ErbB Receptor Tyrosine Kinase: A Molecular Switch Between Cardiac and Neuroectoderm Specification in Human Pluripotent Stem Cells.
Mechanisms determining intrinsic differentiation bias inherent to human pluripotent stem cells (hPSCs) toward cardiogenic fate remain elusive. We evaluated the interplay between ErbB4 and Epidemal growth factor receptor (EGFR or ErbB1) in determining cardiac differentiation in vitro as these receptor tyrosine kinases are key to heart and brain development in vivo. Our results demonstrate that during cardiac differentiation, cell fate biases exist in hPSCs due to cardiac/neuroectoderm divergence post cardiac mesoderm stage. Stage-specific up-regulation of EGFR in concert with persistent Wnt3a signaling post cardiac mesoderm favors commitment toward neural progenitor cells (NPCs). Inhibition of EGFR abrogates these effects with enhanced (>twofold) cardiac differentiation efficiencies by increasing proliferation of Nkx2-5 expressing cardiac progenitors while reducing proliferation of Sox2 expressing NPCs. Forced overexpression of ErbB4 rescued cardiac commitment by augmenting Wnt11 signaling. Convergence between EGFR/ErbB4 and canonical/noncanonical Wnt signaling determines cardiogenic fate in hPSCs. Stem Cells 2016;34:2461-2470.
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
Chrishan J A
CJ
Ramachandra
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore. ashish.mehta@nhcs.com.sg.|Cardiovascular Academic Clinical Program. ashish.mehta@nhcs.com.sg.
Ashish
A
Mehta
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
Chong Hui
CH
Lua
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
Anuja
A
Chitre
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
K P Myu Mai
KP
Ja
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore. winston.shim.s.n@nhcs.com.sg.|Cardiovascular and Metabolic Disorders Program, DUKE-NUS Graduate Medical School, Singapore. winston.shim.s.n@nhcs.com.sg.
Winston
W
Shim
D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004475:Ectoderm / Q000166:cytology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D038081:Organogenesis; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D060449:Wnt Signaling Pathway
C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4
Cardiac differentiation bias; Cardiomyocytes; ErbB receptor tyrosine kinases; Fate switch; Human pluripotent stem cells; Wnt signaling