The Human Cell Atlas White Paper

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas.

Roland Eils | Hans Clevers | Mary Carmichael | Garry Nolan | Benedict Paten | Aviv Regev | Ehud Shapiro | Herbert Schiller | Jonathan Weissman | Nir Hacohen | Evan Z. Macosko | Deanne Taylor | Ludovic Vallier | Alexander van Oudenaarden | Fiona Watt | Piero Carninci | Nikolaus Rajewsky | Jay W. Shin | Partha Majumder | Sekar Kathiresan | Dana Pe'er | Bernd Bodenmiller | Kristin Ardlie | Ido Amit | Sarah Teichmann | Paola Arlotta | Allon M. Klein | Christian Conrad | Anthony Philippakis | Eric Lander | Adrian Thorogood | Peter Campbell | Arnold Kriegstein | Michael Stratton | Ed Lein | Chris Ponting | Miriam Merad | Bartha Knoppers | Lars Fugger | Christophe Benoist | Musa Mhlanga | Xiaowei Zhuang | Michael J. T. Stubbington | Orit Rozenblatt-Rosen | Leslie Castelo-Soccio | Kai Tan | Moshe Biton | Jayaraj Rajagopal | Ingo Helbig | Deanne M. Taylor | Wolf Reik | Sten Linnarsson | Barbara Wold | Martijn Nawijn | Jeremy Freeman | Allon Klein | Jay Shin | John Marioni | D. Pe’er | G. Nolan | A. Philippakis | E. Shapiro | S. Linnarsson | I. Amit | N. Hacohen | A. Regev | E. Lander | C. Ponting | S. Quake | A. Oudenaarden | B. Wold | S. Teichmann | R. Xavier | P. Arlotta | C. Conrad | R. Eils | E. Lein | M. Stratton | J. Weissman | J. Marioni | K. Ardlie | E. Macosko | B. Knoppers | P. Campbell | B. Bruneau | X. Zhuang | N. Rajewsky | A. Kriegstein | B. Paten | O. Rozenblatt-Rosen | A. Shalek | H. Stunnenberg | Gary D. Bader | S. Kathiresan | H. Clevers | C. Benoist | Bernd Bodenmiller | M. Clatworthy | L. Fugger | M. Haniffa | Seung Kim | P. Majumder | M. Merad | M. Mhlanga | M. Nawijn | W. Reik | M. Stubbington | F. Watt | I. Helbig | A. Thorogood | H. Schiller | D. Graham | L. Vallier | R. Heuckeroth | S. Naik | K. Saeb‐Parsy | K. Skeldon | J. Rajagopal | L. Castelo-Soccio | P. Carninci | S. Macparland | I. McGilvray | Moshe Biton | Jennifer Rood | Ramnik Xavier | Muzlifah Haniffa | Kourosh Saeb-Parsy | Anna Greka | Henk Stunnenberg | Menna Clatworthy | Alex Shalek | Evan Macosko | Shalin Naik | Seung Kim | Jennifer E. Rood | Michael Stubbington | Gary Bader | Benoit Bruneau | Berthold Goettgens | Daniel Graham | Robert Heuckeroth | Jane Lee | Sonya MacParland | Robert Majovski | Ian McGilvray | Steve Quake | Jennifer Rood | Steve Scott | Kenneth Skeldon | Jenna Streicher | Wilko Weicher | Andrew Wells | Human Cell Atlas Organizing Committee | A. Greka | J. Freeman | Kai Tan | J. Streicher | M. Carmichael | Berthold Goettgens | J. Lee | Robert C. Majovski | Steve Scott | Wilko Weicher | A. Wells | B. Bodenmiller | Jenna L. Streicher

[1]  Hans Clevers,et al.  Modeling Development and Disease with Organoids , 2016, Cell.

[2]  I. Novak,et al.  The cystic fibrosis of exocrine pancreas. , 2013, Cold Spring Harbor perspectives in medicine.

[3]  M. Haniffa,et al.  Antigen-Presenting Cells in the Skin. , 2017, Annual review of immunology.

[4]  Asif U. Tamuri,et al.  Genome sequencing of normal cells reveals developmental lineages and mutational processes , 2014, Nature.

[5]  M. M. Rahman,et al.  Worldwide trends in diabetes since 1980 : pooled analysis of 751 population-based measurement studies with over 4 . 4 million participants , 2016 .

[6]  Howard Y. Chang,et al.  An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development , 2014, PLoS genetics.

[7]  B. Knoppers,et al.  Harmonizing Privacy Laws to Enable International Biobank Research , 2015, Journal of Law, Medicine & Ethics.

[8]  S. Levy,et al.  Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. , 2017, The Journal of clinical investigation.

[9]  Richard A. Muscat,et al.  Scaling single cell transcriptomics through split pool barcoding , 2017, bioRxiv.

[10]  Siddharth S. Dey,et al.  Integrated genome and transcriptome sequencing from the same cell , 2014, Nature Biotechnology.

[11]  R. Hruban,et al.  Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells , 2017, Nature Communications.

[12]  E. Shapiro,et al.  Single-cell sequencing-based technologies will revolutionize whole-organism science , 2013, Nature Reviews Genetics.

[13]  C. Ponting,et al.  G&T-seq: parallel sequencing of single-cell genomes and transcriptomes , 2015, Nature Methods.

[14]  P. Maisonneuve,et al.  Epidemiology of chronic pancreatitis: burden of the disease and consequences , 2014, United European gastroenterology journal.

[15]  Karl Deisseroth,et al.  Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease , 2017, Scientific Reports.

[16]  A. Kostic,et al.  An integrative view of microbiome-host interactions in inflammatory bowel diseases. , 2015, Cell host & microbe.

[17]  Daniel Grolimund,et al.  Fast chemical imaging at high spatial resolution by laser ablation inductively coupled plasma mass spectrometry. , 2013, Analytical chemistry.

[18]  George M. Church,et al.  Highly Multiplexed Subcellular RNA Sequencing in Situ , 2014, Science.

[19]  G. Šimić,et al.  Extraordinary neoteny of synaptic spines in the human prefrontal cortex , 2011, Proceedings of the National Academy of Sciences.

[20]  M. Trotter,et al.  Single-cell gene expression profiling reveals functional heterogeneity of undifferentiated human epidermal cells , 2013, Development.

[21]  C. Deming,et al.  Topographical and Temporal Diversity of the Human Skin Microbiome , 2009, Science.

[22]  Rachel G Liao,et al.  A federated ecosystem for sharing genomic, clinical data , 2016, Science.

[23]  Long Cai,et al.  Single cell systems biology by super-resolution imaging and combinatorial labeling , 2012, Nature Methods.

[24]  P. Kharchenko,et al.  Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain , 2017, Nature Biotechnology.

[25]  Qing Li,et al.  Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue , 2013, Proceedings of the National Academy of Sciences.

[26]  Sean C. Bendall,et al.  Multiplexed ion beam imaging of human breast tumors , 2014, Nature Medicine.

[27]  Bartha M Knoppers,et al.  Registered access: a ‘Triple-A' approach , 2016, European Journal of Human Genetics.

[28]  Patrik L. Ståhl,et al.  Visualization and analysis of gene expression in tissue sections by spatial transcriptomics , 2016, Science.

[29]  J. C. Love,et al.  Seq-Well: A Portable, Low-Cost Platform for High-Throughput Single-Cell RNA-Seq of Low-Input Samples , 2017, Nature Methods.

[30]  Ian R. Wickersham,et al.  The BRAIN Initiative Cell Census Consortium: Lessons Learned toward Generating a Comprehensive Brain Cell Atlas , 2017, Neuron.

[31]  Brandon Da Silva,et al.  Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis , 2017, Cell.

[32]  Hans Clevers,et al.  Single-cell messenger RNA sequencing reveals rare intestinal cell types , 2015, Nature.

[33]  V. Gulmans,et al.  Intestinal organoids and personalized medicine in cystic fibrosis: a successful patient-oriented research collaboration , 2016, Current opinion in pulmonary medicine.

[34]  Shuqiang Li,et al.  Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction , 2016, Genome Biology.

[35]  Kirsten L. Frieda,et al.  Synthetic recording and in situ readout of lineage information in single cells , 2016, Nature.

[36]  J. Buhmann,et al.  Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry , 2014, Nature Methods.

[37]  N. Slavov,et al.  SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation , 2017, Genome Biology.

[38]  Stephen C. J. Parker,et al.  Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants , 2013, Proceedings of the National Academy of Sciences.

[39]  D. Tuveson,et al.  Model organoids provide new research opportunities for ductal pancreatic cancer , 2016, Molecular & cellular oncology.

[40]  J. Hoffman,et al.  Congenital heart disease: incidence and inheritance. , 1990, Pediatric clinics of North America.

[41]  Alan C. Evans,et al.  BigBrain: An Ultrahigh-Resolution 3D Human Brain Model , 2013, Science.

[42]  Seung K. Kim,et al.  Gene regulatory networks governing pancreas development. , 2013, Developmental cell.

[43]  Elizabeth A. Calle,et al.  Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. , 2014, Cell stem cell.

[44]  Mauro J. Muraro,et al.  De Novo Prediction of Stem Cell Identity using Single-Cell Transcriptome Data , 2016, Cell stem cell.

[45]  Evan W. Newell,et al.  Mapping the human DC lineage through the integration of high-dimensional techniques , 2017, Science.

[46]  Andrew C. Adey,et al.  Single-Cell Transcriptional Profiling of a Multicellular Organism , 2017 .

[47]  E. Shapiro,et al.  A generic, cost-effective, and scalable cell lineage analysis platform , 2016, Genome research.

[48]  Andrew C. Adey,et al.  Comprehensive single cell transcriptional profiling of a multicellular organism by combinatorial indexing , 2017 .

[49]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[50]  O. Ornatsky,et al.  Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. , 2009, Analytical chemistry.

[51]  Jeffrey R Moffitt,et al.  High-performance multiplexed fluorescence in situ hybridization in culture and tissue with matrix imprinting and clearing , 2016, Proceedings of the National Academy of Sciences.

[52]  O. Stegle,et al.  Single-cell epigenomics: Recording the past and predicting the future , 2017, Science.

[53]  P. Rakic A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution , 1995, Trends in Neurosciences.

[54]  David A. Weitz,et al.  Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices , 2017, Nature Reviews Genetics.

[55]  J. Chang,et al.  Expansion microscopy , 2018, Journal of microscopy.

[56]  J. Nathans,et al.  Flat mount imaging of mouse skin and its application to the analysis of hair follicle patterning and sensory axon morphology. , 2014, Journal of visualized experiments : JoVE.

[57]  Cole Trapnell,et al.  Scalable and efficient single-cell DNA methylation sequencing by combinatorial indexing , 2017, bioRxiv.

[58]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[59]  Salah Ayoub,et al.  Cell fixation and preservation for droplet-based single-cell transcriptomics , 2017, BMC Biology.

[60]  Catalin C. Barbacioru,et al.  mRNA-Seq whole-transcriptome analysis of a single cell , 2009, Nature Methods.

[61]  Mark I. McCarthy,et al.  Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants , 2013, Nature Genetics.

[62]  M. Clatworthy,et al.  Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone , 2017, Cell.

[63]  Z. Kmieć,et al.  Cooperation of Liver Cells in Health and Disease , 2001, Advances in Anatomy Embryology and Cell Biology.

[64]  Aparna Bhaduri,et al.  Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR. , 2015, Developmental cell.

[65]  Andrew C. Adey,et al.  Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing , 2015, Science.

[66]  Bernd Bodenmiller,et al.  Multiplexed Epitope-Based Tissue Imaging for Discovery and Healthcare Applications. , 2016, Cell systems.

[67]  A. Greka Human genetics of nephrotic syndrome and the quest for precision medicine , 2016, Current opinion in nephrology and hypertension.

[68]  J. DeFelipe,et al.  Microstructure of the neocortex: Comparative aspects , 2002, Journal of neurocytology.

[69]  I. Amit,et al.  Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types , 2014, Science.

[70]  D. Koller,et al.  The Immunological Genome Project: networks of gene expression in immune cells , 2008, Nature Immunology.

[71]  T. Tuschl,et al.  Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis. , 2017, JCI insight.

[72]  Karl Deisseroth,et al.  Multiplexed Intact-Tissue Transcriptional Analysis at Cellular Resolution , 2016, Cell.

[73]  Alvaro Plaza Reyes,et al.  Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos , 2016, Cell.

[74]  R. Aebersold,et al.  On the Dependency of Cellular Protein Levels on mRNA Abundance , 2016, Cell.

[75]  Cynthia C. Hession,et al.  Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons , 2016, Science.

[76]  Samuel Aparicio,et al.  High-throughput microfluidic single-cell RT-qPCR , 2011, Proceedings of the National Academy of Sciences.

[77]  Bin Zhou,et al.  Transcriptomic Profiling Maps Anatomically Patterned Subpopulations among Single Embryonic Cardiac Cells. , 2016, Developmental cell.

[78]  H. Clevers,et al.  Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche , 2009, Nature.

[79]  David W. Nauen,et al.  Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure , 2016, Cell.

[80]  Scott A. Rifkin,et al.  Imaging individual mRNA molecules using multiple singly labeled probes , 2008, Nature Methods.

[81]  Allan R. Jones,et al.  Comprehensive transcriptional map of primate brain development , 2016, Nature.

[82]  Aviv Regev,et al.  Massively-parallel single nucleus RNA-seq with DroNc-seq , 2017, Nature Methods.

[83]  J. Schug,et al.  Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes , 2016, Molecular metabolism.

[84]  W. Schubert,et al.  Analyzing proteome topology and function by automated multidimensional fluorescence microscopy , 2006, Nature Biotechnology.

[85]  F. Tang,et al.  Tracing haematopoietic stem cell formation at single-cell resolution , 2016, Nature.

[86]  S. Quake,et al.  Single cell transcriptome analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns , 2017, bioRxiv.

[87]  Howard Y. Chang,et al.  Anatomic Demarcation by Positional Variation in Fibroblast Gene Expression Programs , 2006, PLoS genetics.

[88]  Parsing the Pancreas , 2017, The New England journal of medicine.

[89]  Robert Kevin Grigsby,et al.  Federal Policy for the Protection of Human Subjects , 1993, Research on social work practice.

[90]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human colonic crypt stem cells. , 2003, The Journal of clinical investigation.

[91]  Allon M. Klein,et al.  Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells , 2015, Cell.

[92]  Aaron S. Andalman,et al.  Structural and molecular interrogation of intact biological systems , 2013, Nature.

[93]  N. Slavov,et al.  SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation , 2017, Genome Biology.

[94]  Stephen R Quake,et al.  Single-cell multimodal profiling reveals cellular epigenetic heterogeneity , 2016, Nature Methods.

[95]  I. Amit,et al.  Single-cell spatial reconstruction reveals global division of labor in the mammalian liver , 2016, Nature.

[96]  Fabian J Theis,et al.  The Human Cell Atlas , 2017, bioRxiv.

[97]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[98]  M. Ronaghi,et al.  Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain , 2016, Science.

[99]  Evan Z. Macosko,et al.  Comprehensive Classification of Retinal Bipolar Neurons by Single-Cell Transcriptomics , 2016, Cell.

[100]  Howard Y. Chang,et al.  Single-cell chromatin accessibility reveals principles of regulatory variation , 2015, Nature.

[101]  Carolina Wählby,et al.  In situ sequencing for RNA analysis in preserved tissue and cells , 2013, Nature Methods.

[102]  R. Poulsom,et al.  Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors , 2013, eLife.

[103]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[104]  G. Nolan,et al.  Mass Cytometry: Single Cells, Many Features , 2016, Cell.

[105]  Junhyong Kim,et al.  CYCLOPS reveals human transcriptional rhythms in health and disease , 2017, Proceedings of the National Academy of Sciences.

[106]  M. McCarthy,et al.  Human islet function following 20 years of cryogenic biobanking , 2015, Diabetologia.

[107]  Allan R. Jones,et al.  Comprehensive cellular‐resolution atlas of the adult human brain , 2016, The Journal of comparative neurology.

[108]  U. Landegren,et al.  Protein detection using proximity-dependent DNA ligation assays , 2002, Nature Biotechnology.

[109]  Karen L. Mohlke,et al.  A map of open chromatin in human pancreatic islets , 2010, Nature Genetics.

[110]  Christopher S. Stevenson,et al.  Nondestructive cryomicro-CT imaging enables structural and molecular analysis of human lung tissue. , 2017, Journal of applied physiology.

[111]  Edward S Boyden,et al.  Nanoscale Imaging of RNA with Expansion Microscopy , 2016, Nature Methods.

[112]  Rona S. Gertner,et al.  Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells , 2013, Nature.

[113]  F. Watt Mammalian skin cell biology: At the interface between laboratory and clinic , 2014, Science.

[114]  R. Knight,et al.  Microbial Skin Inhabitants: Friends Forever , 2016, Cell.

[115]  N. Neff,et al.  Reconstructing lineage hierarchies of the distal lung epithelium using single cell RNA-seq , 2014, Nature.

[116]  “Common Rule,et al.  Federal Policy for the Protection of Human Subjects. Final rule. , 2017, Federal register.

[117]  Rona S. Gertner,et al.  Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity , 2015, Cell.

[118]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[119]  B. Bruneau The developmental genetics of congenital heart disease , 2008, Nature.

[120]  R. Heeren,et al.  A critical evaluation of the current state-of-the-art in quantitative imaging mass spectrometry , 2014, Analytical and Bioanalytical Chemistry.

[121]  S. P. Fodor,et al.  Combinatorial labeling of single cells for gene expression cytometry , 2015, Science.

[122]  Justin P Sandoval,et al.  Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex , 2017, Science.

[123]  Allan R. Jones,et al.  Transcriptional Landscape of the Prenatal Human Brain , 2014, Nature.

[124]  Bernd Bodenmiller,et al.  AirLab: a cloud-based platform to manage and share antibody-based single-cell research , 2016, Genome Biology.

[125]  S. Mazmanian,et al.  The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. , 2017, Immunity.

[126]  Scott M. Palmer,et al.  LungMAP: The Molecular Atlas of Lung Development Program , 2017, American journal of physiology. Lung cellular and molecular physiology.

[127]  Miriam Merad,et al.  Regulation of macrophage development and function in peripheral tissues , 2015, Nature Reviews Immunology.

[128]  William Stafford Noble,et al.  Massively multiplex single-cell Hi-C , 2016, Nature Methods.

[129]  L. Cai,et al.  In Situ Transcription Profiling of Single Cells Reveals Spatial Organization of Cells in the Mouse Hippocampus , 2016, Neuron.

[130]  K. Furie,et al.  Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2007, Circulation.

[131]  Nicola K. Wilson,et al.  Resolving Early Mesoderm Diversification through Single Cell Expression Profiling , 2016, Nature.

[132]  C. Ponting,et al.  Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity , 2015, Nature Methods.

[133]  G. Giebisch Coupled ion and fluid transport in the kidney. , 1972, The New England journal of medicine.

[134]  Maria Kasper,et al.  Single-Cell Transcriptomics Reveals that Differentiation and Spatial Signatures Shape Epidermal and Hair Follicle Heterogeneity , 2016, Cell systems.

[135]  Alex A. Pollen,et al.  Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex , 2014, Nature Biotechnology.

[136]  Mauro J. Muraro,et al.  A Single-Cell Transcriptome Atlas of the Human Pancreas , 2016, Cell systems.

[137]  R. Knight,et al.  Molecular cartography of the human skin surface in 3D , 2015, Proceedings of the National Academy of Sciences.

[138]  D. Rimm Next-gen immunohistochemistry , 2014, Nature Methods.

[139]  Charles H. Yoon,et al.  Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq , 2016, Science.

[140]  James A. Gagnon,et al.  Whole-organism lineage tracing by combinatorial and cumulative genome editing , 2016, Science.

[141]  E. Shapiro,et al.  A biological-computational human cell lineage discovery platform based on duplex molecular inversion probes , 2017, bioRxiv.

[142]  Rebecca Hodge,et al.  STRT-seq-2i: dual-index 5ʹ single cell and nucleus RNA-seq on an addressable microwell array , 2017, bioRxiv.

[143]  I. Amit,et al.  Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors , 2015, Cell.

[144]  Yi Liu,et al.  Single-Cell Gene Expression Profiling , 2022 .

[145]  N. Hacohen,et al.  Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors , 2017, Science.

[146]  F. Conlon,et al.  Myocardial lineage development. , 2010, Circulation research.

[147]  Donald M. Bell,et al.  Lineage-dependent spatial and functional organization of the mammalian enteric nervous system , 2017, Science.

[148]  X. Zhuang,et al.  Spatially resolved, highly multiplexed RNA profiling in single cells , 2015, Science.

[149]  G. Sanguinetti,et al.  scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells , 2018, Nature Communications.

[150]  J. Stenvang,et al.  Homogenous 96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity, and Excellent Scalability , 2014, PloS one.

[151]  Eric S. Lander,et al.  Composite measurements and molecular compressed sensing for highly efficient transcriptomics , 2017, bioRxiv.

[152]  A. Regev,et al.  Spatial reconstruction of single-cell gene expression data , 2015 .

[153]  Guohua Zhang,et al.  Polymer-based elemental tags for sensitive bioassays. , 2007, Angewandte Chemie.

[154]  A. Tanay,et al.  Single-cell epigenomics: techniques and emerging applications , 2015, Nature Reviews Genetics.

[155]  Laura J. Scott,et al.  Genetic regulatory signatures underlying islet gene expression and type 2 diabetes , 2017, Proceedings of the National Academy of Sciences.

[156]  E. Passegué,et al.  The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors , 2017, Nature.

[157]  Howard Y. Chang,et al.  Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function. , 2016, Cell metabolism.

[158]  Timur Zhiyentayev,et al.  Single-cell in situ RNA profiling by sequential hybridization , 2014, Nature Methods.

[159]  Karen Sachs,et al.  Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators , 2012, Nature Biotechnology.

[160]  Ravi S. Misra,et al.  Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development , 2017, Thorax.

[161]  B. Bruneau Signaling and transcriptional networks in heart development and regeneration. , 2013, Cold Spring Harbor perspectives in biology.

[162]  L. Henry,et al.  Global epidemiology of nonalcoholic fatty liver disease—Meta‐analytic assessment of prevalence, incidence, and outcomes , 2016, Hepatology.

[163]  Erik K. Malm,et al.  A Human Protein Atlas for Normal and Cancer Tissues Based on Antibody Proteomics* , 2005, Molecular & Cellular Proteomics.

[164]  F S Fay,et al.  Visualization of single RNA transcripts in situ. , 1998, Science.

[165]  Hans Clevers,et al.  A functional CFTR assay using primary cystic fibrosis intestinal organoids , 2013, Nature Medicine.

[166]  W. Reik,et al.  Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity , 2016, Genome Biology.

[167]  Pei-Rong Wang,et al.  Deconstructing pancreas development to reconstruct human islets from pluripotent stem cells. , 2010, Cell stem cell.

[168]  H. Swerdlow,et al.  Large-scale simultaneous measurement of epitopes and transcriptomes in single cells , 2017, bioRxiv.

[169]  D. Planchard,et al.  Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities , 2017, Journal of Crohn's & colitis.

[170]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[171]  H. Clevers,et al.  Regulation and plasticity of intestinal stem cells during homeostasis and regeneration , 2016, Development.

[172]  Benjamin D. Greenbaum,et al.  Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses , 2017, Cell.

[173]  Feng Zhang,et al.  DroNc-Seq: Deciphering cell types in human archived brain tissues by massively-parallel single nucleus RNA-seq , 2017, bioRxiv.

[174]  Hazen P Babcock,et al.  High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization , 2016, Proceedings of the National Academy of Sciences.

[175]  J. Marioni,et al.  High-throughput spatial mapping of single-cell RNA-seq data to tissue of origin , 2015, Nature Biotechnology.

[176]  D. M. Smith,et al.  Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes , 2016, Cell metabolism.

[177]  Matt Thomson,et al.  Low Dimensionality in Gene Expression Data Enables the Accurate Extraction of Transcriptional Programs from Shallow Sequencing. , 2016, Cell systems.

[178]  Sean C. Bendall,et al.  viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia , 2013, Nature Biotechnology.