Discussion: Early Macrophage Infiltration Improves Fat Graft Survival by Inducing Angiogenesis and Hematopoietic Stem Cell Recruitment

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Autologous fat grafting is a common procedure in both aesthetic and reconstructive surgery.1 Over the past few years, significant advancements have been made to improve harvesting and delivery of autologous fat. Despite this, overall fat graft retention remains somewhat unpredictable and widely variable. Research directed toward understanding the molecular, cellular, and physiologic effects of autologous fat transfer is needed to improve survival and long-term retention.
Dong et al. have worked to elucidate the detailed mechanism of engraftment of autologous fat, most recently by focusing on the critical role of macrophages. They have shown that the subset of M2 macrophages are integral in improving survival and retention of autologous fat grafts.2 Another study, by Phipps et al., later showed that supplementation with M2 macrophages stimulates angiogenesis to improve fat graft survival.3 To further support the role of macrophages in fat grafting, Cai et al. found that macrophage-mediated inflammation enhanced extracellular matrix synthesis after fat grating.4 However, a balance must be established, as prolonged macrophage infiltration contributes to fibrosis and capsule formation in fat grafts.
In this work, they hypothesized that fat survival would be influenced by macrophage activation or depletion. Activation of early macrophages would improve fat graft survival, and depletion of macrophages would impair fat graft survival. Furthermore, they proposed that this macrophage effect may be facilitated through angiogenesis and stem cell recruitment. Using a murine model of fat transfer from the inguinal fat pad to the scalp, they characterized the kinetics of macrophage infiltration following fat grafting. Although elegant studies have demonstrated the differential cellular contribution of tissue regeneration and remodeling after fat grafting5 and the distribution of M1 versus M2 macrophages,6 this study nicely quantifies the cellular distribution in the stromal vascular fraction and demonstrates a clear increase in the M2-to-M1 ratio over a 4-week period. The authors suggested a possible link between the M2 macrophages and increased transforming growth factor-β, vascular endothelial growth factor, basic fibroblast growth factor, and angiogenesis based on quantitative reverse-transcription polymerase chain reaction from the entire stromal vascular fraction and whole-mount staining that co-localized macrophages with vessels. Although intriguing, this hypothesis would have been strengthened if fluorescence-activated cell sorting–isolated M2 cells had been used for gene expression analysis or specific M2 markers had been used in semiquantitative immunostaining across this timeframe.
The authors used repeated daily injections of liposome-encapsulated clodronate to deplete all local macrophages and macrophage colony-stimulating factor supplement to activate macrophages in the early phase. It was unclear why a control liposome was not used to determine whether there was any effect of liposome treatment on their results as they had done in previous studies.4 In addition, it is worth noting that macrophage colony-stimulating factor is not a macrophage-specific growth factor. Liposome-clodronate and macrophage colony-stimulating factor affected overall macrophage percentage in the stromal vascular fraction, but the authors did not distinguish between M1 and M2 subsets, which would have strengthened their hypothesis that M2 macrophages are the critical subset to fat retention. Graft retention was assessed as a fat graft weight after excision, and their data demonstrated a decrease in total graft weight with clodronate treatment and improved retention with macrophage colony-stimulating factor treatment. A more accurate portrayal would have been to present these data as a true percentage of the exact mass initially placed at the time of grafting. Although the data demonstrate differences in gross weight, the use of computed tomography–assisted volumetric imaging as done by Phipps et al.3 would be an interesting adjunct to see alterations in fat graft structure in vivo.
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