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

Theodora Yung, Frankie Poon, Minggao Liang, Sabrina Coquenlorge, Emily C. McGaugh, Chi-chung Hui, Michael D. Wilson, M. Cristina Nostro () and Tae-Hee Kim ()
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Theodora Yung: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children
Frankie Poon: University Health Network
Minggao Liang: University of Toronto
Sabrina Coquenlorge: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children
Emily C. McGaugh: University Health Network
Chi-chung Hui: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children
Michael D. Wilson: University of Toronto
M. Cristina Nostro: University Health Network
Tae-Hee Kim: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12624-5

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