Mapping human brain cell type origin and diseases through single-cell transcriptomics

Abstract

The human brain, a pinnacle of biological complexity, comprises a diverse array of cell types that regulate cognition and maintain neural homeostasis. Advances in single-cell transcriptomics have revolutionized neuroscience by enabling high-resolution molecular profiling, revealing unprecedented insights into cellular heterogeneity, lineage dynamics, and disease-associated states. Large-scale brain-mapping initiatives have identified numerous novel cell types, yet their functional roles in health and disease remain poorly understood. This review synthesizes current knowledge of brain cell diversity, from neurogenesis to pathological states, and highlights key gene markers that define cellular identity and function. By integrating insights from single-cell transcriptomics, we explore how cellular diversity shapes brain function and contributes to disease mechanisms, providing a foundation for future research and translational applications.

Fig. 1. Neurogenesis during fetal brain development, cortical neuronal subtypes, and associated neurodevelopmental and neurodegenerative disorders.

The left panel shows fetal neurogenesis in the developing neocortex, highlighting progenitor zones (ventricular, subventricular, intermediate) and migrating neurons. The middle panel depicts mature cortical layers with excitatory and inhibitory neurons. The right panel presents neurodevelopmental and neurodegenerative disorders linked to neuronal imbalances. Figure created using BioRender.com.

Fig. 2. Single-cell RNA sequencing technology.

a Workflow of scRNA-seq experiment. Schematic representation outlining the sequential steps involved in scRNA-seq, including single-cell isolation, cDNA synthesis, library preparation, sequencing, and subsequent data analysis. b Applications of scRNA-seq. Illustration highlighting diverse applications of scRNA-seq, ranging from cell type identification to dissecting cellular heterogeneity in complex biological systems. Figure created with BioRender.com.

Fig. 3. Motor cortex cell type taxonomy.

Circular dendrogram depicting primary motor cortex cell type classification [50]. Cell-type relationships were modelled using single-cell transcriptomic and epigenomic data from the BRAIN Initiative Cell Census Network (BICCN) study (PMID: 34616075), which profiled the primary motor cortex in humans, marmosets, and mice. Hierarchical structure was derived from curated parent–child relationships and node metadata (e.g., species, cell type annotations, proportions) provided in Supplementary Table 2. The directed graph was constructed using the igraph R package and visualized as a circular dendrogram using ggraph, employing a dendrogram layout optimized for tree structures. Node labels were radially aligned, and diagonal curved edges illustrate branching hierarchy. Species-specific cell types are distinguished by color (Human, Marmoset, Mouse), and additional attributes are visualized using a Viridis colormap. Cluster proportions represent the relative abundance of each neuronal or non-neuronal population. This figure highlights the cross-species conservation and diversity of cortical cell types in the primary motor cortex.

Fig. 4. Compilation of human brain cell type studies.

Comprehensive representation of 11 studies identifying diverse brain cell types within the human brain. A collection of papers published in Science, Science Advances, and Science Translational Medicine by the NIH’s BRAIN Initiative – Cell Census Network (BICCN) presents a large-scale, multi-omics analysis of human brain cell types. Figure created using BioRender.com.