»Our aim is to understand how progenitor cells of the pancreas read architectural cues to choose between expansion and differentiation. We use these principles to recapitulate the process in vitro from stem cells.«
More specifically, Professor Grapin-Botton and her group investigate the impact of the cellular and organ architecture on the cells’ fate choices and how single cells act in a community to generate an organ. To do so, they use mouse genetics, live imaging in 3D and they developed 3D in vitro “organoid” culture systems modelling development. More recently they used human in vitro stem cell models investigate human development. These studies are intended to gain insight into human syndromes impairing pancreas development and they guide the generation of replacement beta cells for Diabetes therapy.
3D culture models of pancreas development: we have developed systems to expand pancreas progenitors from a few cells or single cells in 3D in vitro (protocol). This leads to the formation of organoids similar to a pancreas in vitro. We use these in vitro models together with in silico modelling to understand how different cell types with a specific spatial arrangement are created from one cell or an initially homogeneous group of cells. We are adapting these systems to control the differentiation of beta cells from stem cells to build a model of human pancreas development and disease. Using genetic modifications of human stem cells we can test how perturbations of genes associated with Diabetes risk cause the disease.
Contributions of individual cells to organ community: During pancreas development progenitors proliferate, expanding the size of the organ while a subset of them differentiates to generate the endocrine cells that regulate glucose levels and acinar cells contributing to food digestion. Using clonal analysis, live imaging and single cell PCR and sequencing, we study how each cell makes such decisions, the role of stochastic processes and logic rules. By understanding the process we hope to control it and generate numerous beta cells for diabetes therapy.
Architectural cues controlling cell differentiation and proliferation: The differentiation of pancreatic cells occurs largely from polarized progenitors aligned in ducts. Using in vivo investigations in mice we are investigating whether this architectural environment and more specifically planar cell polarity controls the differentiation of pancreatic cell types. To do so, we are investigating in which cell types this pathway is active, how it is organized in space and the role of genes controlling the architecture in syndromes associating kidney cysts and diabetes. We recently found that pancreatic cells secrete pancreatic juice from very early during development which may create a flow controlling the organization of the ductal tree and possibly differentiation.
Larsen, Hjalte L., Laura Martín-Coll, Alexander V. Nielsen, Chris V.E. Wright, Ala Trusina, Yung Hae Kim* & Anne Grapin-Botton* (2017) Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis. Nat Commun., 8(1):605. doi: 10.1038/s41467-017-00258-4. * Co-corresponding
Petersen, Maja B.K., Ajuna Azad, Camilla Ingvorsen, Katia Hess, Matthias Hansson, Anne Grapin-Botton* & Christian Honoré* (2017) Single-Cell Gene Expression Analysis of a Human ESC Model of Pancreatic Endocrine Development Reveals Different Paths to β-Cell Differentiation. Stem Cell Reports. 9(4):1246-1261. doi: 10.1016/j.stemcr.2017.08.009. * Co-corresponding
Kim, Yung Hae, Hjalte List Larsen, Paul Rue, Laurence A. Lemaire, Jorge Ferrer & Anne Grapin-Botton (2015). Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas. PLoS Biology, 13(3), e1002111, doi:10.1371/journal.pbio.1002111.
Lemaire, Laurence A., Joan Goulley, Yung Hae Kim, Solenne Carat, Patrick Jacquemin, Jacques Rougemont, Daniel B. Constam & Anne Grapin-Botton (2015). Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. Development, 142(5), 858-870, doi: 10.1242/dev.114611.
Greggio, Chiara, Filippo De Franceschi, Manuel Figueiredo-Larsen, Samy Gobaa, Adrian Ranga, Henrik Semb, Matthias Lutolf & Anne Grapin-Botton (2013). Artificial three-dimensional niches deconstruct pancreas development in vitro. Development, 140(21), 4452-4462, doi:10.1242/dev.096628.
Cortijo, Cedric, Mathieu Gouzi, Fadel Tissir & Anne Grapin-Botton (2012). Planar Cell Polarity Controls Pancreatic Beta Cell Differentiation and Glucose Homeostasis. Cell Reports, 2(6), 1593-1606, doi:10.1016/j.celrep.2012.10.016.
Johansson, Kerstin A., Umut Dursun, Nathalie Jordan, Guoqiang Gu, Friedrich Beermann, Gérard Gradwohl & Anne Grapin-Botton (2007). Temporal Control of Neurogenin3 Activity in Pancreas Progenitors Reveals Competence Windows for the Generation of Different Endocrine Cell Types. Developmental Cell, 12(3), 457-465, doi: 10.1016/j.devcel.2007.02.010.