PMCID
stringclasses 24
values | Title
stringclasses 24
values | Sentences
stringlengths 2
40.7k
|
|---|---|---|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
telencephalon; Th, thalamus; vTelen, ventral telencephalon.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
a, Overview of HNOCA construction pipeline.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
b, Metadata of biological samples included in HNOCA.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
c–f, UMAP of the integrated HNOCA, coloured by level 2 cell type annotations (c), gene expression profiles of selected markers (d), sample ages (e) and differentiation protocol types (f).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
g, Proportions of cells assigned to different cell types in the HNOCA.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Every stacked bar represents one biological sample, grouped by datasets and ordered by increasing sample ages.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Top bars show 36 datasets, organoid differentiation protocols, protocol types.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Bottom bars show the sample age.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
h, UMAP of the integrated HNOCA coloured by top-ranked diffusion component (DC1) on the real-time-informed transition matrix between cells.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The stream arrows visualize the inferred flow of cell states toward more mature cells.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
i, Marker gene expression profiles along cortical pseudotime.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
j, UMAP of non-telencephalic neurons, coloured and labelled by clusters.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
k, Heatmap showing relative expression of selected genes across different non-telencephalic neuron clusters.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Coloured dots show cluster identities as shown in j. Cb, cerebellum; ChP, choroid plexus; CP, choroid plexus; Hy, hypothalamus; max.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
maximum; MB, midbrain; MH, medulla; min.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
minimum; Oligo, oligodendrocyte; OPC, oligodendrocyte progenitor cell; PSC, pluripotent stem cell; telen.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
telencephalon; Th, thalamus; vTelen, ventral telencephalon.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
To elucidate the dynamics and transitions of cell states and types, we reconstructed a real-age-informed pseudotime of HNOCA cells on the basis of neural optimal transport using moscot (Fig. 1h).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Focusing on the dorsal telencephalic neural trajectory, we observed consistent pseudotemporal expression profiles of marker genes such as SOX2 (neural progenitor cells (NPCs)), BCL11B (deeper layer cortical neurons) and SATB2 (upper layer cortical neurons) (Fig. 1i).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
To further resolve heterogeneity among non-telencephalic neurons, we performed subclustering of this population, which revealed numerous neuronal populations characterized by distinct marker gene expression (Fig. 1j,k).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
To assess our cell type annotation, and more precisely annotate the heterogeneous non-telencephalic neuronal populations, we compared the HNOCA to a recently published single-cell transcriptomic atlas of the developing human brain (Fig. 2a).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We applied scVI and scANVI to the primary reference atlas, and used scArches to project the HNOCA to the same latent space.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The shared latent space allowed us to reconstruct a bipartite weighted k-nearest-neighbour (wkNN) graph between cells in the HNOCA and the primary reference atlas, which was used to transfer the ‘CellClass’ and ‘Subregion’ labels, as well as the neurotransmitter transporter (NTT) information of neuroblasts and neurons to the HNOCA.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The transferred labels are strongly consistent with our assigned labels (Extended Data Fig. 3) and allowed us to refine the regional annotation of HNOCA non-telencephalic NPCs and neurons, as well as the NTT annotation of the non-telencephalic neurons (Fig. 2b), resulting in the final hierarchical HNOCA cell type annotation (Extended Data Fig. 3).Fig.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
2Projection of HNOCA to primary developing human brain cell atlases assists organoid neural cell type annotation and estimation of primary cell type representation.a, UMAP of a human developing brain cell atlas, coloured by NTT subtypes (left), region (middle) and annotated cell classes (right).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
b, UMAP of HNOCA, coloured by the mapped neuron NTT subtypes (left) and regional labels of NPCs, intermediate progenitor cells (IP) and neurons.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
c, Heatmap showing proportions of cells from organoids of different ages matched to cells from different primary developmental (dev.)
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
stages.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
d, Percentages of neural cells representing different regions (telencephalon, diencephalon, midbrain and hindbrain) in different datasets.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The x axes show datasets, descendingly ordered by the total proportions (bar height).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Datasets based on unguided differentiation protocols are marked by dots underneath.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The bars at the bottom of each panel show organoid protocol types.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
e, UMAP of the human developing brain cell atlas coloured by cell population presence within HNOCA datasets (max presence score).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
A low score denotes under-representation of cell state in HNOCA datasets.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
f, Distribution of max presence scores of different cell classes in the human reference atlas.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Eryt.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
erythrocyte; Imm.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
immune; Vas.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
vascular; G-blast, glioblast; F-blast, fibroblast; NC, neural crest; Plac.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
placodes; RG, radial glia; IPC, intermediate progenitor cell; N-blast, neuroblast; N, neuron.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
g, Box plots showing distribution of max presence scores in different primary reference cell clusters.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Bottom side bars show neuronal versus non-neuronal, cell class, region information of primary reference.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
h, UMAP of human developing brain atlas showing primary neural cell types or states under-represented in HNOCA (in red).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Hippo, hippocampus; HyTh, hypothalamus; d, dorsal; v, ventral; CB, cerebellum.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
a, UMAP of a human developing brain cell atlas, coloured by NTT subtypes (left), region (middle) and annotated cell classes (right).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
b, UMAP of HNOCA, coloured by the mapped neuron NTT subtypes (left) and regional labels of NPCs, intermediate progenitor cells (IP) and neurons.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
c, Heatmap showing proportions of cells from organoids of different ages matched to cells from different primary developmental (dev.)
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
stages.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
d, Percentages of neural cells representing different regions (telencephalon, diencephalon, midbrain and hindbrain) in different datasets.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The x axes show datasets, descendingly ordered by the total proportions (bar height).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Datasets based on unguided differentiation protocols are marked by dots underneath.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
The bars at the bottom of each panel show organoid protocol types.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
e, UMAP of the human developing brain cell atlas coloured by cell population presence within HNOCA datasets (max presence score).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
A low score denotes under-representation of cell state in HNOCA datasets.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
f, Distribution of max presence scores of different cell classes in the human reference atlas.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Eryt.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
erythrocyte; Imm.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
immune; Vas.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
vascular; G-blast, glioblast; F-blast, fibroblast; NC, neural crest; Plac.,
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
placodes; RG, radial glia; IPC, intermediate progenitor cell; N-blast, neuroblast; N, neuron.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
g, Box plots showing distribution of max presence scores in different primary reference cell clusters.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Bottom side bars show neuronal versus non-neuronal, cell class, region information of primary reference.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
h, UMAP of human developing brain atlas showing primary neural cell types or states under-represented in HNOCA (in red).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Hippo, hippocampus; HyTh, hypothalamus; d, dorsal; v, ventral; CB, cerebellum.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We also sought to compare organoid cells to stages of human brain development beyond the first trimester.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Focusing on dorsal telencephalon, we compared the transcriptomic profile of HNOCA NPCs and neurons with cells in a primary atlas of human cortex development spanning the first trimester to adolescence.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We observed a transition from cell states observed in the first trimester to more mature states observed in the second-trimester cortex (Fig. 2c), and did not detect substantial matching to later stages.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We extended the comparison to other brain regions using two primary atlases representing the first and second trimester, respectively.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We confirmed increased similarity to second-trimester cell states in older organoids for other brain regions (Extended Data Fig. 3).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We evaluated the capacity of each neural organoid protocol to generate neural cells of different brain regions (Fig. 2d, Extended Data Figs. 3 and 4 and Supplementary Table 2).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Datasets of unguided neural organoids contain cells across all brain regions with proportions varying across datasets, indicating the capacity of unguided protocols to generate many brain regions but with high variability.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
By contrast, datasets derived from guided organoid protocols are strongly enriched for cells of the targeted brain region, but often show an increased proportion of cells of the brain regions neighbouring the targeted regions.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
For example, several datasets derived from midbrain organoid protocols also show high proportions of hindbrain neurons, indicating an imprecision of morphogen guidance.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
To comprehensively evaluate how well organoid protocols represented by the HNOCA generate primary brain cell types, we estimated presence scores for every primary cell type in each HNOCA dataset (Methods).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
A large presence score indicates high frequency and likelihood that cells of a similar type are observed in the HNOCA dataset.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
By normalizing the scores per organoid dataset (Extended Data Fig. 5 and Supplementary Table 3), we obtained a metric to describe how well each primary cell type is represented in at least one HNOCA dataset (Fig. 2d).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
This analysis confirmed the absence of erythrocytes, immune cells and vascular endothelial cells in the HNOCA, all of which are derived from non-neuroectodermal germ layers (Fig. 2e).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
As expected, telencephalic cell types are most strongly represented in HNOCA.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
By contrast, cell types of the thalamus, midbrain and cerebellum are least represented, including thalamic reticular nucleus GABAergic neurons, dorsal midbrain m1-derived GABAergic neurons and m1/m2-derived glutamatergic neurons, and cerebellar Purkinje cells (Fig. 2f,g).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
It is worth noting that, even though these cell types are less abundant in HNOCA datasets than in the primary atlas, certain organoid protocols can generate some of these under-represented cell types (for example, Purkinje cells in posterior brain organoid protocols).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We next aimed to understand the transcriptomic similarities and differences between organoids generated by distinct differentiation protocols as well as between organoids and primary brain tissue.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We identified differentially expressed genes (DEGs), comparing neural cell types in the HNOCA with their primary counterparts (Fig. 3a and Supplementary Table 4).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We found that for most neural cell types, more than one-third (mean 34.4%, standard deviation 12.1%) of DEGs were shared across at least half of the protocols (protocol-common DEGs), suggesting that many transcriptomic differences between organoid and primary cells were independent of organoid protocol (Fig. 3b).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We verified our results using an extra primary human cortex scRNA-seq dataset (Extended Data Fig. 6 and Supplementary Table 5).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
We next assessed differential transcriptomic programmes that were shared across regional neural cell types, and identified a total of 920 ubiquitous, protocol-common DEGs (uDEGs) that were differentially expressed in at least 14 out of the 16 neural cell types (Fig. 3c).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
These uDEGs showed consistent fold changes (r > 0.8) across neuron types and protocols (Fig. 3d), and represent consistent molecular differences between neurons in organoids and those in primary tissues regardless of protocol or neuronal cell type.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Out of all 920 uDEGs, 363 genes were consistently upregulated and 673 genes were consistently downregulated, with only 59 genes (6%) inconsistently differentially expressed across subtypes or protocols (Fig. 3e).Fig.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
3Transcriptomic comparison between organoid neurons and their primary counterpart reveals universal cell stress in organoids.a, Schematic of DE analysis comparing neural cell types in different protocols in HNOCA to their primary counterparts.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
b, Proportions of expressed genes in different neural cell types that show DE in certain fractions of protocols that generate the corresponding subtypes.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Top left, glutamatergic neurons; bottom right, GABAergic neurons.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Colour shows the brain region.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
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.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
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).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
e, Numbers of DEGs per category.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
f, Gene ontology enrichment analysis of downregulated (upper, blue) and upregulated (lower, red) ubiquitous DEGs.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
Sizes of the squares correlate with −log-transformed adjusted P values.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
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).
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
P values, significance of a two-sided Wilcoxon test.
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
i, Heatmap shows pairwise correlation (corr.)
|
PMC11578878
|
An integrated transcriptomic cell atlas of human neural organoids.
|
of the three module scores.
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.