Clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

• Published in: Nature neuroscience Vol. 25; no. 3; pp. 285 - 294
• Main Authors: Ratz, Michael, von Berlin, Leonie, Larsson, Ludvig, Martin, Marcel, Westholm, Jakub Orzechowski, La Manno, Gioele, Lundeberg, Joakim, Frisén, Jonas
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2022; Nature Publishing Group
• Subjects: 631/136/368/2430; 631/378/2571/2578; 631/378/340; animal; animal cell; animal experiment; Animal Genetics and Genomics; animal tissue; Animal tissues; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain architecture; cell clone; Cell Differentiation; cell migration; Cells (biology); Clone Cells; Hippocampus; in vivo study; Integrated approach; male; mammal; Mammals; Medicin och hälsovetenskap; Mice; Microglia; mouse; myeloid progenitor cell; Nervous system; Neurobiology; Neuroepithelial Cells; neuroepithelium; neuroepithelium cell; Neurosciences; nonhuman; phenotype; Phenotypes; Progenitor cells; Progeny; stem cell; Stem Cells; tissue level; tissue section; Transcriptome; Transcriptomics
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-022-01011-x

The mammalian brain contains many specialized cells that develop from a thin sheet of neuroepithelial progenitor cells. Single-cell transcriptomics revealed hundreds of molecularly diverse cell types in the nervous system, but the lineage relationships between mature cell types and progenitor cells are not well understood. Here we show in vivo barcoding of early progenitors to simultaneously profile cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. By reconstructing thousands of clones, we discovered fate-restricted progenitor cells in the mouse hippocampal neuroepithelium and show that microglia are derived from few primitive myeloid precursors that massively expand to generate widely dispersed progeny. We combined spatial transcriptomics with clonal barcoding and disentangled migration patterns of clonally related cells in densely labeled tissue sections. Our approach enables high-throughput dense reconstruction of cell phenotypes and clonal relations at the single-cell and tissue level in individual animals and provides an integrated approach for understanding tissue architecture. Ratz et al. present an easy-to-use method to barcode progenitor cells, enabling profiling of cell phenotypes and clonal relations using single-cell and spatial transcriptomics, providing an integrated approach for understanding brain architecture.