Neighbor-specific gene expression revealed from physically interacting cells during mouse embryonic development

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Development of multicellular organisms is orchestrated by persistent cell–cell communication between neighboring partners. Direct interaction between different cell types can induce molecular signals that dictate lineage specification and cell fate decisions. Current single-cell RNA-seq technology cannot adequately analyze cell–cell contact-dependent gene expression, mainly due to the loss of spatial information. To overcome this obstacle and resolve cell–cell contact-specific gene expression during embryogenesis, we performed RNA sequencing of physically interacting cells (PIC-seq) and assessed them alongside similar single-cell transcriptomes derived from developing mouse embryos between embryonic day (E) 7.5 and E9.5. Analysis of the PIC-seq data identified gene expression signatures that were dependent on the presence of specific neighboring cell types. Our computational predictions, validated experimentally, demonstrated that neural progenitor (NP) cells upregulate Lhx5 and Nkx2-1 genes, when exclusively interacting with definitive endoderm (DE) cells. Moreover, there was a reciprocal impact on the transcriptome of DE cells, as they tend to upregulate Rax and Gsc when in contact with NP cells. Using individual cell transcriptome data, we formulated a means of computationally predicting the impact of one cell type on the transcriptome of its neighboring cell types. We have further developed a distinctive spatial-t-distributed stochastic neighboring embedding to display the pseudospatial distribution of cells in a 2-dimensional space. In summary, we describe an innovative approach to study contact-specific gene regulation during embryogenesis.
OriginalsprogEngelsk
Artikelnummere2205371120
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind120
Udgave nummer2
Antal sider10
ISSN0027-8424
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
ACKNOWLEDGMENTS. The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by a Novo Nordisk Foundation grant (NNF21CC0073729 and previously NNF17CC0027852). We thank the reNEW Genomics Platform (H. Neil, M. Michaut and H. Wollmann), reNEW Flow Cytometry Platform (G. dela Cruz and P. van Dieken), Teresa E. Knudsen, Molly Lowndes, and Yan Fung Wong for critical reading of this manuscript. This work is also supported by Lundbeck

Funding Information:
The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by a Novo Nordisk Foundation grant (NNF21CC0073729 and previously NNF17CC0027852). We thank the reNEW Genomics Platform (H. Neil, M. Michaut and H. Wollmann), reNEW Flow Cytometry Platform (G. dela Cruz and P. van Dieken), Teresa E. Knudsen, Molly Lowndes, and Yan Fung Wong for critical reading of this manuscript. This work is also supported by Lundbeck Foundation (R324-2019-1649 and R313–2019–421) and Cedars-Sinai startup Funds to K.J.W., by Virginia Commonwealth University startup Funds, Masey Cancer Center Startup Funds, Swiss Cancer League, Seeds of Science, Swiss National Science Foundation, Fundação para a Ciência e a Tecnologia, and Fundamental Mandates (Stichting tegen Kanker—Fondation contre le Cancer) to R.G. The National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) to J.K. (No. 2021R1F1A1063914 and 2021M3H9A2096988); La Caixa Funding (LCF/BQ/PR20/11770006) to E.M.; Lundbeck Foundation (R198-2015-412), Independent Research Fund Denmark (8020-00100B and 6110-00009), the Novo Nordisk Foundation (NNF17OC0028218), the Danish National Research Foundation (DNRF116) to J.M.B.; Fundação para a Ciência e a Tecnologia Grant 2020.05319.BD to A.M.P; and Thelma Newmeyer Corman Chair in Cancer Research, the Virginia Commonwealth University Commercialization Fund, NIH grants NIH/National Cancer Institute R01CA259599 and R01CA244993 to P.B.F.

Funding Information:
Foundation (R324-2019-1649 and R313–2019–421) and Cedars-Sinai startup Funds to K.J.W., by Virginia Commonwealth University startup Funds, Masey Cancer Center Startup Funds, Swiss Cancer League, Seeds of Science, Swiss National Science Foundation, Fundação para a Ciência e a Tecnologia, and Fundamental Mandates (Stichting tegen Kanker—Fondation contre le Cancer) to R.G.The National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) to J.K. (No. 2021R1F1A1063914 and 2021M3H9A2096988); La Caixa Funding (LCF/BQ/PR20/11770006) to E.M.; Lundbeck Foundation (R198-2015-412), Independent Research Fund Denmark (8020-00100B and 6110-00009), the Novo Nordisk Foundation (NNF17OC0028218), the Danish National Research Foundation (DNRF116) to J.M.B.; Fundação para a Ciência e a Tecnologia Grant 2020.05319.BD to A.M.P; and Thelma Newmeyer Corman Chair in Cancer Research, the Virginia Commonwealth University Commercialization Fund, NIH grants NIH/National Cancer Institute R01CA259599 and R01CA244993 to P.B.F.

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Copyright © 2023 the Author(s).

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