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Dev Cell. 2019 Jul 29. pii: S1534-5807(19)30586-6. doi: 10.1016/j.devcel.2019.07.014. [Epub ahead of print]

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

Author information

1
Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Biology, University of Mississippi, Oxford, MS 38677, USA.
4
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
5
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: nchi@ucsd.edu.

Abstract

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

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