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.

Stereo Coverage and Overall Stiffness of Biomaterial Arrays Underly Parts of Topography Effects on Cell Adhesion

“…We employed the mold casting method to fabricate the patterned surfaces, as schematically presented in Figure S2, and the topography was controlled with varied array parameters, in particular, heights and diameters. Here, we choose PLLA as the raw material because PLLA as well as its copolymer such as poly­(lactide- co -glycolide) (PLGA) is a kind of polymeric biomaterials widely used in biodegradable implants, − and we choose human umbilical vein endothelial cells (HUVECs) as the model cell type because this is an important cell type widely used in biomaterial studies, in particular for cardiovascular systems. − Roughness, plateau coverage, stereo coverage, and overall stiffness were calculated and correlated to adhesion behaviors of cells on different micropatterns. It is verified that these important parameters can semi-quantify the effects of surface topography on cell adhesion.…”

Effect of Dimethyloxalylglycine on Stem Cells Osteogenic Differentiation and Bone Tissue Regeneration—A Systematic Review

“…Apart from BMSCs, ADSCs have also been investigated for bone tissue regeneration. ADSCs from rats were utilized in three studies [42,66,67], human-derived ADSCs in two studies [48,69], and ADSCs from dogs [46] and rabbits [53] in one study each. Other studies explored the use of human PDLSCs [68] and porcine synovial-derived mesenchymal stem cells (SYN-MSCs) [78].…”

“…Other studies explored the use of human PDLSCs [68] and porcine synovial-derived mesenchymal stem cells (SYN-MSCs) [78]. The most common method for cells extraction is tissue block enzyme digestion [31,[42][43][44][46][47][48]53,66,68,69,75]. Flow cytometry (FCM) analysis was used in some studies to confirm the identity of MSCs, three-line differentiation was used to assess their ability to differentiate into osteogenic, adipogenic, and chondrogenic lineages.…”

Sequential Anti-Infection and Proangiogenesis of DMOG@ZIF-8/Gelatin-PCL Electrospinning Dressing for Chronic Wound Healing

“…Successive hydroxylation and degradation of hypoxia-inducible factor-1α (HIF-1α) by prolyl hydroxylases (PHDs) are essential to inadequate angiogenesis and delayed healing of chronic wounds. Biomolecules, particularly vascular endothelial growth factor (VEGF), are often used to stimulate the growth of new blood vessels . Nonetheless, the application of growth factors still faces several challenges, such as high dosage, short half-life, poor stability, and side effects.…”

“…Biomolecules, particularly vascular endothelial growth factor (VEGF), are often used to stimulate the growth of new blood vessels. 7 Nonetheless, the application of growth factors still faces several challenges, 8 such as high dosage, short half-life, poor stability, and side effects. Dimethyloxalylglycine (DMOG) is a small-molecule drug that promotes angiogenesis and protects HIF-1α from degradation by PHDs during the wound-healing process.…”