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Human organoids – three-dimensional structures of cells that recapitulate important aspects of organ development in vitro – hold tremendous potential for biomedical applications. To help deliver on the promises of combining human organoids with single-cell technology, we have launched an Organoid Cell Atlas pilot project, as a 'Biological Network' within the Human Cell Atlas (HCA), focusing on single-cell profiling of organoids and in vitro cell models (https://www.humancellatlas.org/coordinators/). The Organoid Cell Atlas will foster the production, quality control, dissemination, and utilization of single-cell and spatial genomics data for human organoids, and it will connect such datasets with the comprehensive profiles of primary tissue that are being generated within the HCA. A first step toward establishing the Organoid Cell Atlas has recently been funded by the European Union Horizon 2020 call for "Pilot actions to build the foundations of a human cell atlas" through the "HCA|Organoid" project (http://hca-organoid.eu/). This preprint outlines the rationale for combining human organoids with single-cell technology and the concrete plans for established the Organoid Cell Atlas as a Rosetta Stone for biomedical discovery and regenerative therapy.

scRNA-seq data for this project has been deposited in ArrayExpress under the accession numbers E-MTAB-6072 and E-MTAB-7311. Processed data can be found in https://figshare.com/projects/Treg_scRNA-seq/38864, and analysis notebooks can be found in https://github.com/tomasgomes/Treg_analysis. ; Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation. ; Wethank V. Proserpio, M. Stubbington, T. Hagai, F.V. Braga, V. Svensson, and J. Henriksson for helpful discussions and advice; T. Hagai, R. Vento-Tormo, K. Meyer, and J. Park for critical reading of the manuscript; and B. Koppelman for editorial support. We thank WSI Single-cell Genomic Core Facility, WSI Sequencing Facility, WSI Flow Cytometry facilities, K. Polanski, and the Kennedy Institute Flow Cytometry Facility for expert technical advice and assistance. R.J.M. was supported by a PhD Fellowship from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/51950/2012) and T.G. by the European Union's H2020 research and innovation program ''ENLIGHT-TEN'' under the Marie Sklodowska-Curie grant ...

Grant support: ANH was supported by an EMBO long-term fellowship and a Marie Curiefellowship. NRW was supported by a CRI Irvington Post-doctoral Fellowship. BMJO was supported by an Oxford-UCB Pharma Postdoctoral Fellowship. MJTS and SAT were supported by ERC grant ThSWITCH and ThDEFINE (260507). SC and AM were supported by the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (grant UM1-AI100645). The Rowett Institute of Nutrition and Health receives financial support from the Scottish Government Rural andEnvironmental Sciences and Analytical Services (SG-RESAS). Foundation Louis Jeantet, Wellcome Trust (Investigator award 095688/Z/11/Z), and ERC (ERC/HN/2013/21) supported FPand this project. HHU is supported by the Crohn's & Colitis Foundation of America (CCFA), The Leona M. and Harry B. Helmsley Charitable Trust. SD receive financial support from the ScottishGovernment Rural and Environmental Sciences and Analytical Services (RESAS). ; Peer reviewed ; Publisher PDF

Grant support: ANH was supported by an EMBO long-term fellowship and a Marie Curiefellowship. NRW was supported by a CRI Irvington Post-doctoral Fellowship. BMJO was supported by an Oxford-UCB Pharma Postdoctoral Fellowship. MJTS and SAT were supported by ERC grant ThSWITCH and ThDEFINE (260507). SC and AM were supported by the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (grant UM1-AI100645). The Rowett Institute of Nutrition and Health receives financial support from the Scottish Government Rural andEnvironmental Sciences and Analytical Services (SG-RESAS). Foundation Louis Jeantet, Wellcome Trust (Investigator award 095688/Z/11/Z), and ERC (ERC/HN/2013/21) supported FPand this project. HHU is supported by the Crohn's & Colitis Foundation of America (CCFA), The Leona M. and Harry B. Helmsley Charitable Trust. SD receive financial support from the ScottishGovernment Rural and Environmental Sciences and Analytical Services (RESAS). ; Peer reviewed ; Publisher PDF