. Tam ◽  
Wendy A. Gold
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Core Gene ◽  
Cellular Level ◽  
Neural Cells ◽  
Pathogenic Mutations ◽  
Gene Correlation ◽  
Healthy Control ◽  
Ubiquitination Pathway ◽  
Induced Pluripotent

Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to 18 months of age. Little is known about the consequences of MeCP2 deficiency at a molecular and cellular level before the onset of symptoms in neural cells, and subtle changes at this highly sensitive developmental stage may begin earlier than symptomatic manifestation. Recent transcriptomic studies of patient induced pluripotent stem cells (iPSC)-differentiated neurons and brain organoids harbouring pathogenic mutations in MECP2, have unravelled new insights into the cellular and molecular changes caused by these mutations. Here we interrogated transcriptomic modifications in RTT patients using publicly available RNA-sequencing datasets of patient iPSCs harbouring pathogenic mutations and healthy control iPSCs by Weighted Gene Correlation Network Analysis (WGCNA). Preservation analysis identified core gene pathways involved in translation, ribosomal function, and ubiquitination perturbed in some MECP2 mutant iPSC lines. Furthermore, differential gene expression of the parental fibroblasts and iPSC-derived neurons revealed alterations in genes in the ubiquitination pathway and neurotransmission in fibroblasts and differentiated neurons respectively. These findings might suggest that global translational dysregulation and proteasome ubiquitin function in Rett syndrome begins in progenitor cells prior to lineage commitment and differentiation into neural cells.

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