Comprehensive cell atlas of the first-trimester developing human brain

Abstract

The adult human brain likely comprises more than a thousand kinds of neurons, and an unknown number of glial cell types, but how cellular diversity arises during early brain development is not known. Here, in order to reveal the precise sequence of events during early brain development, we used single-cell RNA sequencing and spatial transcriptomics to uncover cell states and trajectories in human brains at 5 – 14 post-conceptional weeks (p.c.w.). We identified twelve major classes and over 600 distinct cell states, which mapped to precise spatial anatomical domains at 5 p.c.w. We uncovered detailed differentiation trajectories of the human forebrain, and a surprisingly large number of region-specific glioblasts maturing into distinct pre-astrocytes and pre-oligodendrocyte precursor cells (pre-OPCs). Our findings reveal the emergence of cell types during the critical first trimester of human brain development.

Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

“…To examine how these findings relate to in vivo neurodevelopment, we compared our data with publicly available scRNA-seq cluster profiles from developing first trimester fetal forebrains ( Braun et al 2022 ). Using cluster label transfer, we show that cell states present in vivo map to clusters in our in vitro system.…”

“…Using the published data set as a reference, the Bioconductor package clustifyr (v1.10.0) ( Fu et al 2020 ) was used to assign cluster labels from the reference to the DIV24 WT DAPT query data set. Clustifyr builds a scRNA-seq reference by averaging per-cell expression data for each cluster (“clusters” meta data column in Braun et al 2022 ) from the provided Seurat object. Subsequently, clustifyr uses a Spearman correlation-based method to find the query cluster expression profile (WT-DAPT clustering resolution parameter 1.0) with the highest similarities.…”

“…Calculation of similarities between scRNA-seq data sets To compare the scRNA-seq data set from DIV24 WT DAPT-treated cells with a publicly available human fetal brain data set, we used first-trimester forebrain samples (PCW 5-10) from Braun et al (2022), obtained in .h5 format from https://github.com/ linnarsson-lab/developing-human-brain (Supplemental Table S7). The data were subsetted and converted into an AnnData (v0.8.0) (Virshup et al 2021) object in Python (version 3.9.16).…”

RNA regulation in brain function and disease 2022 (NeuroRNA): A conference report

“…Importantly, in the Linnarsson lab, scRNA-seq has been continuously used to uncover the complexity of the mammalian brain. During the conference, the participants had a chance to hear about two new studies, which, shortly after the meeting, became publicly available as preprints (Braun et al, 2022 ; Siletti et al, 2022 ). The first study's aim has been to map the cellular composition of the adult human brain with single-nucleus transcriptomics to obtain a highly resolved molecular atlas.…”

“…The data also give additional insight into the spatial region-specific distribution of glial cells, e.g., mature oligodendrocytes and their progenitors (OPCs), and astrocytes. Switching to the cell atlas of the human developing brain, >1.6 million cells were analyzed from 26 embryos (Braun et al, 2022 ). The study disentangles region specificity of different cell types, including radial glia, neuroblasts, and glioblasts.…”