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Will an Enhanced Endothelial Cell Differentiation Strategy Leave CVDs “Quaking” in their Boots?



Review of “Quaking is a Key Regulator of Endothelial Cell Differentiation, Neovascularization and Angiogenesis” from STEM CELLS by Stuart P. Atkinson

The progressive dysfunction of vascular endothelial cells correlates to the development of cardiovascular disease (CVD), a leading cause of mortality worldwide. Replacement endothelial cells generated via the differentiation of pluripotent stem cells may prove to be a useful tool given improvements to the conversion process and the production of cells with elevated endothelial functionality.  

Basic studies have established high expression of the RNA-binding protein Quaking isoform 5 (QKI-5) during endothelial cell-directed differentiation of induced pluripotent stem cells (iPSCs) and a role in the formation of blood vessels during development [1, 2]. Therefore, researchers from the laboratory of Andriana Margariti (Queen's University Belfast, UK) sought to discover if QKI-5 could contribute to an enhanced endothelial differentiation strategy and leave CVDs “Quaking” in their boots [3]!

To explore QKI-5 function, the authors overexpressed the RNA-binding protein in mouse iPSCs undergoing endothelial cell-directed differentiation (iPSC-ECs). Overexpression induced heightened levels of endothelial cell-associated gene expression (CD144, Vegfa, and Stat3) and further molecular analysis suggested that QKI-5 bound to and stabilized Stat3 RNA and this mediated Vegfr2 activation and Vegf secretion. 

QKI-5 overexpression also augmented angiogenic behavior in iPSC-ECs, as evidenced by heightened levels of vascular tube formation in vitro and vessel formation in vivo in Matrigel plugs. Excitingly, intramuscular injection of QKI-5 overexpressing iPSC-ECs after induction of hind limb ischemia in mice improved neovascularization and promoted significantly higher blood flow when compared to unmodified cells. Furthermore, QKI-5 expression during endothelial cell differentiation of human induced pluripotent stem cells (hiPSC-ECs) boosted in vivo angiogenesis in Matrigel plug assays only seven days after subcutaneous injection in mice.

While this enhanced endothelial cell differentiation strategy may leave CVDs “Quaking” in their boots, it also highlights that basic studies into the molecular mechanisms behind differentiation can lead to exciting advancements in stem cell-based regenerative strategies. 

Keep tuned to the Stem Cells Portal to learn more!


  1. Li Z, Takakura N, Oike Y, et al. Defective smooth muscle development in qkI-deficient mice. Dev Growth Differ 2003;45:449-462.
  2. Noveroske JK, Lai L, Gaussin V, et al. Quaking is essential for blood vessel development. Genesis 2002;32:218-230.
  3. Cochrane A, Kelaini S, Tsifaki M, et al. Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis. STEM CELLS 2017;35:952-966.