We study how single cells self-organize as a community to generate an organ, using the pancreas as a model.
To do so, we developed 3D in vitro “organoid” culture systems modelling development, mouse genetics and live imaging in 3D. We recently developed in vitro models to also investigate this in human. 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.
The development of in vitro organoid models that recapitulate aspects of organogenesis in vitro
Using this models in a systems biology approach to understand self-organization, as well as how interactions between physical and biochemical cues control morphogenesis and differentiation
Using these models to understand how genes expressed during development predispose the fetus to subsequent development of diseases, notably diabetes.
Organoids and pluripotent stem cell models
Live imaging and quantitative analysis of imaged data
High-content image-based screens on organoids
Tan, T.H., Amiri, A., Seijo-Barandiarán, I., Staddon, M.F., Materne, A., Tomas, S., Duclut, C., Popović, M., Grapin-Botton, A. # and Jülicher, F. # (2022) Emergent chirality in active solid rotation of pancreas spheres bioRxiv 2022.09.29.510101; doi: https://doi.org/10.1101/2022.09.29.510101. # Shared last authorship
Beydag-Tasöz, B.S., Verner D’Costa, J., Hersemann, L., Lee, B.H., Luppino, F., Kim, Y.H., Zechner, C. and Grapin-Botton, A. (2023) Integration of transcriptional and imaging single-cell datasets links differentiation and morphogenetic dynamics of pancreatic endocrine progenitors. Developmental Cell, In Press.
Beydag-Tasöz, B.S., Yennek, S. and Grapin-Botton, A. (2023) Towards a better understanding of diabetes mellitus using organoid models. Nat. Rev. Endocrinol. doi: 10.1038/s41574-022-00797-x.
Katsumoto, K., Yennek, S., Chen, C., Delgadillo Silva, L.F., Traikov, S., Sever, D., Azad, A., Shan, J., Vainio, S., Ninov, N., Speier, S. and Grapin-Botton, A. (2022) Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function. Nature Communications 13(1), 6255. doi: 10.1038/s41467-022-33841-5.
Nakamura, A., Wong, Y.F., Venturato, A., Michaut, M., Venkateswaran, S., Santra, M., Gonçalves, C., Larsen, M., Leuschner, M., Kim, Y.H., Brickman, J., Bradley, M. and Grapin-Botton, A. (2022) A long-term feeder-free culture of human pancreatic progenitors on fibronectin or matrix-free polymer potentiates β-cell differentiation. Stem Cell Reports 17(5):1215-1228. doi: 10.1016/j.stemcr.2022.03.013.
Gonçalves, C.A., Larsen, M., Jung, S., Stratmann, J., Nakamura, A., Leuschner, M., Hersemann, L., Keshara,R., Perlman, S., Lundvall, L., Langhoff Thuesen, L., Juul Hare, K., Amit, I., Jørgensen, A., Kim, Y.H., del Sol, A., Grapin-Botton, A. (2021) A 3D system to model human pancreas development and its reference single cell transcriptome atlas reveal signaling pathways required for progenitor expansion. Nature Communications 12(1):3144. doi: 10.1038/s41467-021-23295-6.
Flasse, L., Yennek, S., Cortijo, C., Barandiaran, I.S., Kraus, M.R. and Grapin-Botton, A. (2020) Apical Restriction of the Planar Cell Polarity Component VANGL in Pancreatic Ducts Is Required to Maintain Epithelial Integrity. Cell Rep. 31(8):107677. doi: 10.1016/j.celrep.2020.107677.
Ramond, C., Beydag-Tasöz, B.S., Azad, A., van de Bunt, M., Petersen, M.B.K., Beer, N.L., Glaser, N., Berthault, C., Gloyn, A.L., Hansson, M., McCarthy, M., Honoré, C., Grapin-Botton, A.#, Scharfmann, R.#(2018) Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling. Development, 145(16). pii: dev165480. doi: 10.1242/dev.165480. # Shared last authorship
Dahl-Jensen, S.B., Yennek, S., Flasse, L., Larsen, H.L, Sever, D., Karremore, G., Novak, I., Sneppen, K. # and Grapin-Botton, A. # (2018) Deconstructing the principles of ductal network formation in the pancreas. PLoS Biol., 16(7):e2002842. doi: 10.1371/journal.pbio.2002842. # Shared last authorship
Larsen, H.L., Martín-Coll, L., Nielsen, A.V., Wright, C.V.E., Trusina, A., Kim, Y.H. #, Grapin-Botton, A. # (2017) Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis. Nat Commun. 8:605. doi: 10.1038/s41467-017-00258-4. # Shared last authorship
Greggio, C., De Franceschi, F., Figueiredo-Larsen, M., Gobaa, S., Ranga, A., Semb, H., Lutolf, M. and Grapin-Botton, A. (2013) Artificial three-dimensional niches deconstruct pancreas development in vitro. Development, 140:4452-62. doi: 10.1242/dev.096628.
We study how our organs form during pregnancy. Organs are formed by the interactions of diverse cells, in the same spirit as individual humans interacting to build a society. We study how individual cells organize as a community to generate an organ, especially focusing on the developing pancreas.
To do so, we use the mouse as a model, since it is difficult to know how the pancreas forms in human. We also developed models where we can control cell assemblies in 3D in a dish. The cells form so called organoids, and we can make mouse organoids using mouse cells and human organoids with human cells. These organoids mimic the developing pancreas, and we can use them to “watch” development and understand how the development process is perturbed in disease conditions. Notably, these studies give us insight into human syndromes disrupting pancreas development and help us understand how impaired development can predispose to diabetes later in life. Further, they guide the generation of replacement beta-cells for diabetes therapy.