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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Culture Techniques
  • Cell Differentiation
  • Cell- and Tissue-Based Therapy / methods
  • Diabetes Mellitus / therapy
  • Down-Regulation
  • Embryonic Stem Cells / cytology*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / transplantation
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Organoids / cytology
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Wnt Proteins / metabolism

Substances

  • Hedgehog Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human
  • SUFU protein, human
  • Wnt Proteins

Grant support