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Upregulation of hypoxia‐inducible transcription factor‐1α (HIF‐1α), through prolyl‐hydroxylase domain protein (PHD) inhibition, can be thought of as a master switch that coordinates the expression of a wide repertoire of genes involved in regulating vascular growth and remodeling. We aimed to unravel the effect of specific PHD2 isoform silencing in cell‐based strategies designed to promote therapeutic revascularization in patients with critical limb ischemia (CLI). PHD2 mRNA levels were upregulated whereas that of HIF‐1α were downregulated in blood cells from patients with CLI. We therefore assessed the putative beneficial effects of PHD2 silencing on human bone marrow‐derived mesenchymal stem cells (hBM‐MSC)‐based therapy. PHD2 silencing enhanced hBM‐MSC therapeutic effect in an experimental model of CLI in Nude mice, through an upregulation of HIF‐1α and its target gene, VEGF‐A. In addition, PHD2‐transfected hBM‐MSC displayed higher protection against apoptosis in vitro and increased rate of survival in the ischemic tissue, as assessed by Fluorescence Molecular Tomography. Cotransfection with HIF‐1α or VEGF‐A short interfering RNAs fully abrogated the beneficial effect of PHD2 silencing on the proangiogenic capacity of hBM‐MSC. We finally investigated the effect of PHD2 inhibition on the revascularization potential of ischemic targeted tissues in the diabetic pathological context. Inhibition of PHD‐2 with shRNAs increased postischemic neovascularization in diabetic mice with CLI. This increase was associated with an upregulation of proangiogenic and proarteriogenic factors and was blunted by concomitant silencing of HIF‐1α. In conclusion, silencing of PHD2, by the transient upregulation of HIF‐1α and its target gene VEGF‐A, might improve the efficiency of hBM‐MSC‐based therapies. S tem  C ells   2014;32:231–243

HIF‐Prolyl Hydroxylase 2 Inhibition Enhances the Efficiency of Mesenchymal Stem Cell‐Based Therapies for the Treatment of Critical Limb Ischemia