title: Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas.
abstract: Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self-renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle-dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of β-cells in vitro.
authors.affiliation: DanStem, University of Copenhagen, Copenhagen, Denmark; Ecole Polytechnique Fédérale de Lausanne, Life Sciences, Institute of Bioengineering, Lausanne, Switzerland.
authors.forename: Yung Hae
authors.initials: YH
authors.lastname: Kim
authors.affiliation: DanStem, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hjalte List
authors.initials: HL
authors.lastname: Larsen
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Pau
authors.initials: P
authors.lastname: Rué
authors.affiliation: DanStem, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Lemaire
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom; Institut d'Investigacions August Pi i Sunyer, CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: DanStem, University of Copenhagen, Copenhagen, Denmark; Ecole Polytechnique Fédérale de Lausanne, Life Sciences, Institute of Bioengineering, Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D058948:Cell Tracking; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D055758:SOX9 Transcription Factor; D015534:Trans-Activators; D000097573:Red Fluorescent Protein; C407737:Neurog3 protein, mouse; C527933:Sox9 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein