Longitudinal scRNA-seq analysis in mouse and human informs optimization of rapid mouse astrocyte differentiation protocols

Paul W. Frazel, David Labib, Theodore Fisher, Ran Brosh, Nicolette Pirianian, Anne Marchildon, Jef D. Boeke, Valentina Fossati, Shane A. Liddelow

Research output: Contribution to journalArticlepeer-review

Abstract

Macroglia (astrocytes and oligodendrocytes) are required for normal development and function of the central nervous system, yet many questions remain about their emergence during the development of the brain and spinal cord. Here we used single-cell/single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) to analyze over 298,000 cells and nuclei during macroglia differentiation from mouse embryonic and human-induced pluripotent stem cells. We computationally identify candidate genes involved in the fate specification of glia in both species and report heterogeneous expression of astrocyte surface markers across differentiating cells. We then used our transcriptomic data to optimize a previous mouse astrocyte differentiation protocol, decreasing the overall protocol length and complexity. Finally, we used multi-omic, dual single-nuclei (sn)RNA-seq/snATAC-seq analysis to uncover potential genomic regulatory sites mediating glial differentiation. These datasets will enable future optimization of glial differentiation protocols and provide insight into human glial differentiation.

Original languageEnglish (US)
Pages (from-to)1726-1738
Number of pages13
JournalNature Neuroscience
Volume26
Issue number10
DOIs
StatePublished - Oct 2023

ASJC Scopus subject areas

  • General Neuroscience

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