Mechanosignalling via integrins directs fate decisions of pancreatic progenitors

Anant Mamidi, Christy Prawiro, Philip A. Seymour, Kristian Honnens Lichtenberg, Abigail Jackson, Palle Serup and Henrik Semb ()
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Anant Mamidi: University of Copenhagen
Christy Prawiro: University of Copenhagen
Philip A. Seymour: University of Copenhagen
Kristian Honnens Lichtenberg: University of Copenhagen
Abigail Jackson: University of Copenhagen
Palle Serup: University of Copenhagen
Henrik Semb: University of Copenhagen

Nature, 2018, vol. 564, issue 7734, 114-118

Abstract: Abstract The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells1. Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions1,2. Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin α5 as the extracellular cue that cell-autonomously, via the F-actin–YAP1–Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM–integrin α5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas.

Keywords: Pancreatic Progenitor; Endocrine Lineages; Ngn3 Promoter; YAP Activity; Dolichos Biflorus Agglutinin (DBA) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (6)

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DOI: 10.1038/s41586-018-0762-2

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