Search

Diabetic endotheliopathy is the main cause for impaired angiogenesis and reduced neovascularization that lead to microvascular injury and vascular complications. The pathogenic basis for vascular complications arising from diabetes is complex. Elucidation of key underlying mechanisms will help the development of novel therapies and the discovery of potential biomarkers. The ability to generate functional endothelial cells (ECs) from induced pluripotent stem cells (iPSCs) from small amounts of blood is a novel and powerful tool for cell-based therapies. Human iPSC-derived ECs (iPS-ECs) have a broad range of clinical applications including cell-based therapy, disease modelling and drug screening; they can be used in mechanistic studies towards the development of novel therapies and in the discovery of new biomarkers to be applied in regenerative medicine and treatment of diabetic vasculopathy. Here we utilize transcriptomic and proteomic technologies to assess patient-specific iPS-ECs from diabetic (DiPS-ECs) and non-diabetic (NiPS-ECS) donors 1,2,3,4 in order to investigate the mechanisms driving endotheliopathy in diabetes. Our in vitro and in vivo models recapitulate the effects of hyperglycaemia on the vasculature in the clinical setting. RNA-seq data showed that genes and proteins involved in angiogenesis and EC function were significantly downregulated in DiPS-ECs in comparison to NiPS-ECS (n=3, p Conflict of Interest None

Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications., Vascular endothelial cell (EC) dysfunction contributes to the occurrence of diabetic complications. Here the authors report that in diabetic conditions, upregulation of the RNA binding protein QKI-7 in ECs due to the imbalance of RNA splicing factors CUG-BP and hnRNPM contributes to EC dysfunction, and that in vivo QKI-7 silencing improves blood flow recovery in diabetic mice with limb ischemia.

Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.