Abstract
Tissue engineering is a promising technology used as an alternative to organ/tissue transplantation which is often limited by donor shortage. The construction of large-sized engineered tissue requires a fast and sufficient vascularization process. Previous studies have shown that hypoxia-inducible factor (HIF) -1α may promote the vascularization process implying that stabilized HIF-1α can be applied in the engineering of large-sized tissue. However, the toxicity and off-target effect of previously reported HIF-1α stabilizers limit their clinical application. FG-4592, a small molecule specific HIF stabilizer, was previously investigated as an anti-anemia drug in a phase-III clinical trial. Here we found that FG-4592 promoted tube formation in an in vitro model of angiogenesis by stabilizing HIF-1α and activating vascular endothelial growth factor (VEGF). When FG-4592 immobilized fibrin gel scaffold was implanted into a subcutaneous tissue engineering chamber, the vascularization process was significantly enhanced through the similar mechanisms which was verified in vitro. We conclude that FG-4592 may serve as a pro-angiogenic molecule for the construction of large-sized engineered tissue where intensive angiogenesis is required.
Highlights
Tissue transplantation remains to be the preferred therapy for tissue defects, the shortage of donors is a major obstacle that limits its application
The primary Human umbilical vein endothelial cells (HUVECs) were purchased from Sciencell and cultured with Endothelial Cell medium (ECM) supplemented with 10% fetal bovine serum (FBS), 1% EC growth supplement (ECGS), 1% antibiotics (100IU penicillin and 0.1mg streptomycin per ml)
RAW264.7 were purchased from China Center for Type Culture Collection (CCTCC) and cultured with high glucose DMEM medium supplemented with 10% FBS, 1% antibiotics for cell expansion and replaced with low serum (1% FBS) medium in preparation for further analysis
Summary
Tissue transplantation remains to be the preferred therapy for tissue defects, the shortage of donors is a major obstacle that limits its application. It is important to develop strategies that facilitate the angiogenic process in tissue engineered structures. Previous studies reported hypoxic mimicking agents including divalent iron ions antagonists such as CoCl2 and deferoxamine (DFX) or competitive inhibitors of PHDs such as Dimethyloxallyl Glycine(DMOG)[15,16,17]. FG-4592, a novel small-molecule HIF-PHD inhibitor, was developed using structure-based drug design (SBDD) and high throughput screening (HTS) technologies. It is currently under phase III clinical trials for adult patients with renal anemia[18]. Considering its hypoxia-inducible factor stabilizing effect, we hypothesized that FG-4592 may promote the vascularization process and serve as a pro-angiogenic molecule in tissue engineering and other fields where angiogenesis is required
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