The capability to derive endothelial cell (ECs) from induced pluripotent stem cells (iPSCs) holds huge therapeutic potential for
cardiovascular disease. This study elucidates the precise role of the
RNA-binding protein Quaking
isoform 5 (QKI-5) during EC differentiation from both mouse and human iPSCs (hiPSCs) and dissects how
RNA-binding proteins can improve differentiation efficiency toward
cell therapy for important
vascular diseases. iPSCs represent an attractive cellular approach for regenerative medicine today as they can be used to generate patient-specific therapeutic cells toward autologous
cell therapy. In this study, using the model of iPSCs differentiation toward ECs, the QKI-5 was found to be an important regulator of STAT3 stabilization and
vascular endothelial growth factor receptor 2 (VEGFR2) activation during the EC differentiation process. QKI-5 was induced during EC differentiation, resulting in stabilization of STAT3 expression and modulation of VEGFR2 transcriptional activation as well as
VEGF secretion through direct binding to the
3' UTR of STAT3. Importantly, mouse iPS-ECs overexpressing QKI-5 significantly improved angiogenesis and neovascularization and blood flow recovery in experimental hind limb
ischemia. Notably, hiPSCs overexpressing QKI-5, induced angiogenesis on
Matrigel plug assays in vivo only 7 days after
subcutaneous injection in SCID mice. These results highlight a clear functional benefit of QKI-5 in neovascularization, blood flow recovery, and angiogenesis. Thus, they provide support to the growing consensus that elucidation of the molecular mechanisms underlying EC differentiation will ultimately advance stem cell regenerative
therapy and eventually make the treatment of
cardiovascular disease a reality. The
RNA binding protein QKI-5 is induced during EC differentiation from iPSCs.
RNA binding protein QKI-5 was induced during EC differentiation in parallel with the EC marker CD144. Immunofluorescence staining showing that QKI-5 is localized in the nucleus and stained in parallel with CD144 in differentiated ECs (scale bar = 50 µm). Stem Cells 2017 Stem Cells 2017;35:952-966.