@article{78367c933ab849d4aa2ef71f9463e240,
title = "A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart",
abstract = "The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.",
keywords = "gene expression, heart development, human development, human developmental cell atlas, in situ sequencing, single-cell RNA-sequencing, spatial transcriptomics, spatially resolved transcriptomics",
author = "Michaela Asp and Stefania Giacomello and Ludvig Larsson and Chenglin Wu and Daniel F{\"u}rth and Xiaoyan Qian and Eva W{\"a}rdell and Joaquin Custodio and Johan Reimeg{\aa}rd and Fredrik Salm{\'e}n and Cecilia {\"O}sterholm and St{\aa}hl, \{Patrik L.\} and Erik Sundstr{\"o}m and Elisabet {\AA}kesson and Olaf Bergmann and Magda Bienko and Agneta M{\aa}nsson-Broberg and Mats Nilsson and Christer Sylv{\'e}n and Joakim Lundeberg",
note = "Funding Information: We thank Annelie Mollbrink, PhD, and Erik Wernersson, PhD, for help with experiments. We also thank Matthias Corbascio and Karl-Henrik Grinnemo for discussions and Phil Ewels for critically reviewing the manuscript. We thank the Swedish National Genomics Infrastructure (NGI) and the Eukaryotic Single Cell Genomics facility (ESCG), hosted at SciLifeLab, for infrastructure support. We thank the National Bioinformatics Infrastructure Sweden (NBIS) for computational assistance and Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) for providing computational infrastructure. We thank the KI Developmental Tissue Bank for providing tissue material. We also thank the Live Cell Imaging Facility, Karolinska Institutet (KI), Sweden, with core facility support from the KI infrastructure committee and the Centre for Innovative Medicine at KI. This work was supported by the Erling-Persson family foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Jonasson Center at the Royal Institute of Technology (Sweden) and StratRegen at KI. S.G. and J.R. were financially supported by the Knut and Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. S.G. was also supported by Formas grant 2017-01066\_3. M.A. designed the study, planned and performed the experiments, analyzed the data, interpreted results, wrote the manuscript, and designed and prepared figures. S.G. guided data analysis, analyzed the data, interpreted results, wrote the manuscript, and designed figures. L.L. analyzed the data and interpreted results that contributed to the final manuscript. C.W. performed in situ sequencing experiments and analyzed ISS data. D.F. constructed the 3D reference atlas of the human embryonic heart. X.Q. performed spatial cell type mapping of ISS data and prepared figures and ISS online viewer. E.W. performed tissue sectioning, immunohistochemical staining, guided histological annotations, and prepared and dissociated heart tissue to a single-cell solution. J.C. performed smFISH experiments. J.R. assisted in data analysis. F.S. assisted in experimental set-up and data analysis. C.{\"O}. assisted in the set-up of embryonic material. E.S. and E.{\AA}. dissected and staged the tissue material. M.B. guided smFISH experiments. A.M.-B. assisted in biological guidance. P.L.S. assisted in experimental set-up and data analysis. M.N. guided in situ sequencing experiments. C.S. provided biological guidance, analyzed the data, interpreted biological results, and wrote the manuscript. J.L. conceived and designed the study. All authors helped with manuscript preparation. S.G. P.L.S. and J.L. are scientific advisors to 10x Genomics, which holds IP rights to the ST technology. M.N. and X.Q. hold shares in Cartana AB, a company commercializing in situ sequencing reagents. Funding Information: We thank Annelie Mollbrink, PhD, and Erik Wernersson, PhD, for help with experiments. We also thank Matthias Corbascio and Karl-Henrik Grinnemo for discussions and Phil Ewels for critically reviewing the manuscript. We thank the Swedish National Genomics Infrastructure (NGI) and the Eukaryotic Single Cell Genomics facility (ESCG), hosted at SciLifeLab, for infrastructure support. We thank the National Bioinformatics Infrastructure Sweden (NBIS) for computational assistance and Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) for providing computational infrastructure. We thank the KI Developmental Tissue Bank for providing tissue material. We also thank the Live Cell Imaging Facility, Karolinska Institutet (KI), Sweden, with core facility support from the KI infrastructure committee and the Centre for Innovative Medicine at KI. This work was supported by the Erling-Persson family foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Jonasson Center at the Royal Institute of Technology (Sweden) and StratRegen at KI. S.G. and J.R. were financially supported by the Knut and Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. S.G. was also supported by Formas grant 2017-01066\_3 . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "12",
doi = "10.1016/j.cell.2019.11.025",
language = "English",
volume = "179",
pages = "1647--1660.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier",
number = "7",
}