Self-Organizing Single-Rosette Brain Organoids From Human Pluripotent Stem Cells

Tidball, Andrew M.; Niu, Wei; Ma, Qianyi; Takla, Taylor N; Walker, J Clayton; Margolis, Joshua L; Mojica-Perez, Sandra P.; Chopra, Ravi; Shakkottai, Vikram G.; Li, Jun Z.; Parent, Jack M.

doi:10.2139/ssrn.3925254

Cited by 3 publications

(9 citation statements)

References 26 publications

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“…Inhibitors of apical constriction have been shown previously in our system and in rodent embryo models to result in enlarged dysmorphic lumens and NTDs, respectively [ 37 , 44 ]. SHROOM3 has been shown to be necessary and sufficient to induce apical constriction in cell culture and embryo models [ 45 ], but the mechanism by which VPA leads to NTDs has been less clear.…”

Section: Discussionmentioning

confidence: 95%

“…We have previously reported a protocol for generating self-organizing single rosette spheroids with manual imaging and analysis [ 37 ]. To dramatically increase the throughput and decrease human bias, we have developed an entirely automated pipeline for imaging and analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The SOSR-CO datasets were then filtered for individual lumens and size (7800–31,415 µm 2 ). We used these filters to exclude SOSR-COs that resulted from the fusion of multiple monolayer fragments, as shown in our previous preprint manuscript [ 37 ]. To identify the distinguishing features of particular treatments or genetic variants, we utilized the random forest predictive model, followed by inspecting the individual feature importance.…”

Section: Resultsmentioning

confidence: 99%

“…Since apical constriction is a necessary mechanism of neurulation and inhibitors of apical constriction lead to NTDs in mouse models and increased lumen size in our SOSR-CO model [ 37 ], we decided to measure the apical surface areas of SOSR-COs treated with the dose curve of VPA. We utilized ZO1 immunostaining to increase the fluorescent signal for high magnification confocal microscopy (100×).…”

Section: Resultsmentioning

confidence: 99%

“…Our group and others have published techniques for generating single rosette organoids or neural cyst cultures [ 34 , 35 , 36 , 37 , 38 ]. Our simple model of human neurulation, which we call SOSR-COs (self-organizing single-rosette cortical organoids), overcomes the lack of disease-relevant structural readout in previous brain organoid models.…”

Section: Introductionmentioning

confidence: 99%

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A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects

Takla

Luo

Sudyk

et al. 2023

Cells

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Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3β and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3β at these concentrations. The knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects

Takla

Luo

Sudyk

et al. 2023

Cells

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Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson’s Disease and Cortical Injury

Harary,

Jgamadze,

Kim

et al. 2023

Brain Sciences

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Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through “bystander effects” and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson’s disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson’s disease as well as the use of structured grafts such as brain organoids for cortical repair.

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Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders

Massoumi

Amin

Soleimani

et al. 2023

IJMS

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Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases.

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Self-Organizing Single-Rosette Brain Organoids From Human Pluripotent Stem Cells

Cited by 3 publications

References 26 publications

A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects

A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson’s Disease and Cortical Injury

Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders

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