title: Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis.
abstract: 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.
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Cochrane
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Sophia
authors.initials: S
authors.lastname: Kelaini
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Marianna
authors.initials: M
authors.lastname: Tsifaki
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Bojdo
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Vilà-González
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Daiana
authors.initials: D
authors.lastname: Drehmer
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Caines
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Corey
authors.initials: C
authors.lastname: Magee
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Magdalini
authors.initials: M
authors.lastname: Eleftheriadou
authors.affiliation: Cardiovascular Division, King's College London, London, United Kingdom.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Grieve
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
authors.affiliation: Cardiovascular Division, King's College London, London, United Kingdom.
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Cardiovascular Division, King's College London, London, United Kingdom.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.affiliation: The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
authors.forename: Andriana
authors.identifier: 0000-0001-9303-8371
authors.initials: A
authors.lastname: Margariti
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins; D002454:Cell Differentiation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007511:Ischemia / Q000473:pathology; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012039:Regional Blood Flow; D050796:STAT3 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D015820:Cadherins; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C098217:Qk protein, mouse; C000620563:RNA-binding protein QKI-5, human
keywords: Angiogenesis; Endothelial cell differentiation; Induced pluripotent stem cells; QKI-5; Vascular disease