Abstract

Pancreas organogenesis relies on the expansion of progenitors and their differentiation into acinar, ductal and endocrine cells. We have investigated the contribution of individual progenitors to organogenesis at different times of development using 3-dimensional live imaging, in vivo clonal analysis and single cell transcriptome. Analyses after one division established the role of symmetric renewing, symmetric differentiative and asymmetric divisions, and revealed stochasticity in endocrine fate commitment (Kim et al., PLOS Biology 2015). Analyses over several days addressed cumulative contributions and biases over multiple generations. These experiments revealed a great deal of heterogeneity in the size of clones and in the cell types single progenitors generate, some of which predictable from their transcriptional state and some reflecting stochastic fate commitment.

To investigate how single cells exchange information and form a community, we have set-up a method to grow dissociated pancreas progenitors in 3D. We have observed that small groups but not single cells expand, differentiate and self-organize in culture to form organoids of thousands of cells that reproduce many features of the pancreas (Greggio et al., Development 2013). We find that heterogeneity in Notch/delta signaling in progenitors is at least in part responsible for the community effect and drives progenitor expansion. The talk will focus on self-organization, especially when and how heterogeneity between cells appears.

Finally, we will expand on the development of systems to study human development at a single-cell resolution, based on pluripotent stem cells, human pancreas organoids and benchmarking to human embryos.