Constitutive Expression of HIF‐1α and HIF‐2α in Bone Marrow Stromal Cells Differentially Promotes Their Proangiogenic Properties

• Published in: Stem cells (Dayton, Ohio) Vol. 26; no. 10; pp. 2634 - 2643
• Main Authors: Ben‐Shoshan, Jeremy, Schwartz, Shulamit, Luboshits, Galia, Maysel‐Auslender, Sofia, Barzelay, Aya, Polak‐Charcon, Sylvie, Tzahor, Eldad, Barshack, Iris, Barak, Adiel, Levkovitch‐Verbin, Hani, Keren, Gad, George, Jacob
• Format: Journal Article
• Language: English
• Published: Bristol John Wiley & Sons, Ltd 01-10-2008
• Subjects: Angiogenesis; Bone marrow stromal cells; Cell therapy; Hypoxia‐inducible factor; Paracrine effects
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1634/stemcells.2008-0369

Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in postnatal angiogenesis. Hypoxia‐inducible factors (HIFs) mediate endothelial activation by driving the expression of multiple angiogenic factors. We explored the potential of HIF‐1α and HIF‐2α modification in BMSCs, as a tool to improve cell‐based angiogenic therapy. BMSCs were retrovirally transduced to express stable forms of HIF‐1α and HIF‐2α. HIF‐1α and, to a greater extent, HIF‐2α overexpression promoted differentiation of BMSCs to the endothelial lineage, evident by CD31 and Tie‐2 expression and improved adhesive properties. Whereas chemotaxis toward stromal‐derived factor 1 was higher in both HIF‐α‐expressing BMSCs, enhanced migration toward vascular endothelial growth factor was found only following overexpression of HIF‐2α, supported by a robust expression of its receptor, Flk‐1. HIF‐α expression was associated with upregulation of angiogenic proteins and improved tube formation. Cytokine arrays of endothelial cells stimulated by medium collected from HIF‐α‐expressing BMSCs revealed further angiogenic activation and improved adhesive capacity. Eventually, delivery of HIF‐2α‐transduced BMSCs induced a more robust angiogenic response, compared with sham‐transduced or HIF‐1α‐transduced BMSCs in the corneal micropocket angiogenesis model. Our results support the use of HIF‐α genes, particularly HIF‐2α, to augment the efficacy of future cell‐based therapy.
Disclosure of potential conflicts of interest is found at the end of this article.