Tyrosine Kinase Expressed in Hepatocellular Carcinoma, TEC, Controls Pluripotency and Early Cell Fate Decisions of Human Pluripotent Stem Cells via Regulation of Fibroblast Growth Factor‐2 Secretion

• Published in: Stem cells (Dayton, Ohio) Vol. 35; no. 9; pp. 2050 - 2059
• Main Authors: Vanova, Tereza, Konecna, Zaneta, Zbonakova, Zuzana, La Venuta, Giuseppe, Zoufalova, Karolina, Jelinkova, Sarka, Varecha, Miroslav, Rotrekl, Vladimir, Krejci, Pavel, Nickel, Walter, Dvorak, Petr, Kunova Bosakova, Michaela
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2017
• Subjects: Biomarkers - metabolism; Cardiac differentiation; Cell fate; Cell Line; Cell Lineage - drug effects; Cell Proliferation - drug effects; Cell self-renewal; Differentiation; Down-Regulation - drug effects; Embryonic stem cells; Embryos; Fibroblast growth factor; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - secretion; Fibroblasts; Growth factors; Heart diseases; Hepatocellular carcinoma; Humans; Liver cancer; Mesoderm; Neural differentiation; Pluripotency; Pluripotent stem cells; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - enzymology; Priming; Protein-tyrosine kinase; Protein-Tyrosine Kinases - metabolism; Receptors; Recombinant Proteins - pharmacology; Ribonucleic acid; RNA; Secretion; siRNA; Stem cells; Tyrosine; Tyrosine kinase expressed in hepatocellular carcinoma; Fibroblast growth factor 2; Fibroblast growth factor; Neural differentiation; Cardiac differentiation; Tyrosine kinase expressed in hepatocellular carcinoma; Embryonic stem cells; Pluripotent stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2660

Human pluripotent stem cells (hPSC) require signaling provided by fibroblast growth factor (FGF) receptors. This can be initiated by the recombinant FGF2 ligand supplied exogenously, but hPSC further support their niche by secretion of endogenous FGF2. In this study, we describe a role of tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase in this process. We show that TEC‐mediated FGF2 secretion is essential for hPSC self‐renewal, and its lack mediates specific differentiation. Following both short hairpin RNA‐ and small interfering RNA‐mediated TEC knockdown, hPSC secretes less FGF2. This impairs hPSC proliferation that can be rescued by increasing amounts of recombinant FGF2. TEC downregulation further leads to a lower expression of the pluripotency markers, an improved priming towards neuroectodermal lineage, and a failure to develop cardiac mesoderm. Our data thus demonstrate that TEC is yet another regulator of FGF2‐mediated hPSC pluripotency and differentiation. Stem Cells 2017;35:2050–2059 In human pluripotent stem cell (hPSC), tyrosine kinase expressed in hepatocellular carcinoma (TEC) phosphorylates fibroblast growth factor 2 to enable its secretion and autocrine signaling, which supports the undifferentiated state. During hPSC priming, TEC functions in the mesendodermal priming, while it needs to be downregulated to acquire the neuroectodermal fate.