Florian Malte Hermann - The Role of Epithelial Architecture in Human Pancreatic Endocrine Lineage Allocation

In vitro produced pancreatic β-cells are a potential source for cell replacement therapies, but in order to produce safe cells for therapeutic purposes the biology underlying β-cell specification should be addressed. The objective of this project is to determine the mechanisms underlying pancreatic endocrine lineage allocation with focus on the principal endocrine lineages involved in glucose homeostasis, the α- and β-cell lineages.

In the Semb group a paradigm for how extracellular cues control progression of β-cell differentiation via apical-basal polarity was established (manuscript in preparation), and we speculate that differences in the polarity of pancreatic endocrine progenitors determine the lineage allocation. To assess the hypothesis and mechanistically dissect the role of polarity in human α- and β-cell allocation, apical and endocrine progenitor marker genes (CRB3 and NGN3, respectively) are targeted with fluorescent proteins in human embryonic stem cells (hESCs). In live-cell imaging experiments using the reporter line it is determined whether α- and β-cells derive from non-polarized or polarized endocrine progenitors. Additional strategies are based on pharmacological modification of polarity or cell sorting in conjunction with reseeding.

If regulation of apical-basal polarization determines pancreatic endocrine lineage allocation, it would constitute a new concept for explaining the lineage decisions of organ-specific multipotent progenitors.