New frontiers in modeling tuberous sclerosis with human stem cell‐derived neurons and brain organoids

Blair, John D.; Bateup, Helen S.

doi:10.1002/dvdy.60

Cited by 31 publications

(24 citation statements)

References 108 publications

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“…1). Consistent with results from 2D neuronal cultures, a strong bias towards an astroglial cell fate, altered cell morphology, and activation of mTORC1 signaling were observed in this model [30,42] (Table 1). Additionally, it was shown that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids [30].…”

Section: Three-dimensional Modelssupporting

confidence: 87%

Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Saber

Şahin

2020

Molecular Autism

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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two-and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date.

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Section: Three-dimensional Modelssupporting

confidence: 87%

Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Saber

Şahin

2020

Molecular Autism

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“…These mutations include ASD-associated CNVs such as 15q11q13 deletion (Angelman syndrome) [121] and duplication (Dup15q syndrome) [122], 22q11.2 deletion (DiGeorge syndrome) [123,124], 16p11.2 deletion and duplication [125], and 15q13.3 deletion [126], as well as single-gene mutations including SHANK3 [127][128][129][130], CHD8 [131,132], NRXN1 [133][134][135][136][137], NLGN4 [138], EHMT1 (Kleefstra syndrome) [139], PTCHD1-AS [140], UBE3A (Angelman's syndrome) [141], and CACNA1C (Timothy syndrome) [142] (summarized in Table 1). In this review, we will not discuss fragile X syndrome, Rett's syndrome, and tuberous sclerosis-related autism as they have all been extensively reviewed previously [148][149][150][151][152][153][154].…”

Section: Main Findings From Stem Cell Models Of Asd To Datementioning

confidence: 99%

Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.Early development as a critical period for ASD susceptibility

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“…Hyperactivation of the mTOR pathway has been implicated in the development of cortical tubers as mTORC1 has a well-established role in cell proliferation and cell fate choices [31]. However, molecular mechanisms of tuber formation are difficult to study in animal models as, so far, no animal model of TSC develops an equivalent to cortical tubers [13]. Early knockout of either TSC1 or TSC2 in rodents is lethal necessitating a conditional knockout of TSC1 or TSC2 in either neurons or astrocytes at later stages of neurodevelopment in animal models [32].…”

Section: Discussionmentioning

confidence: 99%

“…However, research into mechanistic insights of seizure generation can be limited when using rodent models owing to significant differences in neuronal organization and brain development between rodents and humans [12]. Moreover, genetic epilepsy syndromes such as TSC are challenging to study in animal models, since pathogenic mechanisms likely originate from events during early neural development, a phase that differs profoundly between rodents and humans in terms of cell type diversity, proliferation zones, and timescales [13,14]. This translational barrier might be an important reason why mechanisms underlying human epileptogenesis are still not fully understood [15] and may, at least partly, explain why a preventative or disease-modifying antiepileptogenic therapy is not available in clinical practice, despite promising preclinical results [16].…”

Section: Introductionmentioning

confidence: 99%

High glucose concentrations mask cellular phenotypes in a stem cell model of tuberous sclerosis complex

Rocktäschel

Sen

Cader

2019

Epilepsy & Behavior

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Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by deletions in the TSC1 or TSC2 genes that is associated with epilepsy in up to 90% of patients. Seizures are suggested to start in benign brain tumors, cortical tubers, or in the perituberal tissue making these tubers an interesting target for further research into mechanisms underlying epileptogenesis in TSC. Animal models of TSC insufficiently capture the neurodevelopmental biology of cortical tubers, and hence, human stem cell-based in vitro models of TSC are being increasingly explored in attempts to recapitulate tuber development and epileptogenesis in TSC. However, in vitro culture conditions for stem cell-derived neurons do not necessarily mimic physiological conditions. For example, very high glucose concentrations of up to 25 mM are common in culture media formulations. As TSC is potentially caused by a disruption of the mechanistic target of rapamycin (mTOR) pathway, a main integrator of metabolic information and intracellular signaling, we aimed to examine the impact of different glucose concentrations in the culture media on cellular phenotypes implicated in tuber characteristics. Here, we present preliminary data from a pilot study exploring cortical neuronal differentiation on human embryonic stem cells (hES) harboring a TSC2 knockout mutation (TSC2−/−) and an isogenic control line (TSC2+/+). We show that the commonly used high glucose media profoundly mask cellular phenotypes in TSC2−/− cultures during neuronal differentiation. These phenotypes only become apparent when differentiating TSC2+/+ and TSC2−/− cultures in more physiologically relevant conditions of 5 mM glucose suggesting that the careful consideration of culture conditions is vital to ensuring biological relevance and translatability of stem cell models for neurological disorders such as TSC. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

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New frontiers in modeling tuberous sclerosis with human stem cell‐derived neurons and brain organoids

Cited by 31 publications

References 108 publications

Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Human in vitro models for understanding mechanisms of autism spectrum disorder

High glucose concentrations mask cellular phenotypes in a stem cell model of tuberous sclerosis complex

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