Probing cellular heterogeneity in the pancreatic microenvironment

The overarching goal of this proposal is to elucidate the functional diversity of the pancreatic mesenchymal lineage. In embryonic tissues, epithelial progenitors receive paracrine signals from the surrounding mesenchymal niche, which can modulate their ability to proliferate and differentiate. The pancreas consists of a variety of specialized epithelial cells, including endocrine and acinar cells, surrounded by a poorly defined heterogeneous mesenchyme. We hypothesise that different mesenchymal lineages define local instructive microenvironments, including cell–cell crosstalk, ECM and signalling molecules, which eventually trigger distinct differentiation programmes from pancreatic progenitors. Sc-RNA-sequencing has generated a transcriptional map of the pancreatic mesenchyme in the mouse embryo. Here, we will unravel the spatial architecture of the identified mesenchymal cell states, linking their position to emerging pancreatic cell identities. Next, we will assess if mesenchymal lineages with a distinct spatial address underlie unique niche regulatory functions, promoting acinar or β-cell differentiation. Finally, we will study the organisation and function of the identified niche microenvironment(s) in human tissue and pluripotent stem cells. The proposed programme will yield novel insight into pancreas biology and will set the stage for manipulating combinatorial pancreatic niches - an important step towards engineering functional β-cells for regenerative medicine applications.