Dimethyloxaloylglycine Increases the Bone Healing Capacity of Adipose-Derived Stem Cells by Promoting Osteogenic Differentiation and Angiogenic Potential

Abstract

Hypoxia inducible factor-1α (HIF-1α) plays an important role in angiogenesis-osteogenesis coupling during bone regeneration, which can enhance the bone healing capacity of mesenchymal stem cells (MSCs) by improving their osteogenic and angiogenic activities. Previous studies transduced the HIF-1α gene into MSCs with lentivirus vectors to improve their bone healing capacity. However, the risks due to lentivirus vectors, such as tumorigenesis, should be considered before clinical application. Dimethyloxaloylglycine (DMOG) is a cell-permeable prolyl-4-hydroxylase inhibitor, which can activate the expression of HIF-1α in cells at normal oxygen tension. Therefore, DMOG is expected to be an alternative strategy for enhancing HIF-1α expression in cells. In this study, we explored the osteogenic and angiogenic activities of adipose-derived stem cells (ASCs) treated with different concentrations of DMOG in vitro, and the bone healing capacity of DMOG-treated ASCs combined with hydrogels for treating critical-sized calvarial defects in rats. The results showed that DMOG had no obvious cytotoxic effects on ASCs and could inhibit the death of ASCs induced by serum deprivation. DMOG markedly increased vascular endothelial growth factor production in ASCs in a dose-dependent manner and improved the osteogenic differentiation potential of ASCs by activating the expression of HIF-1α. Rats with critical-sized calvarial defects treated with hydrogels containing DMOG-treated ASCs had more bone regeneration and new vessel formation than the other groups. Therefore, we believe that DMOG enhanced the angiogenic and osteogenic activity of ASCs by activating the expression of HIF-1α, thereby improving the bone healing capacity of ASCs in rat critical-sized calvarial defects.

Effects of hypoxia on proliferation of human cord blood-derived mesenchymal stem cells

“…In the present study, western blotting demonstrated that the expression levels of HIF-1a in hUCB-MSCs were upregulated in hypoxic cells compared with normoxic cells. Consistent with our date, Ding and colleagues have found that HIF-1a modulates stem cell proliferation under hypoxia (Ding et al 2014), while Co and colleagues did not observe significant difference in HIF-1a mRNA levels between 21 and 5 % chondrogenic culture of equine cord blood mesenchymal stromal cells in vitro (Co et al 2014).…”

Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis

“…The activation of HIF-1α in osteoblasts via the disruption of its degradation pathway produced robust bone modelling early in development7. Consistent with the “promoting osteogenesis by enhancing angiogenesis” theory, HIF-1α pathway activators (DMOG or DFO) or mesenchymal stem cells overexpressing HIF-1α have been shown to improve fracture and bone defect healing35363738394041. HIF-1α that binds to the aryl hydrocarbon receptor nuclear translocator (ARNT) is known as HIF-1β.…”

Role of the Hypoxia-Inducible Factor in Periodontal Inflammation

“…Exposure of PDL stem cells to hypoxia improved their osteogenic potential, mineralization and paracrine release, and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, and p38 MAPK signaling pathways were involved [97][98][99]. It was suggested that HIF, HIF mimicking agents, or HIF stabilizing agents were considered triggers for the initiation and promotion of angiogenic-osteogenic coupling [100,101]. A recent animal study reported new bone and vessels formation induced by the overexpression of HIF-1α via adenovirus, leading to enhanced alveolar bone defect regeneration [102].…”