Adipose-derived mesenchymal stem cells promote the survival of fat grafts via crosstalk between the Nrf2 and TLR4 pathways.
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.
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.|Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China.
Xiaosong
X
Chen
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.|Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China.
Liu
L
Yan
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.
Zhihui
Z
Guo
Department of Burns Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.
Zhaohong
Z
Chen
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.|Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, Fujian 350000, China.
Ying
Y
Chen
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.
Ming
M
Li
Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.
Chushan
C
Huang
Institution of Interventional and Vascular surgery, Tongji Univerity, No 301 Middle Yan Chang Road, Shanghai 200072, China.
Xiaoping
X
Zhang
Department of Cardiac Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, China.
Liangwan
L
Chen
D017667:Adipocytes / Q000166:cytology / Q000276:immunology; D000273:Adipose Tissue / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation; D006085:Graft Survival / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000276:immunology; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000276:immunology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse