Physical stimulation by REAC and BMP4/WNT-1 inhibitor synergistically enhance cardiogenic commitment in iPSCs

PLoS One. 2019 Jan 23;14(1):e0211188. doi: 10.1371/journal.pone.0211188. eCollection 2019.


It is currently known that pluripotent stem cells can be committed in vitro to the cardiac lineage by the modulation of specific signaling pathways, but it is also well known that, despite the significant increase in cardiomyocyte yield provided by the currently available conditioned media, the resulting cardiogenic commitment remains a highly variable process. Previous studies provided evidence that radio electric fields asymmetrically conveyed through the Radio Electric Asymmetric Conveyer (REAC) technology are able to commit R1 embryonic stem cells and human adipose derived stem cells toward a cardiac phenotype. The present study aimed at investigating whether the effect of physical stimulation by REAC in combination with specific chemical inductors enhance the cardiogenic potential in human induced pluripotent stem cells (iPSCs). The appearance of a cardiac-like phenotype in iPSCs cultured in the presence of a cardiogenic medium, based upon BMP4 and a WNT-inhibitor, was consistently increased by REAC treatment used only during the early fate differentiation for the first 72 hours. REAC-exposed iPSCs exhibited an upregulation in the expression of specific cardiogenic transcripts and morphologically in the number of beating clusters, as compared to cells cultured in the cardiogenic medium alone. Our results indicate that physical modulation of cellular dynamics provided by the REAC offers an affordable strategy to mimic iPSC cardiac-like fates in the presence of a cardiogenic milieu.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 4 / antagonists & inhibitors*
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Differentiation*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Radio Waves*
  • Wnt1 Protein / antagonists & inhibitors*
  • Wnt1 Protein / metabolism


  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • WNT1 protein, human
  • Wnt1 Protein

Grant support

M.M. received specific funding from Regione Autonoma della Sardegna (, Fundamental Research Program, L.R. 7/2007 “Promotion of the scientific research and technological innovation in Sardinia” under grant agreement CRP – 60208 and CRP - 59886 AMBROSIA Project, by Banco di Sardegna Foundation (Prot. U858.2014/AI.741.MGB Prat.2014.0178). M.W. and A.S. are employed by Evercyte GmbH, Vienna, but this commercial company only provided financial support in the form of research materials. S.R. and V.F. are partners in IRF Shanghai Medical Sciences, but this company only provided funds for research. All 3 of these funders did not play a role in the study design, data collection and analysis, preparation of the manuscript and decision to publish. The specific roles of M.W, A.S., S.R. and V.F. are articulated in the author contributions’ section.