Supplementation with Extracellular Vesicles Derived from Adipose-Derived Stem Cells Increases Fat Graft Survival and Browning in Mice: A Cell-Free Approach to Construct Beige Fat from White Fat Grafting

Abstract

Background: Growing evidence has demonstrated that adipose-derived stem cell-derived extracellular vesicles enhance the survival of fat grafts and the browning of white adipose tissue. We evaluated whether supplementation with adipose-derived stem cell-derived extracellular vesicles promotes the survival and browning of fat grafts. Methods: Extracellular vesicles derived from adipose-derived stem cells were injected into fat grafts of C57BL/6 mice once per week until postgraft week 12. The grafts were collected and weighed after postgraft weeks 2, 4, and 12. The histological morphology, neovascularization, and the proportion of M2 macrophages of grafts were evaluated. The ability of extracellular vesicles to promote macrophage polarization and catecholamine secretion was detected. Whether the inducement of browning adipose differentiation is extracellular vesicles or the paracrine effect of M2 macrophages polarized by extracellular vesicles was also verified. Results: Grafts treated by extracellular vesicles derived from adipose-derived stem cells showed enhanced beige adipose regeneration with increased neovascularization, M2 macrophage proportion, and norepinephrine secretion at postgraft week 4. Increased retention and decreased fibrosis and necrosis were noted at postgraft week 12. The extracellular vesicles uptake by macrophages promoted M2 type polarization and catecholamine secretion while suppressing M1 type polarization. Of note, browning adipose differentiation with enhanced energy expenditure could be promoted only by the conditioned medium from extracellular vesicle–polarized M2 macrophages but not by extracellular vesicles themselves. Conclusions: Supplementation with extracellular vesicles derived from adipose-derived stem cells increases fat graft survival and browning by which extracellular vesicles–polarized M2 macrophages secrete catecholamines to promote beige adipose regeneration.

Spontaneous Browning of White Adipose Tissue Improves Angiogenesis and Reduces Macrophage Infiltration After Fat Grafting in Mice

“…This browning process occurred in human fat grafting as well but the significance of that is unknown ( Liu et al, 2021 ). The administration of either tamoxifen or extracellular vesicles derived from ASCs to stimulate browning of WAT results in an improvement in fat graft survival and retention ( Cai et al, 2018a ; Zhu et al, 2020 ). However, both of these promote WAT browning indirectly, instead of by directly targeting the white adipocytes and the thermogenic gene program.…”

Exosomes From Adipose-Derived Stem Cells: The Emerging Roles and Applications in Tissue Regeneration of Plastic and Cosmetic Surgery

“…Whereas during the mid to late stages of fat grafting, ASC-exos exerted a pro-adipogenic effect and also increased collagen synthesis level, similarly, to their source of ASCs (Chen B. et al, 2019). Zhu et al (2020) found that in an in vivo mouse model of autologous fat grafting, grafts treated by ASC-EVs significantly exhibited survival with more neovascularization, increased fat retention, and decreased fibrosis and necrosis. The ASC-EVs uptake by macrophages promoted M2 type polarization and catecholamine secretion, thus the M2 macrophages-CM could enhance browning adipose differentiation with enhanced energy expenditure (Zhu et al, 2020).…”

“… Zhu et al (2020) found that in an in vivo mouse model of autologous fat grafting, grafts treated by ASC-EVs significantly exhibited survival with more neovascularization, increased fat retention, and decreased fibrosis and necrosis. The ASC-EVs uptake by macrophages promoted M2 type polarization and catecholamine secretion, thus the M2 macrophages-CM could enhance browning adipose differentiation with enhanced energy expenditure ( Zhu et al, 2020 ). These results suggest that, as a cell-free strategy, ASC-exos could be an effective and appealing path to heighten graft survival in lipotransfer ( Figure 4 ).…”

Application of adipose-derived stem cells in treating fibrosis

“…Studies have shown that ASCs can reduce inflammation. ASCs play an important role in regulating the function of macrophages, including the conversion from pro-inflammatory M1 subtype to the anti-inflammatory M2 subtype and the recruitment of anti-inflammatory macrophages[ 21 - 23 ]. ASCs also exert powerful immunosuppressive properties by inhibiting T cell response[ 13 ].…”

“…However, the low retention rate had always been a troubling issue. Zhu et al [ 23 ] applied ASC-EVs to fat grafts in mice, and measured fat graft survival rate at up to 12 wk post-surgery. Not only did ASC-EVs improve fat retention, they also altered the ratio of M1/M2 macrophages toward an anti-inflammatory state, promoted the browning of white adipose tissue, and reduced fibrosis in fat grafts.…”