A Specialized Niche in the Pancreatic Microenvironment Promotes Endocrine Differentiation

Corinna Cozzitorto, Laura Mueller, Silvia Ruzittu, Nancy Mah, David Willnow, Jean Francois Darrigrand, Heather Wilson, Daniel Khosravinia, Amir Ala Mahmoud, Maurizio Risolino, Licia Selleri, Francesca M. Spagnoli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)
93 Downloads (Pure)

Abstract

The interplay between pancreatic epithelium and the surrounding microenvironment is pivotal for pancreas formation and differentiation as well as adult organ homeostasis. The mesenchyme is the main component of the embryonic pancreatic microenvironment, yet its cellular identity is broadly defined, and whether it comprises functionally distinct cell subsets is not known. Using genetic lineage tracing, transcriptome, and functional studies, we identified mesenchymal populations with different roles during pancreatic development. Moreover, we showed that Pbx transcription factors act within the mouse pancreatic mesenchyme to define a pro-endocrine specialized niche. Pbx directs differentiation of endocrine progenitors into insulin- and glucagon-positive cells through non-cell-autonomous regulation of ECM-integrin interactions and soluble molecules. Next, we measured functional conservation between mouse and human pancreatic mesenchyme by testing identified mesenchymal factors in an iPSC-based differentiation model. Our findings provide insights into how lineage-specific crosstalk between epithelium and neighboring mesenchymal cells underpin the generation of different pancreatic cell types.

Original languageEnglish
Pages (from-to)150-162.e6
JournalDevelopmental Cell
Volume55
Issue number2
Early online date27 Aug 2020
DOIs
Publication statusPublished - 26 Oct 2020

Keywords

  • ECM-Integrin
  • endocrine differentiation
  • iPSC
  • lineage tracing
  • pancreas
  • pancreatic mesenchyme
  • PBX
  • SLIT

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