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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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j, Hallmark glycolysis score of dorsal telencephalic excitatory neurons (dTelen VGLUT-N), split by the three primary developing human brains and 27 organoid datasets with at least 20 dTelen VGLUT-N. The lower panel shows selected features of differentiation protocols that may be relevant to cell stress.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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The protocol and publication indices are shown in Extended Data Fig. 1.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Mat.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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media, maturation media.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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k, Spearman correlations between gene expression profiles of neural cell types in HNOCA and those in the human developing brain atlas, across the variable transcription factors (TFs).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Datasets are in the same order as in Supplementary Table 1.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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a, Schematic of DE analysis comparing neural cell types in different protocols in HNOCA to their primary counterparts.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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b, Proportions of expressed genes in different neural cell types that show DE in certain fractions of protocols that generate the corresponding subtypes.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Top left, glutamatergic neurons; bottom right, GABAergic neurons.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Colour shows the brain region.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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c, Numbers of protocol-common DEGs (DE in at least half of protocols), grouped by the number of neural cell types in which a gene is DE.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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d, Distribution of expression log-fold-change (logFC) correlation of ubiquitous DEGs among different neuron subtype*protocol (that is, each of the neural cell types generated by each of the different protocols).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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e, Numbers of DEGs per category.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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f, Gene ontology enrichment analysis of downregulated (upper, blue) and upregulated (lower, red) ubiquitous DEGs.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Sizes of the squares correlate with −log-transformed adjusted P values.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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g,h, Distribution of the mitochondrial ATP synthesis-coupled electron transport module scores (g), canonical glycolysis module scores (h, left) and the Molecular Signatures Database hallmark glycolysis module scores (h, right), in primary neural cell types (upper, dark) and organoid counterparts (lower, light).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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P values, significance of a two-sided Wilcoxon test.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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i, Heatmap shows pairwise correlation (corr.)
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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of the three module scores.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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j, Hallmark glycolysis score of dorsal telencephalic excitatory neurons (dTelen VGLUT-N), split by the three primary developing human brains and 27 organoid datasets with at least 20 dTelen VGLUT-N. The lower panel shows selected features of differentiation protocols that may be relevant to cell stress.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The protocol and publication indices are shown in Extended Data Fig. 1.
|
PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
|
Mat.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
media, maturation media.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
k, Spearman correlations between gene expression profiles of neural cell types in HNOCA and those in the human developing brain atlas, across the variable transcription factors (TFs).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Datasets are in the same order as in Supplementary Table 1.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Using gene ontology enrichment analysis on the uDEGs, we found downregulated uDEGs enriched in neurodevelopmental processes including neuron cell–cell adhesion and synapse organization (Fig. 3f).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Upregulated uDEGs were enriched in many metabolism-associated terms including mitochondrial ATP synthesis-coupled electron transport (electron transport in short) and canonical glycolysis (Fig. 3f).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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An enrichment of energy-associated pathways has previously been associated with metabolic changes caused by the limitations of current culture conditions.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Also, the Molecular Signatures Database gene set hallmark glycolysis has previously been used to define metabolic states in neural organoids.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Scoring mitochondrial electron transport, canonical glycolysis and hallmark glycolysis gene sets across the HNOCA and the primary reference atlas, we found that all three terms showed significant separation of organoid and primary cells (Fig. 3g,h).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Using the datasets from refs.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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and as representative examples, we identified a similar distribution of glycolysis scores across all neural cell types with an overall increased score in organoid cells (Extended Data Fig. 7).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Focusing on dorsal telencephalic neurons, we compared the distribution of glycolysis scores across organoid differentiation protocols and identified several protocol features that correlated with metabolic cell stress.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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For instance, the usage of maturation media, slicing or cutting of organoids and, to a lesser extent, shaking or spinning of organoids led to overall lower glycolysis scores (Fig. 3h).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Mean glycolysis score and transcriptomic similarity of organoid and primary reference cell types across differentiation protocols were negatively correlated.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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The correlation was significantly reduced when considering only variable transcription factors, indicating that the metabolic changes in organoids have limited impact on the core molecular identity of neuronal cell types (Extended Data Fig. 7).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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This observation is consistent with previous studies of distinct metabolic states of cells in neural organoids relative to the primary tissue, which were shown to not affect neuron fate specification and maturation.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Next, we focused on the expression of 366 variable transcription factors to calculate the correlation between corresponding neuronal cell types in the HNOCA datasets and the primary reference atlas.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We found that both guided and unguided organoid differentiation protocols generated neuronal cell types with comparable similarity to the corresponding primary reference cell types.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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However, we observed brain region-dependent differences in transcriptomic similarity.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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For example, organoid neurons from the dorsal parts of most brain regions showed higher similarity to their primary counterparts across organoid datasets than cell types derived from the ventral parts of most brain regions (Fig. 3i).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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To identify molecular features other than metabolic state that decreased organoid fidelity, we incorporated dorsal telencephalic glutamatergic neurons from four different primary developing human brain atlases as an integrated primary reference, and identified neuron subtype and maturation state heterogeneity (Extended Data Fig. 8).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Projection of dorsal telencephalic neurons in the HNOCA to the primary atlases revealed the corresponding heterogeneity in neural organoids.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Considering metabolic state, maturation state and cell subtype as covariates during DE analysis significantly reduced the number of DEGs, supporting the idea that these are the major factors differentiating organoid and primary brain cells (Extended Data Fig. 8 and Supplementary Table 6).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We observed enriched biological processes that included synaptic vesicle cycle and negative regulation of high voltage-gated calcium channel activity (Extended Data Fig. 8), suggesting that organoids are deficient in these processes.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Of note, these differences are observed across organoid protocols, and highlight areas of consistent transcriptomic divergence between in vitro and primary counterparts.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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The HNOCA, as well as the analytical pipeline we established, provides a framework to query new neural organoid scRNA-seq datasets not included in the HNOCA.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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To showcase this application, we retrieved scRNA-seq data from a recently published multiplexed neural organoid morphogen screen and projected them to the HNOCA and primary reference latent spaces (Fig. 4a, Extended Data Fig. 9 and Supplementary Table 7).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We transferred regional labels and found high consistency with the provided regional annotation, but with higher resolution within each of the broad brain sections of forebrain, midbrain and hindbrain (Fig. 4b).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Our transferred annotation therefore allowed a more comprehensive assessment of the effects of different morphogen conditions on generating neurons of different brain regions (Fig. 4c).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We further calculated presence scores for reference cells in each screen condition and compared the data of the different screen conditions with the 36 HNOCA datasets.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Using hierarchical clustering on average presence scores revealed distinct presence score profiles for many screen conditions (Fig. 4d), suggesting regional cell type composition distinct from the HNOCA datasets.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Next, we summarized the max presence scores for the whole morphogen screen data (Fig. 4e), and compared them to those for the HNOCA data to identify primary reference cell types with increased presence in the screen (Fig. 4f).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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This analysis highlighted several reference cell clusters with significant abundance increase under certain screen conditions (Fig. 4g) such as LHX6/ACKR3/MPPED1 triple-positive GABAergic neurons in the ventral telencephalon and dopaminergic neurons in ventral midbrain.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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In summary, the projection of the morphogen screen query data to HNOCA and primary reference allowed a refined annotation of the morphogen screen data, as well as a comprehensive and quantitative evaluation of the value of new differentiation protocols to generate neuronal cell types previously under-represented or lacking in neural organoids.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Fig. 4Projection of neural organoid morphogen screen scRNA-seq data to HNOCA and human developing brain atlas allows cell type annotation and organoid protocol evaluation.a, Schematic of projecting neural organoid morphogen screen scRNA-seq data to the HNOCA, and a human developing brain reference atlas.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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UMAPs show screen condition groups (left, using morphogens SAG (sonic hedgehog signaling agonist), CHIR, BMP and FGF) and regional annotation of screen data (right).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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b, Comparison of regional annotation of screen data (rows) and scArches-transferred regional labels from the primary reference.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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c, Proportions of cells assigned to different regions on the basis of reference projection.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Every stacked bar represents one screen condition.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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d, Clustering of HNOCA datasets with conditions in the screen data on the basis of average presence scores of clusters in the primary reference.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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The heatmap shows average presence scores per cluster in the primary reference (columns).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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e, UMAP of primary reference coloured by the dissected regions (right) and the maximum presence scores across the screen conditions (left).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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f, Gain of cell cluster coverage of screen conditions relative to HNOCA datasets, with negative values trimmed to zero.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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The grey horizontal line shows the threshold (0.3) to define gained clusters in screen data.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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g, UMAP of the primary reference, with gained clusters highlighted in shades of blue.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Dashed circles highlight two clusters with highest gain of coverage in telencephalon and midbrain, respectively.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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h, Coexpression scores of cluster marker genes of the two clusters highlighted in g, in the primary reference (upper) and screen dataset (lower).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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DA, dopaminergic.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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a, Schematic of projecting neural organoid morphogen screen scRNA-seq data to the HNOCA, and a human developing brain reference atlas.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
|
UMAPs show screen condition groups (left, using morphogens SAG (sonic hedgehog signaling agonist), CHIR, BMP and FGF) and regional annotation of screen data (right).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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b, Comparison of regional annotation of screen data (rows) and scArches-transferred regional labels from the primary reference.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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c, Proportions of cells assigned to different regions on the basis of reference projection.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
|
Every stacked bar represents one screen condition.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
d, Clustering of HNOCA datasets with conditions in the screen data on the basis of average presence scores of clusters in the primary reference.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
|
The heatmap shows average presence scores per cluster in the primary reference (columns).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
e, UMAP of primary reference coloured by the dissected regions (right) and the maximum presence scores across the screen conditions (left).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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f, Gain of cell cluster coverage of screen conditions relative to HNOCA datasets, with negative values trimmed to zero.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The grey horizontal line shows the threshold (0.3) to define gained clusters in screen data.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
g, UMAP of the primary reference, with gained clusters highlighted in shades of blue.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Dashed circles highlight two clusters with highest gain of coverage in telencephalon and midbrain, respectively.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
h, Coexpression scores of cluster marker genes of the two clusters highlighted in g, in the primary reference (upper) and screen dataset (lower).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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DA, dopaminergic.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We next tested whether the integrated HNOCA can serve as a control cohort for assessing organoid models of neural disease.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We collected 11 scRNA-seq datasets from 10 neural organoid disease models and their respective controls (microcephaly, amyotrophic lateral sclerosis, Alzheimer’s disease, autism, fragile-X syndrome (FXS), schizophrenia, neuronal heterotopia, Pitt–Hopkins syndrome, myotonic dystrophy and glioblastoma) (Fig. 5a, Extended Data Fig. 10 and Supplementary Table 8).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We projected the data to the HNOCA and the primary reference atlas to transfer annotations (Fig. 5b–f).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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We found differences in cell type and brain regional composition between disease model organoids and their respective, study-specific control organoids for most studies (Fig. 5g,h).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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These differences might represent disease phenotypes, but could also be the consequence of cell line variability.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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It is therefore important to properly annotate the cell type and regional composition of disease and control organoids to identify disease phenotypes, particularly when analysing disease-associated transcriptomic alterations in a given cell type.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Fig. 5The HNOCA as a control cohort to facilitate cell type annotation and transcriptomic comparison for neural organoid disease-modelling data.a, Overview of disease-modelling neural organoid atlas construction, and projection to primary atlas and HNOCA for downstream analysis.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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b–f, UMAP of integrated disease-modelling neural organoid atlas coloured by predicted cell type annotation (b), predicted regional identities of NPCs, intermediate progenitor cells and neurons (c), publications (d), disease status (e) and marker gene expression (f).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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g,h, Proportions (prop.)
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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of cells assigned to different cell classes (g) and regions (h).
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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Every stacked bar represents one biological sample.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
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Side bars show disease status and publication.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
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i, Schematic of reconstructing matched HNOCA metacell for each cell in the disease-modelling neural organoid atlas.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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j, UMAP of disease-modelling neural organoid atlas, coloured by transcriptomic similarity with the matched HNOCA metacells.
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PMC11578878
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An integrated transcriptomic cell atlas of human neural organoids.
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k, Violin plot indicates distribution of estimated transcriptomic similarities, split by publication.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
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Left, distribution in control cells and right, distribution in disease cells.
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PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
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l, Heatmap showing expression of top DEGs between the AQP4 population in the GBM-2019 dataset and their matched HNOCA metacells.
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