Organoids as a new model system to study neural tube defects

Wu, Yu; Peng, Sai; Finnell, Richard H.; Zheng, Yufang

doi:10.1096/fj.202002348r

Cited by 18 publications

(15 citation statements)

References 86 publications

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“…In our models, the expression of NCAD concentrated at the center of the 3D neuroepithelial cyst model and the rosette model. This distribution marked an inner apical polarity, which is similar to that in the in vivo neural tube and the established in vitro models (Wu et al, 2021). The distributions of NCAD were not affected by high glucose in either model system (Figures 1C, D).…”

Section: Effects Of High Glucose On Model Neural Tube Development Cha...supporting

confidence: 77%

“…To study the effect of high glucose concentrations on actin during secondary neurulation, we used a three dimensional (3D) neuroepithelial cyst model (Zhu et al, 2013) and a rosette model (Shi et al, 2012a;Shi et al, 2012b) It has been suggested that the rosette model is reminiscent of secondary neurulation instead of primary neurulation (Fedorova et al, 2019). The recently developed 3D neuroepithelial cyst model is organoid-like model, which is a good in vitro model to study the cellular events of human neural tube development (Wu et al, 2021). Therefore, we used both models in our study.…”

Section: Introductionmentioning

confidence: 99%

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High glucose causes developmental abnormalities in neuroepithelial cysts with actin and HK1 distribution changes

Peng

Zheng

2023

Front. Cell Dev. Biol.

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It has been reported that the offspring of diabetic pregnant women have an increased risk for neural tube defects. Previous studies in animal models suggested that high glucose induces cell apoptosis and epigenetic changes in the developing neural tube. However, effects on other cellular aspects such as the cell shape changes were not fully investigated. Actin dynamics plays essential roles in cell shape change. Disruption on actin dynamics is known to cause neural tube defects. In the present study, we used a 3D neuroepithelial cyst model and a rosette model, both cultured from human embryonic stem cells, to study the cellular effects caused by high glucose. By using these models, we observed couple of new changes besides increased apoptosis. First, we observed that high glucose disturbed the distribution of pH3 positive cells in the neuroepithelial cysts. Secondly, we found that high glucose exposure caused a relatively smaller actin inner boundary enclosed area, which was unlikely due to osmolarity changes. We further investigated key glucose metabolic enzymes in our models and the results showed that the distribution of hexokinase1 (HK1) was affected by high glucose. We observed that hexokinase1 has an apical-basal polarized distribution and is highest next to actin at the boundaries. hexokinase1 was more diffused and distributed less polarized under high glucose condition. Together, our observations broadened the cellular effects that may be caused by high glucose in the developing neural tube, especially in the secondary neurulation process.

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Section: Effects Of High Glucose On Model Neural Tube Development Cha...supporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

High glucose causes developmental abnormalities in neuroepithelial cysts with actin and HK1 distribution changes

Peng

Zheng

2023

Front. Cell Dev. Biol.

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“…Chick embryos can be cultured ex vivo allowing them to be accessible to manipulation with different nutrients (Bjørnstad, Austdal, Roald, Glover, & Paulsen, 2015). Finally, the sophistication of neural tube organoids has been progressing over the years presenting a model to test variants from sequenced cohorts in a human background (Wu, Peng, Finnell, & Zheng, 2021). Although organoids represent specific neural tube regions and do not completely recapitulate the mechanical aspects of human NTC, they are accessible for treatment with exogenous nutrients allowing an evaluation of potential effects of nutrients on NTC processes in a human genome.…”

Section: Looking Forward In Studying Gene-environment Interactions In Ntdsmentioning

confidence: 99%

Micronutrient imbalance and common phenotypes in neural tube defects

Kakebeen

Niswander

2021

Genesis

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Neural tube defects (NTDs) are among the most common birth defects, with a prevalence of close to 19 per 10,000 births worldwide. The etiology of NTDs is complex involving the interplay of genetic and environmental factors. Since nutrient deficiency is a risk factor and dietary changes are the major preventative measure to reduce the risk of NTDs, a more detailed understanding of how common micronutrient imbalances contribute to NTDs is crucial. While folic acid has been the most discussed environmental factor due to the success that population-wide fortification has had on prevention of NTDs, folic acid supplementation does not prevent all NTDs. The imbalance of several other micronutrients has been implicated as risks for NTDs by epidemiological studies and in vivo studies in animal models. In this review, we highlight recent literature deciphering the multifactorial mechanisms underlying NTDs with an emphasis on mouse and human data. Specifically, we focus on advances in our understanding of how too much or too little retinoic acid, zinc, and iron alter gene expression and cellular processes contributing to the pathobiology of NTDs. Synthesis of the discussed literature reveals common cellular phenotypes found in embryos with NTDs resulting from several micronutrient imbalances. The goal is to combine knowledge of these common cellular phenotypes with mechanisms underlying micronutrient imbalances to provide insights into possible new targets for preventative measures against NTDs.

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“…Due to the complex and heterogenous nature of neural tube disorders, traditional protocols for simple cell‐type derivation from pluripotent stem cells are not adequate to support disease modeling. In recent years, several groups have utilized in vitro PSC‐derived organoid models of neural tube development to model environmental neurotoxicity and disease (Wu, Peng, Finnell, & Zheng, 2021; Zheng, Zhang, Xu, & Wu, 2021). A previous Current Protocols procedure documents the derivation of posterior motor neurons from neuromesodermal progenitors in a 2D monolayer format (Wind & Tsakiridis, 2021).…”

Section: Commentarymentioning

confidence: 99%

Dynamic 3D Combinatorial Generation of hPSC‐Derived Neuromesodermal Organoids With Diverse Regional and Cellular Identities

et al. 2022

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Neuromesodermal progenitors represent a unique, bipotent population of progenitors residing in the tail bud of the developing embryo, which give rise to the caudal spinal cord cell types of neuroectodermal lineage as well as the adjacent paraxial somite cell types of mesodermal origin. With the advent of stem cell technologies, including induced pluripotent stem cells (iPSCs), the modeling of rare genetic disorders can be accomplished in vitro to interrogate cell‐type specific pathological mechanisms in human patient conditions. Stem cell‐derived models of neuromesodermal progenitors have been accomplished by several developmental biology groups; however, most employ a 2D monolayer format that does not fully reflect the complexity of cellular differentiation in the developing embryo. This article presents a dynamic 3D combinatorial method to generate robust populations of human pluripotent stem cell‐derived neuromesodermal organoids with multi‐cellular fates and regional identities. By utilizing a dynamic 3D suspension format for the differentiation process, the organoids differentiated by following this protocol display a hallmark of embryonic development that involves a morphological elongation known as axial extension. Furthermore, by employing a combinatorial screening assay, we dissect essential pathways for optimally directing the patterning of pluripotent stem cells into neuromesodermal organoids. This protocol highlights the influence of timing, duration, and concentration of WNT and fibroblast growth factor (FGF) signaling pathways on enhancing early neuromesodermal identity, and later, downstream cell fate specification through combined synergies of retinoid signaling and sonic hedgehog activation. Finally, through robust inhibition of the Notch signaling pathway, this protocol accelerates the acquisition of terminal cell identities. This enhanced organoid model can serve as a powerful tool for studying normal developmental processes as well as investigating complex neurodevelopmental disorders, such as neural tube defects. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Robust generation of 3D hPSC‐derived spheroid populations in dynamic motion settings Support Protocol 1: Pluronic F‐127 reagent preparation and coating to generate low‐attachment suspension culture dishes Basic Protocol 2: Enhanced specification of hPSCs into NMP organoids Support Protocol 2: Combinatorial pathway assay for NMP organoid protocol optimization Basic Protocol 3: Differentiation of NMP organoids along diverse cellular trajectories and accelerated terminal fate specification into neurons, neural crest, and sclerotome derivatives

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Organoids as a new model system to study neural tube defects

Cited by 18 publications

References 86 publications

High glucose causes developmental abnormalities in neuroepithelial cysts with actin and HK1 distribution changes

High glucose causes developmental abnormalities in neuroepithelial cysts with actin and HK1 distribution changes

Micronutrient imbalance and common phenotypes in neural tube defects

Dynamic 3D Combinatorial Generation of hPSC‐Derived Neuromesodermal Organoids With Diverse Regional and Cellular Identities

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