title: Single-Cell Transcriptomics of the Human Endocrine Pancreas.
abstract: Human pancreatic islets consist of multiple endocrine cell types. To facilitate the detection of rare cellular states and uncover population heterogeneity, we performed single-cell RNA sequencing (RNA-seq) on islets from multiple deceased organ donors, including children, healthy adults, and individuals with type 1 or type 2 diabetes. We developed a robust computational biology framework for cell type annotation. Using this framework, we show that α- and β-cells from children exhibit less well-defined gene signatures than those in adults. Remarkably, α- and β-cells from donors with type 2 diabetes have expression profiles with features seen in children, indicating a partial dedifferentiation process. We also examined a naturally proliferating α-cell from a healthy adult, for which pathway analysis indicated activation of the cell cycle and repression of checkpoint control pathways. Importantly, this replicating α-cell exhibited activated Sonic hedgehog signaling, a pathway not previously known to contribute to human α-cell proliferation. Our study highlights the power of single-cell RNA-seq and provides a stepping stone for future explorations of cellular heterogeneity in pancreatic endocrine cells.
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Yue J
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel kaestner@mail.med.upenn.edu dana.tzfati@mail.huji.ac.il mgolson@mail.med.upenn.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Avrahami
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA kaestner@mail.med.upenn.edu dana.tzfati@mail.huji.ac.il mgolson@mail.med.upenn.edu.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Golson
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA kaestner@mail.med.upenn.edu dana.tzfati@mail.huji.ac.il mgolson@mail.med.upenn.edu.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D044085:Microfluidics / Q000379:methods; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D059467:Transcriptome / Q000235:genetics*