Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis

• Published in: Stem cells (Dayton, Ohio) Vol. 35; no. 4; pp. 952 - 966
• Main Authors: Cochrane, Amy, Kelaini, Sophia, Tsifaki, Marianna, Bojdo, James, Vilà‐González, Marta, Drehmer, Daiana, Caines, Rachel, Magee, Corey, Eleftheriadou, Magdalini, Hu, Yanhua, Grieve, David, Stitt, Alan W., Zeng, Lingfang, Xu, Qingbo, Margariti, Andriana
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.04.2017; John Wiley and Sons Inc
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; Angiogenesis; Animals; Antigens, CD; Autografts; Blood flow; Cadherins; Cardiovascular disease; Cardiovascular diseases; Cell Differentiation; Differentiation (biology); Disease Models, Animal; Endothelial cell differentiation; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Hindlimb - blood supply; Hindlimb - pathology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunofluorescence; Induced pluripotent stem cells; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Ischemia; Ischemia - pathology; Medical treatment; Mice, Inbred C57BL; Molecular modelling; Neovascularization, Physiologic; Nuclei; Pluripotency; Protein Binding; Proteins; Qk protein; QKI‐5; Recovery; Regenerative Medicine; Regional Blood Flow; Ribonucleic acid; RNA; RNA-binding protein; RNA-Binding Proteins - metabolism; Stabilization; Stat3 protein; STAT3 Transcription Factor - metabolism; Stem cell transplantation; Stem cells; Therapy; Transcription activation; Vascular disease; Vascular diseases; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptor 2; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascularization; Vascular disease; Angiogenesis; Endothelial cell differentiation; Induced pluripotent stem cells; QKI-5
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2594

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 The RNA binding protein QKI‐5 is induced during EC differentiation from iPS cells. 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).