Adipose-derived mesenchymal stem cells promote the survival of fat grafts via crosstalk between the Nrf2 and TLR4 pathways

Abstract

Autologous fat grafting is an effective reconstructive surgery technique; however, its success is limited by inconsistent graft retention and an environment characterized by high oxidative stress and inflammation. Adipose-derived stem cells (ADSCs) increase the survival of fat grafts, although the underlying mechanisms remain unclear. Here, TLR4−/− and Nrf2−/− mice were used to explore the effects of oxidative stress and inflammation on the viability and function of ADSCs in vitro and in vivo. Enrichment of fat grafts with ADSCs inhibited inflammatory cytokine production, enhanced growth factor levels, increased fat graft survival, downregulated NADPH oxidase (NOX)1 and 4 expression, increased vascularization and reduced ROS production in a manner dependent on toll-like receptor (TLR)-4 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Immunohistochemical analysis showed that exposure to hypoxia enhanced ADSC growth and promoted the differentiation of ADSCs into vascular endothelial cells. Hypoxia-induced inflammatory cytokine, growth factor and NOX1/4 upregulation, as well as increased ROS production and apoptosis in ADSCs were dependent on TLR4 and Nrf2, which also modulated the effect of ADSCs on promoting endothelial progenitor cell migration and angiogenesis. Western blot analyses showed that the effects of hypoxia on ADSCs were regulated by crosstalk between Nrf2 antioxidant responses and NF-κB- and TLR4-mediated inflammatory responses. Taken together, our results indicate that ADSCs can increase the survival of fat transplants through the modulation of inflammatory and oxidative responses via Nrf2 and TLR4, suggesting potential strategies to improve the use of ADSCs for cell therapy.

Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury

“…ADSCs were positive for the MSC markers CD29, CD90, CD44, and CD105 and negative for the endothelial markers CD 3 4 and vWF, as previously reported (Fig. 1) [20]. …”

“…The isolation and culture of ADSCs were conducted as previously described [20]. Briefly, male Sprague-Dawley rats (80–120 g) were euthanized, and adipose tissue was obtained from the inguinal depots and washed with phosphate-buffered saline (PBS) to remove any residual blood.…”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…Furthermore, the morphology and release of inflammatory factors are positively related to passage number, as late‐passaged MSCs are flatter and more enlarged in morphology and release higher levels of inflammatory factors, including interferon gamma (IFN γ ) and TNF‐α . The apoptosis rate of MSCs may also be increased via the release of nuclear factor erythroid2‐related factor 2 (Nrf2), nuclear factor (NF)‐κB, Toll‐like receptor 4 (TLR4) and other inflammatory factors . Jeong et al argued that expression of apoptosis‐related genes in bone marrow derived MSCs is notably increased at the early stage of passaging but not altered in subsequent passaging stages.…”

Fructose 1,6-Bisphosphate as a Protective Agent for Experimental Fat Grafting

“…It is noteworthy that administration of FBP reduced inflammatory infiltration in fat grafts. It has been proposed that, among the different cellular and molecular mechanism, the tissue inflammation due to hypoxia may enhance oxidative stress and affect fat tissue graft survival . Macrophages have attracted considerable recent attention in adipose tissue biology following the discovery that they play a substantial role in the inflammatory process .…”