Human Pluripotent Stem Cell Differentiation into Functional Epicardial Progenitor Cells

Stem Cell Reports. 2017 Dec 12;9(6):1754-1764. doi: 10.1016/j.stemcr.2017.10.023. Epub 2017 Nov 22.


Human pluripotent stem cells (hPSCs) are widely used to study cardiovascular cell differentiation and function. Here, we induced differentiation of hPSCs (both embryonic and induced) to proepicardial/epicardial progenitor cells that cover the heart during development. Addition of retinoic acid (RA) and bone morphogenetic protein 4 (BMP4) promoted expression of the mesodermal marker PDGFRα, upregulated characteristic (pro)epicardial progenitor cell genes, and downregulated transcription of myocardial genes. We confirmed the (pro)epicardial-like properties of these cells using in vitro co-culture assays and in ovo grafting of hPSC-epicardial cells into chick embryos. Our data show that RA + BMP4-treated hPSCs differentiate into (pro)epicardial-like cells displaying functional properties (adhesion and spreading over the myocardium) of their in vivo counterpart. The results extend evidence that hPSCs are an excellent model to study (pro)epicardial differentiation into cardiovascular cells in human development and evaluate their potential for cardiac regeneration.

Keywords: cardiovascular; differentiation; human pluripotent stem cells; proepicardium; progenitor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / administration & dosage
  • Cardiovascular System / cytology
  • Cardiovascular System / growth & development
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Culture Techniques / methods
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Chick Embryo
  • Embryonic Development / genetics*
  • Gene Expression Regulation, Developmental / drug effects
  • Heart / drug effects
  • Heart / growth & development*
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Myocardium / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Pericardium / cytology
  • Pericardium / growth & development
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Stem Cells / cytology
  • Tretinoin / administration & dosage


  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Tretinoin
  • Receptor, Platelet-Derived Growth Factor alpha