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Human spinal cord organoids revealed cell intercalation as a conserved morphogenic mechanism for lumem formation

ABSTRACT: Neural tube defects (NTDs) are severe anatomical malformations of the nervous system that occur during embryonic development when the neural tube (NT) fails to form correctly. To gain insights into the biological basis of NTDs, we generated human NT organoids with defined anterior and posterior identities. We achieved this by guiding human pluripotent stem cells towards the neural lineage, resulting in the self-assembly of polarized cells around a single lumen, exhibiting subcellular architecture and dynamics similar to those of the embryonic NT. Through transcriptome profiling, we identified that the posterior organoids possessed a spinal cord identity. To better replicate the in vivo morphogenesis of the secondary NT, we developed a modified culture condition, which revealed that lumen resolution in the spinal cord organoids involves cell intercalation and is dependent on the activity of Yes-associated protein (YAP). We believe that these findings will contribute to our understanding of caudal skin-covered NTDs, which are among the most common birth defects observed in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233686 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Background: In the early stage of embryonic development, the neural tube (NT) cannot be closed properly due to some complex factors such as, environmental factors, genetic factors and the relationship between various factors, leading to the occurrence of neural tube defects (NTDs). Methods: In this study, we induced the mouse model of NTDs by feeding mice a low-folate diet and injecting 1.5mg/kg methotrexate on E7.5. Fetal mice were achieved at E13.5, then we extracted proteins from brain tissue with trypsin digestion. After enzymatic digestion, peptides were labeled with TMT/iTRAQ and then separated in high-performance liquid chromatography (HPLC) for subsequent LC-MS/MS analysis. To analyze the functional enrichment of differentially expressed proteins(DEPs) in the NTDs mice tissues with low folate induction, we used Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway annotation to analyze proteomic changes. Results: Low folate induced mouse model was successfully constructed. Folate was used as a sensitizing agent, the teratogenicity rate of the NTDs fetal mice was increased to 36.5% when methotrexate was injected to maternal mice at E7.5. 6614 proteins were identified by mass spectrometry, among them, 5656 proteins were quantified. In the following proteomic analysis, GO classification and KEGG pathway enrichment analysis were conducted, and heatmaps were drawn for differentially expressed proteins(DEPs). Moreover, the main pathways associated with NTDs, such as Hedgehog, Wnt, p53, Hippo signaling pathways, and one carbon pool by folate, can be identified through the generation of a protein-protein interaction (PPI) network. It was also found that the regulation of ribosomal proteins has a certain impact on neural tube development, such as RPL13 and RPL14, which are upregulated in NTDs. Conclusions: Our results revealed proteomic changes in the tissues of low folate induced NTDs mice, as well as validation showed that ribosomal proteins play a regulatory role during the development of NTDs, it provides new ideas for the pathogenesis and preventive measures of NTDs.

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Human spinal cord organoids revealed cell intercalation as a conserved morphogenic mechanism for lumem formation

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