Review

. 2019 Apr 8;49(1):10-29.

doi: 10.1016/j.devcel.2019.03.001. Epub 2019 Mar 28.

The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

Deanne M Taylor¹, Bruce J Aronow², Kai Tan³, Kathrin Bernt⁴, Nathan Salomonis⁵, Casey S Greene⁶, Alina Frolova⁷, Sarah E Henrickson⁸, Andrew Wells⁹, Liming Pei¹⁰, Jyoti K Jaiswal¹¹, Jeffrey Whitsett¹², Kathryn E Hamilton¹³, Sonya A MacParland¹⁴, Judith Kelsen¹³, Robert O Heuckeroth¹⁵, S Steven Potter¹⁶, Laura A Vella¹⁷, Natalie A Terry¹³, Louis R Ghanem¹³, Benjamin C Kennedy¹⁸, Ingo Helbig¹⁹, Kathleen E Sullivan⁸, Leslie Castelo-Soccio²⁰, Arnold Kreigstein²¹, Florian Herse²², Martijn C Nawijn²³, Gerard H Koppelman²⁴, Melissa Haendel²⁵, Nomi L Harris²⁶, Jo Lynne Rokita²⁷, Yuanchao Zhang²⁸, Aviv Regev²⁹, Orit Rozenblatt-Rosen³⁰, Jennifer E Rood³⁰, Timothy L Tickle³¹, Roser Vento-Tormo³², Saif Alimohamed⁵, Monkol Lek³³, Jessica C Mar³⁴, Kathleen M Loomes¹³, David M Barrett⁴, Prech Uapinyoying³⁵, Alan H Beggs³⁶, Pankaj B Agrawal³⁷, Yi-Wen Chen¹¹, Amanda B Muir¹³, Lana X Garmire³⁸, Scott B Snapper³⁹, Javad Nazarian¹¹, Steven H Seeholzer⁴⁰, Hossein Fazelinia⁴¹, Larry N Singh⁴², Robert B Faryabi⁴³, Pichai Raman²⁷, Noor Dawany²⁷, Hongbo Michael Xie²⁷, Batsal Devkota²⁷, Sharon J Diskin⁴, Stewart A Anderson⁴⁴, Eric F Rappaport⁴⁵, William Peranteau⁴⁶, Kathryn A Wikenheiser-Brokamp⁴⁷, Sarah Teichmann⁴⁸, Douglas Wallace⁴⁹, Tao Peng⁵⁰, Yang-Yang Ding⁴, Man S Kim²⁷, Yi Xing⁵¹, Sek Won Kong⁵², Carsten G Bönnemann⁵³, Kenneth D Mandl⁵², Peter S White⁵

Affiliations

¹ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: taylordm@email.chop.edu.
² Department of Biomedical Informatics, University of Cincinnati College of Medicine, and Cincinnati Children's Hospital Medical Center, Division of Biomedical Informatics, Cincinnati, OH 45229, USA. Electronic address: Bruce.Aronow@cchmc.org.
³ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: tank1@email.chop.edu.
⁴ Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Department of Biomedical Informatics, University of Cincinnati College of Medicine, and Cincinnati Children's Hospital Medical Center, Division of Biomedical Informatics, Cincinnati, OH 45229, USA.
⁶ Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Philadelphia, PA 19102, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, Kyiv 03143, Ukraine.
⁸ Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia and the Institute for Immunology, the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁹ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁰ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹¹ Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA; Center for Genetic Medicine Research, Children's National Medical Center, NW, Washington, DC, 20010-2970, USA.
¹² Cincinnati Children's Hospital Medical Center, Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati, OH 45229, USA.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁴ Multi-Organ Transplant Program, Toronto General Hospital Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁷ Division of Infectious Diseases, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁸ Division of Neurosurgery, Department of Surgery, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁹ Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁰ Department of Pediatrics, Section of Dermatology, The Children's Hospital of Philadelphia and University of Pennsylvania Perleman School of Medicine, Philadelphia, PA 19104, USA.
²¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²² Experimental and Clinical Research Center, A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
²³ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁵ Oregon Clinical & Translational Research Institute, Oregon Health & Science University, Portland, OR, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
²⁶ Environmental Genomics and Systems Biology Division, E. O. Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁷ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁸ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
²⁹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institure of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
³⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³¹ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³² Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK.
³³ Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
³⁴ Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia.
³⁵ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Center for Genetic Medicine Research, Children's National Medical Center, NW, Washington, DC, 20010-2970, USA.
³⁶ Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁷ The Manton Center for Orphan Disease Research, Divisions of Newborn Medicine and of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁸ Department of Computational Medicine & Bioinformatics, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA.
³⁹ Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴⁰ Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴¹ Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴² Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴³ Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁴ Department of Psychiatry, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴⁵ Nucleic Acid PCR Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
⁴⁶ Department of Surgery, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁷ Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Divisions of Pathology & Laboratory Medicine and Pulmonary Biology in the Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁴⁸ Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK; European Molecular Biology Laboratory - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK; Cavendish Laboratory, Theory of Condensed Matter, 19 JJ Thomson Ave, Cambridge CB3 1SA, UK.
⁴⁹ Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵⁰ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵¹ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵² Computational Health Informatics Program, Boston Children's Hospital, Departments of Biomedical Informatics and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁵³ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

PMID: 30930166
PMCID: PMC6616346
DOI: 10.1016/j.devcel.2019.03.001

Review

The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

Deanne M Taylor et al. Dev Cell. 2019.

. 2019 Apr 8;49(1):10-29.

doi: 10.1016/j.devcel.2019.03.001. Epub 2019 Mar 28.

Authors

Affiliations

¹ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: taylordm@email.chop.edu.
² Department of Biomedical Informatics, University of Cincinnati College of Medicine, and Cincinnati Children's Hospital Medical Center, Division of Biomedical Informatics, Cincinnati, OH 45229, USA. Electronic address: Bruce.Aronow@cchmc.org.
³ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: tank1@email.chop.edu.
⁴ Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Department of Biomedical Informatics, University of Cincinnati College of Medicine, and Cincinnati Children's Hospital Medical Center, Division of Biomedical Informatics, Cincinnati, OH 45229, USA.
⁶ Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Philadelphia, PA 19102, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, Kyiv 03143, Ukraine.
⁸ Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia and the Institute for Immunology, the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁹ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁰ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹¹ Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA; Center for Genetic Medicine Research, Children's National Medical Center, NW, Washington, DC, 20010-2970, USA.
¹² Cincinnati Children's Hospital Medical Center, Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati, OH 45229, USA.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁴ Multi-Organ Transplant Program, Toronto General Hospital Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁷ Division of Infectious Diseases, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁸ Division of Neurosurgery, Department of Surgery, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁹ Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁰ Department of Pediatrics, Section of Dermatology, The Children's Hospital of Philadelphia and University of Pennsylvania Perleman School of Medicine, Philadelphia, PA 19104, USA.
²¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²² Experimental and Clinical Research Center, A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
²³ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁵ Oregon Clinical & Translational Research Institute, Oregon Health & Science University, Portland, OR, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
²⁶ Environmental Genomics and Systems Biology Division, E. O. Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁷ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁸ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
²⁹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institure of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
³⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³¹ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³² Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK.
³³ Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
³⁴ Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia.
³⁵ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Center for Genetic Medicine Research, Children's National Medical Center, NW, Washington, DC, 20010-2970, USA.
³⁶ Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁷ The Manton Center for Orphan Disease Research, Divisions of Newborn Medicine and of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁸ Department of Computational Medicine & Bioinformatics, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA.
³⁹ Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴⁰ Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴¹ Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴² Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴³ Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁴ Department of Psychiatry, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴⁵ Nucleic Acid PCR Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
⁴⁶ Department of Surgery, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁷ Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Divisions of Pathology & Laboratory Medicine and Pulmonary Biology in the Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁴⁸ Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK; European Molecular Biology Laboratory - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, South Cambridgeshire CB10 1SA, UK; Cavendish Laboratory, Theory of Condensed Matter, 19 JJ Thomson Ave, Cambridge CB3 1SA, UK.
⁴⁹ Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵⁰ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, and the Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵¹ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵² Computational Health Informatics Program, Boston Children's Hospital, Departments of Biomedical Informatics and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁵³ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

PMID: 30930166
PMCID: PMC6616346
DOI: 10.1016/j.devcel.2019.03.001

Abstract

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

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Figures

**Figure 1.. Compiling a Pediatric Single-Cell Atlas.**
A pediatric single-cell atlas can consist of multi-omics data from hundreds to many thousands of cells isolated from multiple tissues from normally developing and disease-affected individuals. Single cells can be grouped into cell types that have unique molecular profiles representing primary programs for that cell type as well as sub-state-specific additional programming. The utility of a single-cell atlas is the possibility to map molecular signatures driving developmental, physiological, and pathological processes. Thus, single cell-based signatures can reveal the roles and responses of multiple cell lineages that dictate a given organ’s and/or tissue’s collective biology.

**Figure 2.. Potential Applications for a PCA.**
The PCA has the potential to map and illuminate the cellular basis of normal and abnormal development, cell- and organ-level differentiation, and compensatory and causal processes of disease. **(A)** Healthy children are frequently in a global state of growth activation compared to adults through the effects of growth factors, leading to profound impacts on gene expression and cell and tissue interactions, especially in the context of perturbations due to genetics, acquired somatic mutations, environment, infectious disease, and pharmacologics. **(B)** All of the outputs of a pediatric single-cell atlas are interrelated to provide a holistic outlook on how cells and tissues interact, differentiate, and function with each other in times of normal versus disease states

**Figure 3.. Example of Data Reuse When Datasets Are Analyzed from the Perspective of Building the PCA.**
Reanalysis of the Human Brain Single-Cell Survey Study (Darmanis et al., 2015; NIH GEO GSE84465) yields a series of gene expression modules that exhibit the greatest differential expression between cell classes, subclasses, and stages. The heatmap shows the top 200 differentially expressed genes per each cell type, subtype, and stage (log2(TPM+1)) and highlights the the major signatures of fetal and postnatal neurons while contrasting the lack of representation of mature differentiated neuron subtypes (cells on the right side of heatmap; signature modules on the lower half of heatmap) in fetal neurons (middle portion of the heatmap). Very few of the top stage-specific neuronal genes overlap (fetal neurons versus postnatal neurons) despite enrichment of similar functions with completely different genes comprising those categories. Moreover, there are also subtle, albeit fundamental, shifts in the biological functions of the developmental stage gene modules. An interactive view of this data can be seen at http://toppcell.cchmc.org/.

**Figure 4.. Enrichment Analysis of the Major Signature Overexpressed in Fetal Neurons versus Those from Postnatal and Adult Human Brain.**
Modular analysis of data shown in Figure 3 yields functional associations (rectangles) shared by the top 200 contrasting genes (hexagons) and their links to Gene Ontology, mouse gene knockout phenotype, or human OMIM gene-associated phenotype terms (phenotype-associated genes [yellow hexagons] which are connected by separately colored edges per phenotype group. This example highlights the necessity of profiling fetal and pediatric cells and genes, which have similar functions and processes compared to their adult counterparts but impact development, function, and physiology at different stages of development through different gene and regulatory programs. It also indicates that critical genetic associations can only be fully appreciated in the context of fetal stage neurons rather than their mature counterparts. Network analysis carried out using the “top 200 fetal quiescent neuron” gene-expression signature shown in Figure 3 as analyzed using the http://toppcluster.cchmc.org/ multiple-annotations biological network analysis functions to generate XGMML output that was then clustered in Cytoscape (Shannon et al., 2003).

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The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

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The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

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