Role of BMP signaling in pancreatic progenitor differentiation from human embryonic stem cells

Stem Cell Rev Rep. 2013 Oct;9(5):569-77. doi: 10.1007/s12015-013-9435-6.


Transplantation of pancreatic progenitors derived from human embryonic stem cells (hESCs) is a promising way to treat diabetes. Strategies to obtain the required cell mass would rely on the up scaling of current differentiation protocols, or the proliferation of committed progenitors. We aimed at finding conditions that maintain a proliferating pancreatic progenitor pool and we assessed the role of BMP4 signaling in this process. hESCs were differentiated into PDX1 positive pancreatic progenitor stage following our established protocol with few modifications, and then the progenitor cells were passaged in a defined proliferation medium (PM). During passage, the effect of BMP4 signaling on the differentiation and proliferation of pancreatic progenitors was examined by RT-PCR and immunofluorescence analysis. We found that PDX1 positive pancreatic progenitors proliferated and gained NKX6.1 expression in the PM, whereas they failed to express NKX6.1 if BMP signaling was inhibited with Noggin. In this latter condition, part of the progenitors rather generated pro-endocrine cells denoted by NGN3 and synaptophysin expression. On the contrary, addition of BMP4 to the PM promoted the early derivation of PDX1 and NKX6.1 coexpressing pancreatic progenitors. Our findings are in line with mouse pancreas development, and indicate that BMP4 signaling is required for the derivation and maintenance of hESC-derived PDX1+NKX6.1+ pancreatic progenitors. These results are instructive for guiding the development of an efficient pancreas differentiation protocol in view of diabetes cell replacement therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Culture Media / pharmacology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pancreas / cytology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Stem Cell Transplantation / methods
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Synaptophysin / genetics
  • Synaptophysin / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transplantation, Heterologous


  • BMP4 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Protein 4
  • Culture Media
  • Homeodomain Proteins
  • NEUROG3 protein, human
  • NKX6-1 protein, human
  • Nerve Tissue Proteins
  • Synaptophysin
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein