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Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development.

ABSTRACT: Neurogenesis processes differ in different areas of the cortex in many species, including humans. Here, we performed single-cell transcriptome profiling of the four cortical lobes and pons during human embryonic and fetal development. We identified distinct subtypes of neural progenitor cells (NPCs) and their molecular signatures, including a group of previously unidentified transient NPCs. We specified the neurogenesis path and molecular regulations of the human deep-layer, upper-layer, and mature neurons. Neurons showed clear spatial and temporal distinctions, while glial cells of different origins showed development patterns similar to those of mice, and we captured the developmental trajectory of oligodendrocyte lineage cells until the human mid-fetal stage. Additionally, we verified region-specific characteristics of neurons in the cortex, including their distinct electrophysiological features. With systematic single-cell analysis, we decoded human neuronal development in temporal and spatial dimensions from GW7 to GW28, offering deeper insights into the molecular regulations underlying human neurogenesis and cortical development.

SUBMITTER: Fan X

PROVIDER: S-EPMC7450478 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development.

Fan Xiaoying X Fu Yuanyuan Y Zhou Xin X Sun Le L Yang Ming M Wang Mengdi M Chen Ruiguo R Wu Qian Q Yong Jun J Dong Ji J Wen Lu L Qiao Jie J Wang Xiaoqun X Tang Fuchou F

Science advances 20200821 34

Neurogenesis processes differ in different areas of the cortex in many species, including humans. Here, we performed single-cell transcriptome profiling of the four cortical lobes and pons during human embryonic and fetal development. We identified distinct subtypes of neural progenitor cells (NPCs) and their molecular signatures, including a group of previously unidentified transient NPCs. We specified the neurogenesis path and molecular regulations of the human deep-layer, upper-layer, and mat ...[more]

PMID: 32923614

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Project description:The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

Project description:Newly differentiated pancreatic β cells lack proper insulin secretion profiles of mature functional β cells. The global gene expression differences between paired immature and mature β cells have been studied, but the dynamics of transcriptional events, correlating with temporal development of glucose-stimulated insulin secretion (GSIS), remain to be fully defined. This aspect is important to identify which genes and pathways are necessary for β-cell development or for maturation, as defective insulin secretion is linked with diseases such as diabetes. In this study, we assayed through RNA sequencing the global gene expression across six β-cell developmental stages in mice, spanning from β-cell progenitor to mature β cells. A computational pipeline then selected genes differentially expressed with respect to progenitors and clustered them into groups with distinct temporal patterns associated with biological functions and pathways. These patterns were finally correlated with experimental GSIS, calcium influx, and insulin granule formation data. Gene expression temporal profiling revealed the timing of important biological processes across β-cell maturation, such as the deregulation of β-cell developmental pathways and the activation of molecular machineries for vesicle biosynthesis and transport, signal transduction of transmembrane receptors, and glucose-induced Ca2+ influx, which were established over a week before β-cell maturation completes. In particular, β cells developed robust insulin secretion at high glucose several days after birth, coincident with the establishment of glucose-induced calcium influx. Yet the neonatal β cells displayed high basal insulin secretion, which decreased to the low levels found in mature β cells only a week later. Different genes associated with calcium-mediated processes, whose alterations are linked with insulin resistance and deregulation of glucose homeostasis, showed increased expression across β-cell stages, in accordance with the temporal acquisition of proper GSIS. Our temporal gene expression pattern analysis provided a comprehensive database of the underlying molecular components and biological mechanisms driving β-cell maturation at different temporal stages, which are fundamental for better control of the in vitro production of functional β cells from human embryonic stem/induced pluripotent cell for transplantation-based type 1 diabetes therapy.

Project description:UnlabelledWhen viruses infect their host cells, they can make defective virus-like particles along with intact virus. Cells coinfected with virus and defective particles often exhibit interference with virus growth caused by the competition for resources by defective genomes. Recent reports of the coexistence and cotransmission of such defective interfering particles (DIPs) in vivo, across epidemiological length and time scales, suggest a role in viral pathogenesis, but it is not known how DIPs impact infection spread, even under controlled culture conditions. Using fluorescence microscopy, we quantified coinfections of vesicular stomatitis virus (VSV) expressing a fluorescent reporter protein and its DIPs on BHK-21 host cell monolayers. We found that viral gene expression was more delayed, infections spread more slowly, and patterns of spread became more "patchy" with higher DIP inputs to the initial cell. To examine how infection spread might depend on the behavior of the initial coinfected cell, we built a computational model, adapting a cellular automaton (CA) approach to incorporate kinetic data on virus growth for the first time. Specifically, changes in observed patterns of infection spread could be directly linked to previous high-throughput single-cell measures of virus-DIP coinfection. The CA model also provided testable hypotheses on the spatial-temporal distribution of the DIPs, which remain governed by their predator-prey interaction. More generally, this work offers a data-driven computational modeling approach for better understanding of how single infected cells impact the multiround spread of virus infections across cell populations.ImportanceDefective interfering particles (DIPs) compete with intact virus, depleting host cell resources that are essential for virus growth and infection spread. However, it is not known how such competition, strong or weak, ultimately affects the way in which infections spread and cause disease. In this study, we address this unmet need by developing an integrated experimental-computational approach, which sheds new light on how infections spread. We anticipate that our approach will also be useful in the development of DIPs as therapeutic agents to manage the spread of viral infections.

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Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development.

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Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development.

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