Hox6 genes modulate in vitro differentiation of mESCs to insulin-producing cells

In Vitro Cell Dev Biol Anim. 2016 Oct;52(9):974-982. doi: 10.1007/s11626-016-0066-5. Epub 2016 Jul 21.


The differentiation of glucose-responsive, insulin-producing cells from ESCs in vitro is promising as a cellular therapy for the treatment of diabetes, a devastating and common disease. Pancreatic β-cells are derived from the endoderm in vivo and therefore most current protocols attempt to generate a pure population of first endoderm, then pancreas epithelium, and finally insulin-producing cells. Despite this, differentiation protocols result in mixed populations of cells that are often poorly defined, but also contain mesoderm. Using an in vitro mESC-to-β cell differentiation protocol, we show that expression of region-specific Hox genes is induced. We also show that the loss of function of the Hox6 paralogous group, genes expressed only in the mesenchyme of the pancreas (not epithelium), affect the differentiation of insulin-producing cells in vitro. This work is consistent with the important role for these mesoderm-specific factors in vivo and highlights contribution of supporting mesenchymal cells in in vitro differentiation.

Keywords: Endocrine cells; Hox genes; In vitro ESC differentiation; Insulin-producing cells; Pancreas development.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / pharmacology
  • Cell Culture Techniques
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Endoderm / cytology
  • Gene Expression Regulation / drug effects
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mesoderm / cytology
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism*
  • Mutation / genetics


  • Bone Morphogenetic Protein 4
  • Homeodomain Proteins
  • Hox6 protein, mouse
  • Insulin