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Angiogenesis by transplantation of HIF‐1α modified EPCs into ischemic limbs
Author(s) -
Jiang Meng,
Wang Binyao,
Wang Changqian,
He Ben,
Fan Huahua,
Guo Taylor B.,
Shao Qin,
Gao Li,
Liu Yan
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21416
Subject(s) - progenitor cell , angiogenesis , endothelial progenitor cell , transplantation , cd31 , hypoxia (environmental) , transfection , therapeutic angiogenesis , vascular endothelial growth factor , hypoxia inducible factors , biology , peripheral blood mononuclear cell , microbiology and biotechnology , immunology , stem cell , cancer research , chemistry , neovascularization , medicine , cell culture , in vitro , vegf receptors , gene , biochemistry , genetics , organic chemistry , oxygen
Hypoxia inducible factor‐1α (HIF‐1α) is a key determinant of oxygen‐dependent gene regulation in angiogenesis. HIF‐1α overexpression may be beneficial in cell therapy of hypoxia‐induced pathophysiological processes, such as ischemic heart disease. To address this issue, human peripheral blood mononuclear cells (PBMNCs) were induced to differentiate into endothelial progenitor cells (EPCs), and then were transfected with either an HIF‐1α‐expressing or a control vector and cultured under normoxia or hypoxia. Hypoxia‐induced HIF‐1α mRNA and protein expression was increased after HIF‐1α transfection. This was accompanied by VEGF mRNA induction and increased VEGF secretion. Hypoxia‐stimulated VEGF mRNA induction was significantly abrogated by HIF‐1α‐specific siRNA. Functional studies showed that HIF‐1α overexpression further promoted hypoxia‐induced EPC differentiation, proliferation and migration. The expressions of endothelial cell markers CD31, VEGFR2 (Flk‐1) and eNOS as well as VEGF and NO secretions were also increased. Furthermore, in an in vivo model of hindlimb ischemia, HIF‐1α‐transfected EPCs homed to the site of ischemia. A higher revascularization potential was also demonstrated by increased capillary density at the injury site. Our results revealed that endothelial progenitor cells ex vivo modification by hypoxia inducible factor‐1α gene transfection is feasible and may offer significant advantages in terms of EPC expansion and treatment efficacy. J. Cell. Biochem. 103: 321–334, 2008. © 2007 Wiley‐Liss, Inc.