MicroRNA-199b Modulates Vascular Cell Fate During iPS Cell Differentiation by Targeting the Notch Ligand Jagged1 and Enhancing VEGF Signaling

Stem Cells. 2015 May;33(5):1405-18. doi: 10.1002/stem.1930.


Aims: Recent ability to derive endothelial cells (ECs) from induced pluripotent stem (iPS) cells holds a great therapeutic potential for personalized medicine and stem cell therapy. We aimed that better understanding of the complex molecular signals that are evoked during iPS cell differentiation toward ECs may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration.

Methods and results: In this study, we have generated mouse iPS cells from fibroblasts using established protocol. When iPS cells were cultivated on type IV mouse collagen-coated dishes in differentiation medium, cell differentiation toward vascular lineages were observed. To study the molecular mechanisms of iPS cell differentiation, we found that miR-199b is involved in EC differentiation. A step-wise increase in expression of miR-199 was detected during EC differentiation. Notably, miR-199b targeted the Notch ligand JAG1, resulting in vascular endothelial growth factor (VEGF) transcriptional activation and secretion through the transcription factor STAT3. Upon shRNA-mediated knockdown of the Notch ligand JAG1, the regulatory effect of miR-199b was ablated and there was robust induction of STAT3 and VEGF during EC differentiation. Knockdown of JAG1 also inhibited miR-199b-mediated inhibition of iPS cell differentiation toward smooth muscle markers. Using the in vitro tube formation assay and implanted Matrigel plugs, in vivo, miR-199b also regulated VEGF expression and angiogenesis.

Conclusions: This study indicates a novel role for miR-199b as a regulator of the phenotypic switch during vascular cell differentiation derived from iPS cells by regulating critical signaling angiogenic responses. Stem Cells 2015;33:1405-1418.

Keywords: Angiogenesis; Endothelial cell differentiation; Induced pluripotent stem cells; Signal transduction; Tissue regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / cytology*
  • Calcium-Binding Proteins / metabolism*
  • Cell Differentiation*
  • Cell Lineage*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Ligands
  • Membrane Proteins / metabolism*
  • Mice
  • MicroRNAs / metabolism*
  • Neovascularization, Physiologic
  • Phenotype
  • Receptors, Notch / metabolism
  • STAT3 Transcription Factor / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Transcriptional Activation / genetics
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Ligands
  • Membrane Proteins
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • Receptors, Notch
  • STAT3 Transcription Factor
  • Serrate-Jagged Proteins
  • Vascular Endothelial Growth Factor A