Canonical Wnt5b Signaling Directs Outlying Nkx2.5+ Mesoderm into Pacemaker Cardiomyocytes

Dev Cell. 2019 Sep 23;50(6):729-743.e5. doi: 10.1016/j.devcel.2019.07.014. Epub 2019 Aug 8.


Pacemaker cardiomyocytes that create the sinoatrial node are essential for the initiation and maintenance of proper heart rhythm. However, illuminating developmental cues that direct their differentiation has remained particularly challenging due to the unclear cellular origins of these specialized cardiomyocytes. By discovering the origins of pacemaker cardiomyocytes, we reveal an evolutionarily conserved Wnt signaling mechanism that coordinates gene regulatory changes directing mesoderm cell fate decisions, which lead to the differentiation of pacemaker cardiomyocytes. We show that in zebrafish, pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling to initiate the cardiac pacemaker program, including activation of pacemaker cell differentiation transcription factors Isl1 and Tbx18 and silencing of Nkx2.5. Moreover, applying these developmental findings to human pluripotent stem cells (hPSCs) notably results in the creation of hPSC-pacemaker cardiomyocytes, which successfully pace three-dimensional bioprinted hPSC-cardiomyocytes, thus providing potential strategies for biological cardiac pacemaker therapy.

Keywords: 3D bioprinting; Wnt5b; canonical Wnt signaling; differentiation; human pluripotent stem cells; pacemaker cardiomyocytes; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bioprinting
  • Cell Differentiation
  • Gene Expression Regulation, Developmental
  • Homeobox Protein Nkx-2.5 / metabolism*
  • Humans
  • Loss of Function Mutation / genetics
  • Mesoderm / metabolism*
  • Models, Cardiovascular
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Signal Transduction*
  • Stem Cells / metabolism
  • Wnt Proteins / metabolism*
  • Zebrafish


  • Homeobox Protein Nkx-2.5
  • Wnt Proteins