Format

Send to

Choose Destination
Nat Commun. 2019 Oct 11;10(1):4647. doi: 10.1038/s41467-019-12624-5.

Sufu- and Spop-mediated downregulation of Hedgehog signaling promotes beta cell differentiation through organ-specific niche signals.

Author information

1
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
3
McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada.
4
Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
5
Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.
6
Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Canada.
7
McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada. cnostro@uhnresearch.ca.
8
Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. cnostro@uhnresearch.ca.
9
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada. tae-hee.kim@sickkids.ca.
10
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. tae-hee.kim@sickkids.ca.

Abstract

Human embryonic stem cell-derived beta cells offer a promising cell-based therapy for diabetes. However, efficient stem cell to beta cell differentiation has proven difficult, possibly due to the lack of cross-talk with the appropriate mesenchymal niche. To define organ-specific niche signals, we isolated pancreatic and gastrointestinal stromal cells, and analyzed their gene expression during development. Our genetic studies reveal the importance of tightly regulated Hedgehog signaling in the pancreatic mesenchyme: inactivation of mesenchymal signaling leads to annular pancreas, whereas stroma-specific activation of signaling via loss of Hedgehog regulators, Sufu and Spop, impairs pancreatic growth and beta cell genesis. Genetic rescue and transcriptome analyses show that these Sufu and Spop knockout defects occur through Gli2-mediated activation of gastrointestinal stromal signals such as Wnt ligands. Importantly, inhibition of Wnt signaling in organoid and human stem cell cultures significantly promotes insulin-producing cell generation, altogether revealing the requirement for organ-specific regulation of stromal niche signals.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center