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Induction of Expansion and Folding in Human Cerebral Organoids.
An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle re-entry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex.
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The neurosecretory axons in the neurohypophysis of the rat: an electron microscopic study.
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Study of the rat neostriatum using a combined Golgi-electron microscope technique and serial sections.
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β-Hydroxybutyrate Exposure is Associated with Increased TH+ Neuron Abundance and Dopaminergic-Related Transcriptional Features in Human Midbrain Organoids.
Neuronal differentiation is a highly regulated process in which morphogens establish cellular identities through coordinated transcriptional programs. However, the contribution of physiologically derived metabolites to human neural development remains poorly understood. β-hydroxybutyrate (bhb) has been recognized as an inflammatory, epigenetic, energetic, and neuroprotective regulator. We differentiated midbrain floor plate neural precursor cells (mfNPC) from human embryonic stem cells to generate midbrain organoids (MBOs), which were exposed to bhb. Although dopaminergic differentiation occurred in control MBOs, treatment with 1 mM bhb for 16 days significantly increased both the number of Tyrosine hydroxylase-positive (TH⁺) neurons, and the corresponding transcripts assessed by bulk RNA sequencing. Such transcriptomic profiling revealed modest but consistent bhb-associated changes in trophic, neuronal and dopaminergic transcripts. To further characterize these changes, we performed gene set enrichment analysis using curated cell phenotypes-associated transcriptional programs. These analyses indicated that bhb treatment is associated with shifts in the enrichment scores of dopaminergic programs in day 16 MBOs. At the epigenomic level, we used CUT&RUN assays to map H3K27 acetylation, and the selected candidates H3K27ac regions after bhb treatment were linked to their closest neighboring genes, suggesting positive enrichment of neural and dopaminergic gene ontology categories at both time points. Unsupervised analysis of H3K27ac-enriched regions revealed three major clusters detected across differentiation, although present in both control and bhb-treated MBOs. Motif enrichment analysis of clustering regions identified distinct predicted transcription factor binding motifs in mfNPC and MBOs. Finally, we integrated this motif analysis, enhancer annotation, and our transcriptomic data on a web platform, Enhancer Network Explorer, to explore relationships between H3K27ac profiles, transcriptional changes and bhb exposure during human MBOs differentiation. Together, our results indicate that bhb treatment is associated with increased TH-positive cell abundance and with population-level changes related to neurodevelopmental transcriptional programs. These findings suggest that bhb might support early human midbrain differentiation and provide a starting point for future studies addressing the mechanisms linking metabolic cues, chromatin-associated regulation and dopaminergic differentiation.
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[The fine structure of the bulbus olfactorius of the hen].
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Development has the answer: Unraveling psychiatric disorders via thalamocortical organoids.
Dissecting the role of the thalamus in neuropsychiatric disorders requires new models to analyze complex genetic interactions. In this issue of Cell Stem Cell, Shin et al. use patient-derived thalamocortical organoids to investigate 22q11.2 microdeletion impact on thalamic development, revealing significant transcriptional dysregulation linked to psychiatric disorders.
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Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1.
UTX is a chromatin modifier required for development and neural lineage specification, but how it controls these biological processes is unclear. To determine the molecular mechanisms of UTX, we identified novel UTX protein interaction partners. Here we show that UTX and 53BP1 directly interact and co-occupy promoters in human embryonic stem cells and differentiating neural progenitor cells. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and disruption of the 53BP1-UTX interaction abrogated human, but not mouse, neurogenesis in vitro. The 53BP1-UTX interaction is required to upregulate key neurodevelopmental genes during the differentiation of human embryonic stem cells into neurons or into cortical organoids. 53BP1 promotes UTX chromatin binding, and in turn H3K27 modifications and gene activation, at a subset of genomic regions, including neurogenic genes. Overall, our data suggest that the 53BP1-UTX interaction supports the activation of key genes required for human neurodevelopment.
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Interfacial Morphology Shapes Endothelial Organization and Function in a Blood-Brain Barrier-on-a-Chip.
Organ-on-a-chip technologies have advanced rapidly as platforms for modeling human physiology and disease. In particular, the integration of hydrogels has enabled closer mimicry of tissue microenvironments and facilitated coupling with organoids and other three-dimensional cellular systems. Despite these advances, the mechanical stability of hydrogels and the integrity of the barrier interface remain poorly controlled, limiting reproducibility and functional fidelity in barrier-on-a-chip models such as the blood-brain barrier (BBB). Herein, we present a three-channel BBB-on-a-chip (μBBB) that incorporates an in situ photo-cross-linkable hydrogel system to precisely regulate interfacial stability during device operation. Computational fluid dynamics analysis revealed that subtle variations in hydrogel interface morphology markedly alter local shear stress distribution, with slightly protruded interfaces providing more favorable conditions for endothelial organization. Guided by these insights, we introduced a biocompatible photo-cross-linkable agent that reinforces the stability of the hydrogel interface, yielding a robust and stable barrier-forming surface. Stabilization of the hydrogel interface significantly improved endothelial cell viability, reduced cell invasion into the matrix, and enhanced BBB-associated functional readouts. Transcriptomic analysis further revealed lower inflammation- and sprouting-related pathways, consistent with a more quiescent and physiologically relevant endothelial phenotype. Together, this work identifies hydrogel-cell interfacial stability as a critical yet underappreciated determinant of μBBB performance and offers a simple, adaptable strategy to improve the reliability of hydrogel-integrated organ-on-a-chip systems.
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Choroid plexus absorption of horseradish peroxidase from the cerebral ventricles.
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Extensive ultrastructural changes in rat mammotrophs following administration of the dopamine agonist ergocristine-reflecting inhibition of prolactin release.
We have demonstrated an extensive reorganization of organelles in mammotrophs immediately following administration of ergocristine (a dopamine agonist) to estradiol-primed male rats. Our ultrastructural findings are consistent with our previous results that ergocristine can block prolactin release without any noticeable latent period. Following three-week priming of male rats with estradiol implants, ergocristine was administered by a bolus injection through an indwelling cannula. Within two min of its administration, ergocristine induced dramatic changes in the ultrastructure of mammotrophs, i.e., (1) increased numbers of secretory granules, (2) peripheral relocation of rough endoplasmic reticulum which tends to sequester secretory granules, (3) change in location of nucleus and (4) increased numbers of intracellular bodies associated with secretory granules. We suggest that the extensive ultrastructural changes that occurred in such a short period following ergocristine administration may be indications of specific factors associated with blockage of hormone release.