Hypoxic Preconditioning Enhances Cellular Viability and Pro-angiogenic Paracrine Activity: The Roles of VEGF-A and SDF-1a in Rat Adipose Stem Cells

Abstract

To achieve the full therapeutic potential of implanted adipose stem cells (ASCs) in vivo, it is crucial to improve the viability and pro-angiogenic properties of the stem cells. Here, we first simulated the conditions of ischemia and hypoxia using the in vitro oxygen-glucose deprivation (OGD) model and confirmed that hypoxic preconditioning of ASCs could provide improved protection against OGD and enhance ASC viability. Second, we assessed the effect of hypoxic preconditioning on pro-angiogenic potential of ASCs, with a particular focus on the role of vascular endothelial growth factor-A (VEGF-A) and stromal derived factor-1a (SDF-1a) paracrine activity in mediating angiogenesis. We found that the conditioned medium of ASCs (ASCCM) with hypoxic preconditioning enhanced angiogenesis by a series of angiogenesis assay models in vivo and in vitro through the upregulation of and a synergistic effect between VEGF-A and SDF-1a. Finally, to investigate the possible downstream mechanisms of VEGF/VEGFR2 and SDF-1a/CXCR4 axes-driven angiogenesis, we evaluated relevant protein kinases involved the signal transduction pathway of angiogenesis and showed that VEGF/VEGFR2 and SDF-1a/CXCR4 axes may synergistically promote angiogenesis by activating Akt. Collectively, our findings demonstrate that hypoxic preconditioning may constitute a promising strategy to enhance cellular viability and angiogenesis of transplanted ASCs, therein improving the success rate of stem cell-based therapies in tissue engineering.

Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair

“…Several studies indicate that serum-free media may benefit mesenchymal stem cells proliferation, differentiation, and paracrine activity while maintaining their stemness, immunosuppressive and antifibrotic abilities [40][41][42]. In general, secretomes collected under serum-free conditions are much more appropriate for clinical use because of reduced contamination and safety concerns related to xenogeneic infectious agents [43][44][45].…”

Multifunctional porous poly (L-lactic acid) nanofiber membranes with enhanced anti-inflammation, angiogenesis and antibacterial properties for diabetic wound healing

“…It remains a challenge to induce vascularization in engineered tissues by delivering just one growth factor (e.g., VEGF or PDGF-BB). As a key upstream transcription factor, HIF-1α plays important roles in bone tissue engineering via VEGF [ 38 , 39 ] and stromal cell-derived factor 1 (SDF-1) generation to upregulate the VEGF-induced vascularization and SDF-1 induced progenitor cells recruitment [ 40 , 41 ]. HIF-1α and VEGF gene expression levels in Raw 264.7 cells were significantly increased after 24 h of SCS treatment (Fig.…”

Application of adipose-derived stem cells in ischemic heart disease: theory, potency, and advantage

“…In vitro studies have shown that ASCs generate high concentration of VEGF into the supernatant, especially when cocultured with human umbilical vein endothelial cells or endothelial progenitor cells (14,37). Furthermore, under the hypoxic conditions which imitated the in vivo environment of IHD, ASCs secreted higher amounts of VEGF, HGF, and stromal-derived factor-1 (SDF-1) compared to normoxic conditions (38)(39)(40). The lesion-associated hypoxia, which curbed the survival of engrafted stem cells, would inevitably lead to the activation of hypoxia-inducible factor 1, resulting in increased VEGF release, its classical target gene (41).…”