HIF-Prolyl Hydroxylase 2 Inhibition Enhances the Efficiency of Mesenchymal Stem Cell-Based Therapies for the Treatment of Critical Limb Ischemia. (3rd January 2014)

• Record Type: Journal Article
• Authors: HoWangYin, Kiave-Yune; Loinard, Céline; Bakker, Wineke; Guérin, Coralie L.; Vilar, José; D'Audigier, Clément; Mauge, Laetitia; Bruneval, Patrick; Emmerich, Joseph; Lévy, Bernard I.; Pouysségur, Jacques; Smadja, David M.; Silvestre, Jean-Sébastien
• Is Part Of: Stem cells. Volume 32:Number 1(2014:Jan.)
• Page Start: 231
• Page End: 243
• Publication Date: 2014-01-03
• Subjects: Ischemia -- Angiogenesis -- Hypoxia -- Mesenchymal stem cells -- Growth factor -- Transcription factor; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1540
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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. Stem Cells 2014;32:231–243