Chemically induced hypoxia by dimethyloxalylglycine (DMOG)-loaded nanoporous silica nanoparticles supports endothelial tube formation by sustained VEGF release from adipose tissue-derived stem cells.

ABSTRACT

Inadequate vascularization leading to insufficient oxygen and nutrient supply in deeper layers of bioartificial tissues remains a limitation in current tissue engineering approaches to which pre-vascularization offers a promising solution. Hypoxia triggering pre-vascularization by enhanced vascular endothelial growth factor (VEGF) expression can be induced chemically by dimethyloxalylglycine (DMOG). Nanoporous silica nanoparticles (NPSNPs, or mesoporous silica nanoparticles, MSNs) enable sustained delivery of molecules and potentially release DMOG allowing a durable capillarization of a construct. Here we evaluated the effects of soluble DMOG and DMOG-loaded NPSNPs on VEGF secretion of adipose tissue-derived stem cells (ASC) and on tube formation by human umbilical vein endothelial cells (HUVEC)-ASC co-cultures. Repeated doses of 100 µM and 500 µM soluble DMOG on ASC resulted in 3- to 7-fold increased VEGF levels on day 9 (P < 0.0001). Same doses of DMOG-NPSNPs enhanced VEGF secretion 7.7-fold (P < 0.0001) which could be maintained until day 12 with 500 µM DMOG-NPSNPs. In fibrin-based tube formation assays, 100 µM DMOG-NPSNPs had inhibitory effects whereas 50 µM significantly increased tube length, area and number of junctions transiently for 4 days. Thus, DMOG-NPSNPs supported endothelial tube formation by upregulated VEGF secretion from ASC and thus display a promising tool for pre-vascularization of tissue-engineered constructs. Further studies will evaluate their effect in hydrogels under perfusion.