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Cell types and clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

View ORCID ProfileMichael Ratz, Leonie von Berlin, View ORCID ProfileLudvig Larsson, View ORCID ProfileMarcel Martin, View ORCID ProfileJakub Orzechowski Westholm, View ORCID ProfileGioele La Manno, View ORCID ProfileJoakim Lundeberg, Jonas Frisén
doi: https://doi.org/10.1101/2021.08.31.458418
Michael Ratz
1Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden
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Leonie von Berlin
1Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden
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Ludvig Larsson
2Science for Life Laboratory, KTH Royal Institute of Technology, 106 91, Stockholm, Sweden
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Marcel Martin
3Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Box 1031, 17 121 Solna, Sweden
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Jakub Orzechowski Westholm
3Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Box 1031, 17 121 Solna, Sweden
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Gioele La Manno
4Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden
5Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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Joakim Lundeberg
2Science for Life Laboratory, KTH Royal Institute of Technology, 106 91, Stockholm, Sweden
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Jonas Frisén
1Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden
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  • For correspondence: Jonas.frisen@ki.se
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Summary

The mammalian brain contains a large number of specialized cells that develop from a thin sheet of neuroepithelial progenitor cells1,2. Recently, high throughput single-cell technologies have been used to define the molecular diversity of hundreds of cell types in the nervous system3,4. However, the lineage relationships between mature brain cells and progenitor cells are not well understood, because transcriptomic studies do not allow insights into clonal relationships and classical fate-mapping techniques are not scalable5,6. Here we show in vivo barcoding of early progenitor cells that enables simultaneous profiling of cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. We reconstructed thousands of clones to uncover the existence of 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. By coupling spatial transcriptomics with clonal barcoding, we disentangle migration patterns of clonally related cells in densely labelled tissue sections. Compared to classical fate mapping, 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.

Competing Interest Statement

JF and JL are consultants to 10X Genomics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 01, 2021.
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Cell types and clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics
Michael Ratz, Leonie von Berlin, Ludvig Larsson, Marcel Martin, Jakub Orzechowski Westholm, Gioele La Manno, Joakim Lundeberg, Jonas Frisén
bioRxiv 2021.08.31.458418; doi: https://doi.org/10.1101/2021.08.31.458418
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Cell types and clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics
Michael Ratz, Leonie von Berlin, Ludvig Larsson, Marcel Martin, Jakub Orzechowski Westholm, Gioele La Manno, Joakim Lundeberg, Jonas Frisén
bioRxiv 2021.08.31.458418; doi: https://doi.org/10.1101/2021.08.31.458418

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