Adipose tissue (AT) is present in large quantity and represents the ideal filler for correcting and remodeling purposes. For two decades, extensive work has been done on adipose-derived stem/stromal cells (ASCs) and their use in regenerative medicine.1,2 Those cells would be the key factor for fat graft survival because of their ability to differentiate and synthesize growth factors.3,4 However, ASCs are not the only cellular component involved in graft survival. This review aims to describe other parameters that can have an effect on graft survival, with a focus on macrophage polarization, vascularization promotion, and extracellular matrix (ECM) remodeling. We also depict the effect of aging on those phenomena.
Adipose Tissue AGING
The main function of subcutaneous AT is energy storage through lipids. It is a major endocrine organ5 with strong immunomodulatory properties,6–8 and also undergoes changes with age.9 Age induces facial subcutaneous AT deflation.10,11 AT volume decrease leads to a loss of projection, inducing excessive traction on the lower eyelid.12 Using magnetic resonance imaging, Wysong et al. observed an age-related decrease in AT thickness in infraorbital and temporal zones and on the medial cheek.13 In contrast to these findings, Gosain et al. showed an increase in fat volume in the medial cheek on aged people.14 Age is negatively correlated with preadipocyte proliferation on subcutaneous but not omental depots. Furthermore, preadipocyte proliferation and differentiation capacities are down-regulated with age.15 There are also differences between fat depots, as preadipocyte properties vary according to their localization.16 Facial adipocytes have different morphology according to their fat depot; for instance, the average adipocyte size of nasolabial fat is larger than deep medial cheek fat.17 In addition, several reports have shown that age reduces vascularity, angiogenic capacity, and vascular endothelial growth factor (VEGF) expression, and increases fibrosis in aged AT mice.18 Ultraviolet irradiation could also impairs AT by inhibition of preadipocyte differentiation, mediated by inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor-α.19,20
Adipose-Derived Stem/Stromal Cells
Since the mid-1990s, autologous fat grafting has become a standard technique in plastic surgery. Lipofilling is now admitted as an alternative to synthetic polymer fillers.21–23 AT is not only a simple filler for volumetric effects, but also combines regenerative effects in skin on grafting.24,25 AT is composed of adipocytes and stromal vascular fraction (SVF) cells, including immune cells (eg, macrophages and lymphocytes), endothelial cells and their progenitors, smooth muscle cells, pericytes, and mesenchymal stem/stromal cells called ASCs26–31 (Fig. 1). ASCs were described by Zuk et al. in early 2000s.32,33 They are multipotent cells with high differentiation capacity27,34 that have gained attention for therapeutic and cosmetic applications.3,35 They are used to treat and improve wound healing,36–39 scars,24,40–43 hair regeneration,44,45 and facial aging.46,47 Fat grafting improves skin quality, leading to a reduction of dermal epidermal junction flattening, with noticeable reconstruction of normal ridge pattern and dermal papillae.48,49 However, two systematic reviews focusing on therapeutic and aesthetic use of lipofilling for skin quality improvement, wound healing, and hair growth demonstrate that these findings may be somewhat limited because of no significant effect on healthy skin.50,51 The authors conclude that even if the clinical outcomes show improvement, there is no robust clinical study (with high level of evidence) that shows a significant effect on skin quality.
As ASCs can modify surrounding cell behavior, they can remodel dermal ECM.42,46 ASCs promote dermal fibroblasts and epidermal keratinocyte proliferation and migration, not only by cell-to-cell direct contact, but also by paracrine activation through secretory factors. ASCs can also enhance the secretion of ECM proteins such as collagens or fibronectin52–55 and act as modulators of ECM by collagen and matrix metalloproteinase (MMP)/tissue inhibitors of MMP synthesis regulation.56–61 Indeed, ASCs can modulate homeostasis of MMPs and their endogenous inhibitors (tissue inhibitors of MMPs).62–64 Those cells are known to induce a better collagen organization and a decrease of α-smooth muscle actin expression, markers of dermal fibrosis improvement.65–67 ASC can inhibit profibrotic factors such as transforming growth factor (TGF)-β1 or IL-668–70 and increase the antifibrotic factor TGF-β3.43 The antifibrotic effect of ASCs is also mediated by their paracrine activity. Indeed, ASCs secrete basic fibroblast growth factor (b-FGF), also called FGF-2,71,72 hepatocyte growth factor (HGF),71–74 and IL-10,75 which are known to decrease TGF-β1 expression,76 stop fibroblast-to-myofibroblast differentiation,77,78 and induce myofibroblast apoptosis.61,79
Effect on Immune Cells
ASCs have strong immunomodulatory effects on both innate and adaptive immune systems.80 These cells are able to partially suppress lymphocyte proliferation and inhibit B-lymphocyte proliferation and differentiation into plasmocytic cells.81 Treatment with SVF cells or ASCs greatly attenuated the activities of T-helper 1 and T-helper 17 cells and their associated proinflammatory cytokines.82 Some studies have shown that ASC secretome is a pivotal player in immunomodulatory or angiogenic properties.83–85 However, cell characteristics may vary between patients according to age, sex, body mass index (BMI), or metabolic state. As an example, ASCs derived from patients affected by type 2 diabetes showed increased expression of inflammatory markers and high reduction of their immunosuppressive activities.86
Focus on Macrophages
ASCs can modulate monocyte and macrophage behavior through soluble factors.87 Some authors suggested that ASCs could modulate inflammation through regulation of macrophage polarization. Indeed, ASC-conditioned media (CM) significantly reduced the production of TNFα, nitric oxide, and prostaglandin E2 and the activation of nuclear factor-κB by macrophages.87 Co-culture of M0 or M1 macrophages with ASCs or ASC-CM increases alternative M2 macrophage marker expression such as CD206, CD163, or IL-10.82,88–92 This alternative activation is paired with a decrease of proinflammatory M1 macrophage markers such as CD80, IL-1β, IL-6, or TNF-α. Some immunomodulatory roles of ASCs remain unclear, such as expression of toll-like receptors,93,94 hematopoiesis support,95 and cytokine release at a basal or stimulated state.73 New therapeutic strategies are considering use of ASC-CM or extracellular vesicles to modulate inflammation,92,96 as cells secrete inflammatory cytokines such as granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, IL-6, IL-8, or TNF-α.55,72,73,97 Macrophage polarization switches from M0 or M1 to M2 could be mediated by those soluble factors. Indeed, exosomes from ASCs polarize macrophages toward M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3.98
Because of their ubiquitous presence and ability to secrete numerous cytokines, macrophages can interfere at each angiogenic step. Macrophages can modulate ECM by MMP synthesis,99 synthesized factors that can modulate endothelial cell proliferation and migration either in a proangiogenic (Ang2, b-FGF, TNF-α, VEGFC) or antiangiogenic (IL-10, TSP-1, VEGFAxxxb) pathway.100 M2 macrophages are known to promote angiogenesis and tissue regeneration, whereas M1 macrophages are considered antiangiogenic, although these classifications are controversial. Jetten et al. indicated that M2 macrophages have higher potential to increase the number of endothelial cells and tubular structures when compared to M1 macrophages.101 In contrast, Spiller et al. have demonstrated that M1 macrophages secrete high levels of angiogenic stimulators, including VEGF, and M2 macrophages secrete high levels of PDGF-BB (a chemoattractant-stabilizing pericytes), promote anastomosis of sprouting endothelial cells, and secrete the highest levels of MMP9, an important protease involved in vascular remodeling.102
These data suggest that ASCs could affect immune cells, especially macrophages, leading to a proresolutive phenotype. This immunomodulation could improve tissue regeneration, as alternatively activated macrophages increase angiogenesis.
Role in Vascularization
Beneficial effects of ASCs on wound healing involved promotion of vascular regeneration. ASCs can differentiate into endothelial vascular cells103–105 and promote the vascular network when co-cultured with endothelial cells.106 Furthermore, endothelial cells co-cultured with either ASCs or bone marrow–derived stromal cells induce stable vascular structures.107 However, ASC co-cultures developed more junctions and higher network density within the same time frame.107 ASCs bear many hallmarks of pericytes and provide vascular stability through functional interaction with endothelial cells.108 Fat grafts supplemented with ASCs have a higher capillary density, indicating that ASCs could promote neovascularization through expression of various growth factors, including VEGFA and insulin-like growth factor-1.109 Paracrine function is a key factor of ASC regenerative effects, and many authors have been interested in the ASC secretome.73,110 Those cells are able to synthesize a high variety of factors such as leptin, VEGF, HGF, b-FGF, TGF-β, IL-8, platelet-derived growth factor (PDGF), PlGF, or SDF-1,71–74,97,111–116 involved at different steps of angiogenesis. ASCs can form capillary-like tubes, which are dependent on PDGF and the b-FGF signaling pathway.117 ASCs increased endothelial cells growth and reduced endothelial cell apoptosis through VEGF, HGF, and TGF-β secretion.72 ASCs support endothelial tubulogenesis by VEGF-A and VEGF-D expression.113 FGF and VEGF are promoters for ASC proliferation, migration, attachment, and endothelial differentiation and have a co-stimulatory effect on ASC endotheliogenesis.118
Impact of Aging on ASCs
The regenerative potential of ASCs is based on their differentiation potential and paracrine effects.3,4,119 However, mesenchymal stem/stromal cell functionality declines with age.120 Aging decreases osteogenic differentiation121,122 and ASC telomere length.114,123–125 The effect of aging on proliferation and adipogenic potential is still controversial.121,123 Some authors state that aging has no effect on ASC yield, viability, and proliferation,126,127 whereas others show that cellular proliferation and migration decrease with age.121,122,128 Another study shows no correlation between age and ASC yield, or with the capacity of preadipocytes to undergo differentiation.129 Furthermore, ASC immunomodulatory potential is increased in infants compared to elderly, as they better suppress T-cell proliferation, down-regulate the secretion of interferon-γ, and increase the percentage of T-regulatory cells.122 Another study shows that aged ASCs failed to induce CD3+CD4+ T-cell suppression compared to young ASCs.130 Age also impairs angiogenic capacities of ASCs,18,131 as it decreases the ability of ASCs to differentiate toward endothelial cells and secretion of proangiogenic factors.131 Surprisingly, the literature is scarce concerning the effect of aging on ASC secretome. Aging reduces VEGF and b-FGF mRNA expression from white AT and isolated cells18,123 and protein expression of TGF-β1 and fibronectin.132 Angiogenic factors (VEGF, PlGF, HGF, angiopoetin-1, and angiogenin) protein and mRNA expression from ASC-CM decrease with patient age, whereas no changes were observed in the levels of antiangiogenic factors thrombospondin-1 and endostatin.114,125 Although those studies have been performed on in vitro conditions, future research should explore their role in vivo.
FAT GRAFT RETENTION
For more than a century, surgeons had used AT as a filling product. In 1893, Neuber was the first to use fat to correct facial scar.133 In the 1980s, multiple surgeons described the use of fat grafts in the cosmetic field. Despite promising therapeutic applications of fat grafting, the long-term results are often disappointing because of variable and unpredictable partial absorption.134–136 Several studies have reported resorption rates of 20% to 70% within 1 year, especially for large-volume fat grafting.136–140 In the mid-1990s, Coleman introduced a new technique to decrease traumatic handling of fat during liposuction.141,142 Even if his technique remains the standard for fat grafting, the numerous optimizations of each step of the procedure143,144 (eg, harvesting, processing, and injection) make comparisons between studies very difficult. However, many studies focus on survival rate of graft volume injected without taking into account the recipient-site volume. Khouri and Khouri suggested replacing percentage graft retention by more clinically relevant percentage augmentation: final volume augmented/initial recipient-site volume.145,146
Fat Graft Survival Theories
In 1923, Neuhof and Hirschfeld proposed the host replacement theory.147 In this theory, grafted fat cells die after transplantation and are partly replaced by infiltration either by host cells, which become fat cells, or by fibrous tissue.
In 1950, Peer contradicted this theory and proposed the cell survival theory,148,149 defined as follows: “Living human autogenous grafts tend to retain their specific structure, following free transplantation in unlike tissue, when the cells survive as living entities. When the cells fail to survive, the graft is replaced by fibrous tissue or mixed connective-tissue derivatives.” In his studies, Peer also demonstrated survival of the graft vascular system and anastomosis between host blood vessels and the vascular system of the graft, previously excluded.
Both graft survival and host replacement theories can explain partly fat graft survival process. In 2012, Eto et al. challenged the cell survival theory and found that adipocytes die easily under ischemic conditions, whereas ASCs or progenitor cells could survive and were activated and contributed to AT repair later.150 The authors have proposed the graft replacement theory, which defined the injected AT particle into three main zones. The most superficial zone is called the “surviving zone,” where both adipocytes and ASCs survive; the “regenerating zone,” where adipocytes die but ASCs survive and provide new adipocytes to replace the dead ones; and the “necrotic zone,” where adipocytes and ASCs die.
Parcel Size and Injected Volume
After Eto et al. highlighted the impact of fat microdroplets graft size,150 some teams described other essential parameters to improve fat graft survival (eg, oxygen diffusion). Khouri et al., have nicely modeled parameters involved in fat graft percentage augmentation.151 The study predicts that fat particles thinner than 0.16 cm in radius do not have a region of central necrosis, because oxygen supply is sufficient for all cells included in the particle. Otherwise, several surgeons have suggested that injecting too much fat into a small recipient site can increase interstitial fluid pressure (IFP) enough to constrict capillaries, inducing ischemia in the grafted tissues.152–154 The model described by Khouri et al. predicts that a given tissue compartment can accommodate approximately 60% of its weight in interstitial fluid before reaching a critical IFP (9 mmHg), beyond which any additional fluid causes a drastic IFP increase and capillary perfusion decrease.151 The injection step is crucial, as fat grafts have to be distributed in small droplets at varying depths in the soft tissue to allow oxygen supply and avoid excessive IFP at the recipient site.
ASCs and Vascularization
As seen above, fat graft survival depends on surgical techniques but also on the AT biology. Philips et al. demonstrated that there is a strong correlation between SVF percentage of CD34+ progenitors and human graft retention in mice.135 These CD34+ progenitors could be ASCs, and their concentration within the SVF may be one of the factors used to predict human fat graft percentage augmentation. Other studies have also demonstrated that ASC-enriched grafts improved fat graft survival through angiogenesis stimulation,103,109,155–158 and that fat graft enriched in proangiogenic factors improved the graft viability by means of increased vascularization.159,160 As high-density fat contained more vasculogenic progenitor cells and vascularity cytokines, this fat induces a better fat graft survival compared to low-density fat.161 These studies show that, through their proangiogenic capacities, ASCs could improve fat graft percentage augmentation.
Match between Harvest and Recipient Site
Although the literature suggests that AT is of mesoderm origin, one study demonstrates that adipocytes around the salivary gland come from neural crest of neuroectoderm.162 It has recently been reported that the individual fat depots exhibit distinct embryonic origins and express different HOX codes.163–165 Kouidhi et al. have shown the existence of an opposite gradient from the upper to the lower body between expressions of HOXC10 and the neural crest marker PAX3, which highlights diverse embryonic origins.166,167 Those data are completed by another study that show a different HOX code between abdominal and facial preadipocytes.168 Another study demonstrates different mouse AT embryonic origins according to the fat depot.169 Kouidhi et al. have highlighted the match between embryonic origin from AT donor and receptor sites as a critical parameter for clinical outcomes,166,167 as a mismatch of embryonic origins between harvested and recipient AT could lead to an impairment of grafted ASCs for tissue regeneration.170 Furthermore, some authors show that facial preadipocytes have a better adipogenic potential compared to abdominal ones.171 However, Kouidhi et al. have shown that ASCs extracted from either chin or knee have the same triglyceride concentration and lipolytic activity but that chin ASCs have the potential to differentiate into brown-like adipocytes, whereas knee ASCs can only differentiate into white adipocytes.166
Considered together, those data highlight the difference in regenerative potential according to the harvest site. In contrast, studies on donor-site influence on graft survival remain conflicting.172 However, those studies have investigated differences between knee, thigh, abdomen, or breast, but did not take into account facial AT.
Some authors mentioned that donor age could decrease fat graft survival in mice, according to the recipient site.173,174 Interestingly, another study concludes that according to fat process, age has a negative or no effect on volume retention.136 Donor sex could matter in fat graft survival, as fat graft volume retention was higher and reaches a stable state earlier in men than in women.175 Otherwise, even if low estrogen level induced favorable inflammation status and adipocyte hypertrophy (which improve fat graft retention), a continuing decreased estrogen level led to fat graft fibrosis.176 Inflammatory status, including macrophage and cytokine release, could also play a key role in graft percentage augmentation, even if this phenomenon is yet to be described.177 Phipps and colleagues have demonstrated that fat graft supplementation with M2 macrophages improve autologous fat graft volume retention with a higher vascular density, suggesting that M2 macrophages improve fat graft survival by promoting angiogenesis.178 Intriguingly, the prevalence of M2 macrophages has been correlated with a higher BMI and prevalence of M1 macrophages has been correlated with a lower BMI.179 The authors suggest that inflammatory response of lower BMI patients could inhibit angiogenesis and decrease blood flow of the graft, leading to a lower graft survival.
Fat graft survival is multiparametric and could rely on ASC number and potential, vascularization potential, age, BMI, sex, or embryonic origin. Several studies mentioned also that all processes of fat grafting, including the harvesting site or cannula, processing step, or surgeon gesture for injection, could influence graft survival.143,172,180
Mesenchymal cells from hypodermis, ASCs, are key players in regeneration of surrounding tissues such as dermis or AT itself. Their regenerative potential is expressed through their multipotency or paracrine effects.3,4 ASCs have numerous beneficial effects on ECM remodeling, immunity, and vascularization, summarized in Figure 2. As lipofilling is used for soft-tissue reconstruction, the oncologic safety of fat grafting is a hot topic. One study shows an increase of breast cancer cells when co-cultured with ASCs.181 However, another study analyzed the effect of ASCs and lipoaspirate on proliferation of human breast cancer cell lines and revealed there is no proliferation increase of the cells.182 The authors even observed that lipoaspirate and ASCs inhibit the proliferation of breast cancer cells. Furthermore, a cohort study examining 300 affected breasts reconstructed with fat grafting (and 300 matched control patients) shows no significant differences in the locoregional recurrence rates between groups after 5-year follow-up, suggesting that there is no evidence that fat grafting is associated with increased rates for cancer relapse in patients with breast cancer.183
Aging is a phenomenon that impairs all tissues and is characterized by proliferative and differentiation capacities decrease of cell types. ASC regenerative potential has been demonstrated in many fields, including cutaneous aging.46,47 Beneficial ASC effects on fibroblasts and adipocytes and their ECM could be impaired with age. However, despite these promising results with ASCs, several questions remain. The impact of age on ASC yield, proliferative capacity, or multipotent potential still needs to be elucidated,123,126 as does the effect of aging on ASC paracrine function. Indeed, there is no study to date concerning aging impact on complete secretome quality and quantity. Some authors mentioned that age could act negatively on graft survival. However, other factors listed in Figure 3 need to be taken in account, such as embryonic origin or HOX code match between harvested and recipient site, particle size, or inflammatory state of AT. Vascularization speed of AT after injection is also a therapeutic path encountered. ASCs strongly interact with surrounding cells, especially with vascular cells such as endothelial cells or pericytes, and immune cells such as macrophages. Cell-to-cell communication is mediated by soluble factors. We still do not know how donor age influences ASC capacity to polarize macrophages. Moreover, the link between ASCs, macrophage polarization, and vascularization has not been well described yet. Further research should be undertaken to investigate the aging effect on fat depots from different anatomical sites, regarding regenerative potential and paracrine function. This work could lead to determination of factors involved in graft percentage augmentation and open new therapeutic ways for fat grafting.
1. Shukla L, Yuan Y, Shayan R, Greening DW, Karnezis T. Fat therapeutics: the clinical capacity of adipose-derived stem cells and exosomes for human disease and tissue regeneration. Front Pharmacol. 2020;11:158.
2. Glass GE, Ferretti P. Adipose-derived stem cells in aesthetic surgery. Aesthet Surg J. 2019;39:423–438.
3. Mizuno H, Tobita M, Uysal AC. Concise review: adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells. 2012;30:804–810.
4. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007;100:1249–1260.
5. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548–2556.
6. Bray GA, Ryan DH, eds. Overweight and the Metabolic Syndrome: From Bench to Bedside. New York: Springer; 2006.
7. Mohammadi Ayenehdeh J, Niknam B, Rasouli S, et al. Immunomodulatory and protective effects of adipose tissue-derived mesenchymal stem cells in an allograft islet composite transplantation for experimental autoimmune type 1 diabetes. Immunol Lett. 2017;188:21–31.
8. Mattar P, Bieback K. Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells. Front Immunol. 2015;6:560.
9. Florido R, Tchonia T, Kirkland JL. Aging and adipose tissue. Masoro EJ, Austad SN, eds. In: Handbook of the Biology of Aging. 7th ed. Boston: Elsevier 2011:119–139.
10. Fitzgerald R, Graivier MH, Kane M, et al. Update on facial aging. Aesthet Surg J. 2010;30:11S–24S.
11. Mertens A, Foyatier JL, Mojallal A. Quantitative analysis of midface fat compartments mass with ageing and body mass index, anatomical study. Ann Chir Plast Esthet. 2016;61:798–805.
12. Jelks GW, Jelks EB. Preoperative evaluation of the blepharoplasty patient: bypassing the pitfalls. Clin Plast Surg. 1993;20:213–223; discussion 224.
13. Wysong A, Kim D, Joseph T, MacFarlane DF, Tang JY, Gladstone HB. Quantifying soft tissue loss in the aging male face using magnetic resonance imaging. Dermatol Surg. 2014;40:786–793.
14. Gosain AK, Klein MH, Sudhakar PV, Prost RW. A volumetric analysis of soft-tissue changes in the aging midface using high-resolution MRI: implications for facial rejuvenation. Plast Reconstr Surg. 2005;115:1143–1152; discussion 1153–1155.
15. Sepe A, Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Aging and regional differences in fat cell progenitors: a mini-review. Gerontology. 2011;57:66–75.
16. Cartwright MJ, Tchkonia T, Kirkland JL. Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Exp Gerontol. 2007;42:463–471.
17. Wan D, Amirlak B, Giessler P, et al. The differing adipocyte morphologies of deep versus superficial midfacial fat compartments: a cadaveric study. Plast Reconstr Surg. 2014;133:615e–622e.
18. Donato AJ, Henson GD, Hart CR, et al. The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J Physiol. 2014;592:4083–4096.
19. Li WH, Pappas A, Zhang L, Ruvolo E, Cavender D. IL-11, IL-1alpha, IL-6, and TNF-alpha are induced by solar radiation in vitro and may be involved in facial subcutaneous fat loss in vivo. J Dermatol Sci. 2013;71:58–66.
20. Li WH, Pappas A, Zhang L, Cavender D. Sunscreens may prevent UV-induced facial fat loss by blocking the production of IL-11. Paper presented at: 2011 SID Annual Meeting; May 4–7, 2011; Phoenix, AZ.
21. Coleman SR, Saboeiro AP. Fat grafting to the breast revisited: safety and efficacy. Plast Reconstr Surg. 2007;119:775–785; discussion 786–787.
22. Banyard DA, Salibian AA, Widgerow AD, Evans GR. Implications for human adipose-derived stem cells in plastic surgery. J Cell Mol Med. 2015;19:21–30.
23. Mojallal A, Lequeux C, Shipkov C, et al. Improvement of skin quality after fat grafting: clinical observation and an animal study. Plast Reconstr Surg. 2009;124:765–774.
24. Coleman SR. Structural fat grafting: more than a permanent filler. Plast Reconstr Surg. 2006;118:108S–120S.
25. Bellini E, Grieco MP, Raposio E. The science behind autologous fat grafting. Ann Med Surg (Lond.). 2017;24:65–73.
26. Yoshimura K, Shigeura T, Matsumoto D, et al. Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J Cell Physiol. 2006;208:64–76.
27. Bourin P, Bunnell BA, Casteilla L, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15:641–648.
28. Han J, Koh YJ, Moon HR, et al. Adipose tissue is an extramedullary reservoir for functional hematopoietic stem and progenitor cells. Blood. 2010;115:957–964.
29. McIntosh K, Zvonic S, Garrett S, et al. The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells. 2006;24:1246–1253.
30. Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006;7:14.
31. Yoshimura K, Suga H, Eto H. Adipose-derived stem/progenitor cells: roles in adipose tissue remodeling and potential use for soft tissue augmentation. Regen Med. 2009;4:265–273.
32. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–4295.
33. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–228.
34. Schaffler A, Buchler C. Concise review: adipose tissue-derived stromal cells—basic and clinical implications for novel cell-based therapies. Stem Cells. 2007;25:818–827.
35. Lim MH, Ong WK, Sugii S. The current landscape of adipose-derived stem cells in clinical applications. Expert Rev Mol Med. 2014;16:e8.
36. Lau K, Paus R, Tiede S, Day P, Bayat A. Exploring the role of stem cells in cutaneous wound healing. Exp Dermatol. 2009;18:921–933.
37. Rodriguez J, Boucher F, Lequeux C, et al. Intradermal injection of human adipose-derived stem cells accelerates skin wound healing in nude mice. Stem Cell Res Ther. 2015;6:241.
38. Nie C, Zhang G, Yang D, et al. Targeted delivery of adipose-derived stem cells via acellular dermal matrix enhances wound repair in diabetic rats. J Tissue Eng Regen Med. 2015;9:224–235.
39. Kato Y, Iwata T, Morikawa S, Yamato M, Okano T, Uchigata Y. Allogeneic transplantation of an adipose-derived stem cell sheet combined with artificial skin accelerates wound healing in a rat wound model of type 2 diabetes and obesity. Diabetes. 2015;64:2723–2734.
40. Coleman SR. Structural fat grafts: the ideal filler?. Clin Plast Surg. 2001;28:111–119.
41. Sardesai MG, Moore CC. Quantitative and qualitative dermal change with microfat grafting of facial scars. Otolaryngol Head Neck Surg. 2007;137:868–872.
42. Tang X, Li F, Wang D, et al. The influences of adipose-derived stem cells (ASCs) on epithelial-mesenchymal cross-talk factors in the early stage of scar formation. Int J Clin Exp Med. 2017;10:266–275.
43. Yun IS, Jeon YR, Lee WJ, et al. Effect of human adipose derived stem cells on scar formation and remodeling in a pig model: a pilot study. Dermatol Surg. 2012;38:1678–1688.
44. Won CH, Yoo HG, Kwon OS, et al. Hair growth promoting effects of adipose tissue-derived stem cells. J Dermatol Sci. 2010;57:134–137.
45. Fukuoka H, Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty. 2015;15:e10.
46. Charles-de-Sa L, Gontijo-de-Amorim NF, Maeda Takiya C, et al. Antiaging treatment of the facial skin by fat graft and adipose-derived stem cells. Plast Reconstr Surg. 2015;135:999–1009.
47. Coleman SR, Katzel EB. Fat grafting for facial filling and regeneration. Clin Plast Surg. 2015;42:289–300, vii.
48. Bruno A, Delli Santi G, Fasciani L, Cempanari M, Palombo M, Palombo P. Burn scar lipofilling: immunohistochemical and clinical outcomes. J Craniofac Surg. 2013;24:1806–1814.
49. Del Papa N, Caviggioli F, Sambataro D, et al. Autologous fat grafting in the treatment of fibrotic perioral changes in patients with systemic sclerosis. Cell Transplant. 2015;24:63–72.
50. van Dongen JA, Langeveld M, van de Lande LS, Harmsen MC, Stevens HP, van der Lei B. The effects of facial lipografting on skin quality: a systematic review. Plast Reconstr Surg. 2019;144:784e–797e.
51. Walocko FM, Eber AE, Kirsner RS, Badiavas E, Nouri K. Systematic review of the therapeutic roles of adipose tissue in dermatology. J Am Acad Dermatol. 2018;79:935–944.
52. Lee SH, Jin SY, Song JS, Seo KK, Cho KH. Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts. Ann Dermatol. 2012;24:136–143.
53. Lu W, Yu J, Zhang Y, et al. Mixture of fibroblasts and adipose tissue-derived stem cells can improve epidermal morphogenesis of tissue-engineered skin. Cells Tissues Organs. 2012;195:197–206.
54. Kim WS, Park BS, Sung JH, et al. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci. 2007;48:15–24.
55. Moon KM, Park YH, Lee JS, et al. The effect of secretory factors of adipose-derived stem cells on human keratinocytes. Int J Mol Sci. 2012;13:1239–1257.
56. Xie JL, Bian HN, Qi SH, et al. Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing. Wound Repair Regen. 2008;16:576–581.
57. Shi JH, Guan H, Shi S, et al. Protection against TGF-beta1-induced fibrosis effects of IL-10 on dermal fibroblasts and its potential therapeutics for the reduction of skin scarring. Arch Dermatol Res. 2013;305:341–352.
58. Xie J, Bian H, Qi S, et al. Effects of basic fibroblast growth factor on the expression of extracellular matrix and matrix metalloproteinase-1 in wound healing. Clin Exp Dermatol. 2008;33:176–182.
59. Shi HX, Lin C, Lin BB, et al. The anti-scar effects of basic fibroblast growth factor on the wound repair in vitro and in vivo. PLoS One. 2013;8:e59966.
60. Sherriff-Tadano R, Ohta A, Morito F, et al. Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism. Mod Rheumatol. 2006;16:364–371.
61. Iekushi K, Taniyama Y, Azuma J, et al. Hepatocyte growth factor attenuates renal fibrosis through TGF-beta1 suppression by apoptosis of myofibroblasts. J Hypertens. 2010;28:2454–2461.
62. Denkovskij J, Bagdonas E, Kusleviciute I, et al. Paracrine potential of the human adipose tissue-derived stem cells to modulate balance between matrix metalloproteinases and their inhibitors in the osteoarthritic cartilage in vitro. Stem Cells Int. 2017;2017:9542702.
63. Son WC, Yun JW, Kim BH. Adipose-derived mesenchymal stem cells reduce MMP-1 expression in UV-irradiated human dermal fibroblasts: therapeutic potential in skin wrinkling. Biosci Biotechnol Biochem. 2015;79:919–925.
64. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol. 2014;34:132–143.
65. Chen W, Xia ZK, Zhang MH, et al. Adipose tissue-derived stem cells ameliorates dermal fibrosis in a mouse model of scleroderma. Asian Pac J Trop Med. 2017;10:52–56.
66. Borovikova AA, Ziegler ME, Banyard DA, et al. Adipose-derived tissue in the treatment of dermal fibrosis: antifibrotic effects of adipose-derived stem cells. Ann Plast Surg. 2018;80:297–307.
67. Zhang Q, Liu LN, Yong Q, Deng JC, Cao WG. Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model. Stem Cell Res Ther. 2015;6:145.
68. Deng J, Shi Y, Gao Z, et al. Inhibition of pathological phenotype of hypertrophic scar fibroblasts via coculture with adipose-derived stem cells. Tissue Eng Part A. 2018;24:382–393.
69. Jiang X, Jiang X, Qu C, et al. Intravenous delivery of adipose-derived mesenchymal stromal cells attenuates acute radiation-induced lung injury in rats. Cytotherapy. 2015;17:560–570.
70. Sun W, Ni X, Sun S, et al. Adipose-derived stem cells alleviate radiation-induced muscular fibrosis by suppressing the expression of TGF-beta1. Stem Cells Int. 2016;2016:5638204.
71. Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol. 2005;25:2542–2547.
72. Rehman J, Traktuev D, Li J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–1298.
73. Kilroy GE, Foster SJ, Wu X, et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol. 2007;212:702–709.
74. Cui L, Liu B, Liu G, et al. Repair of cranial bone defects with adipose derived stem cells and coral scaffold in a canine model. Biomaterials. 2007;28:5477–5486.
75. Xu Y, Guo S, Wei C, et al. The comparison of adipose stem cell and placental stem cell in secretion characteristics and in facial antiaging. Stem Cells Int. 2016;2016:7315830.
76. Nakagome K, Dohi M, Okunishi K, Tanaka R, Miyazaki J, Yamamoto K. In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-beta in the lung. Thorax. 2006;61:886–894.
77. Faehling M, Hetzel M, Anders D, Trischler G, Bachem M. Antifibrotic role of HGF in sarcoidosis. Lung. 2012;190:303–312.
78. Liu Y, Yang J. Hepatocyte growth factor: new arsenal in the fights against renal fibrosis?. Kidney Int. 2006;70:238–240.
79. Funato N, Moriyama K, Shimokawa H, Kuroda T. Basic fibroblast growth factor induces apoptosis in myofibroblastic cells isolated from rat palatal mucosa. Biochem Biophys Res Commun. 1997;240:21–26.
80. Law S, Chaudhuri S. Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges. Am J Stem Cells. 2013;2:22–38.
81. Ceccarelli S, Pontecorvi P, Anastasiadou E, Napoli C, Marchese C. Immunomodulatory effect of adipose-derived stem cells: the cutting edge of clinical application. Front Cell Dev Biol. 2020;8:236.
82. Bowles AC, Wise RM, Gerstein BY, et al. Immunomodulatory effects of adipose stromal vascular fraction cells promote alternative activation macrophages to repair tissue damage. Stem Cells. 2017;35:2198–2207.
83. Kapur SK, Katz AJ. Review of the adipose derived stem cell secretome. Biochimie. 2013;95:2222–2228.
84. Eleuteri S, Fierabracci A. Insights into the secretome of mesenchymal stem cells and its potential applications. Int J Mol Sci. 2019;20:4597.
85. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18:1852.
86. Serena C, Keiran N, Ceperuelo-Mallafre V, et al. Obesity and type 2 diabetes alters the immune properties of human adipose derived stem cells. Stem Cells. 2016;34:2559–2573.
87. Guillen MI, Platas J, Perez Del Caz MD, Mirabet V, Alcaraz MJ. Paracrine anti-inflammatory effects of adipose tissue-derived mesenchymal stem cells in human monocytes. Front Physiol. 2018;9:661.
88. Yin X, Pang C, Bai L, Zhang Y, Geng L. Adipose-derived stem cells promote the polarization from M1 macrophages to M2 macrophages (in Chinese). Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016;32:332–338.
89. Manning CN, Martel C, Sakiyama-Elbert SE, et al. Adipose-derived mesenchymal stromal cells modulate tendon fibroblast responses to macrophage-induced inflammation in vitro. Stem Cell Res Ther. 2015;6:74.
90. Park HJ, Kim J, Saima FT, et al. Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem Biophys Res Commun. 2018;498:988–995.
91. Manferdini C, Paolella F, Gabusi E, et al. Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation. Osteoarthritis Cartilage. 2017;25:1161–1171.
92. Lo Sicco C, Reverberi D, Balbi C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6:1018–1028.
93. Lombardo E, DelaRosa O, Mancheno-Corvo P, Menta R, Ramirez C, Buscher D. Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications for immunogenicity and immunosuppressive potential. Tissue Eng Part A. 2009;15:1579–1589.
94. Cho HH, Bae YC, Jung JS. Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells. 2006;24:2744–2752.
95. Nakao N, Nakayama T, Yahata T, et al. Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol. 2010;177:547–554.
96. Seo Y, Shin TH, Kim HS. Current strategies to enhance adipose stem cell function: an update. Int J Mol Sci. 2019;20:3827.
97. Prichard HL, Reichert W, Klitzman B. IFATS collection: adipose-derived stromal cells improve the foreign body response. Stem Cells. 2008;26:2691–2695.
98. Zhao H, Shang Q, Pan Z, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67:235–247.
99. Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol. 2015;44–46:94–112.
100. Corliss BA, Azimi MS, Munson JM, Peirce SM, Murfee WL. Macrophages: an inflammatory link between angiogenesis and lymphangiogenesis. Microcirculation. 2016;23:95–121.
101. Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 2014;17:109–118.
102. Spiller KL, Anfang RR, Spiller KJ, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials. 2014;35:4477–4488.
103. Matsumoto D, Sato K, Gonda K, et al. Cell-assisted lipotransfer: supportive use of human adipose-derived cells for soft tissue augmentation with lipoinjection. Tissue Eng. 2006;12:3375–3382.
104. Altman AM, Matthias N, Yan Y, et al. Dermal matrix as a carrier for in vivo delivery of human adipose-derived stem cells. Biomaterials. 2008;29:1431–1442.
105. Fischer LJ, McIlhenny S, Tulenko T, et al. Endothelial differentiation of adipose-derived stem cells: effects of endothelial cell growth supplement and shear force. J Surg Res. 2009;152:157–166.
106. Traktuev DO, Prater DN, Merfeld-Clauss S, et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ Res. 2009;104:1410–1420.
107. Pill K, Melke J, Muhleder S, et al. Microvascular networks from endothelial cells and mesenchymal stromal cells from adipose tissue and bone marrow: a comparison. Front Bioeng Biotechnol. 2018;6:156.
108. Traktuev DO, Merfeld-Clauss S, Li J, et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res. 2008;102:77–85.
109. Zhu M, Zhou Z, Chen Y, et al. Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Ann Plast Surg. 2010;64:222–228.
110. Salgado AJ, Reis RL, Sousa NJ, Gimble JM. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. 2010;5:103–110.
111. Matsuda K, Falkenberg KJ, Woods AA, Choi YS, Morrison WA, Dilley RJ. Adipose-derived stem cells promote angiogenesis and tissue formation for in vivo tissue engineering. Tissue Eng Part A. 2013;19:1327–1335.
112. Delle Monache S, Calgani A, Sanita P, et al. Adipose-derived stem cells sustain prolonged angiogenesis through leptin secretion. Growth Factors. 2016;34:87–96.
113. Hsiao ST, Asgari A, Lokmic Z, et al. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev. 2012;21:2189–2203.
114. Efimenko A, Starostina E, Kalinina N, Stolzing A. Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning. J Transl Med. 2011;9:10.
115. Devarajan E, Song YH, Krishnappa S, Alt E. Epithelial-mesenchymal transition in breast cancer lines is mediated through PDGF-D released by tissue-resident stem cells. Int J Cancer. 2012;131:1023–1031.
116. Zhao J, Hu L, Liu J, Gong N, Chen L. The effects of cytokines in adipose stem cell-conditioned medium on the migration and proliferation of skin fibroblasts in vitro. Biomed Res Int. 2013;2013:578479.
117. Gehmert S, Gehmert S, Hidayat M, et al. Angiogenesis: the role of PDGF-BB on adipose-tissue derived stem cells (ASCs). Clin Hemorheol Microcirc. 2011;48:5–13.
118. Khan S, Villalobos MA, Choron RL, et al. Fibroblast growth factor and vascular endothelial growth factor play a critical role in endotheliogenesis from human adipose-derived stem cells. J Vasc Surg. 2017;65:1483–1492.
119. Eto H, Suga H, Inoue K, et al. Adipose injury-associated factors mitigate hypoxia in ischemic tissues through activation of adipose-derived stem/progenitor/stromal cells and induction of angiogenesis. Am J Pathol. 2011;178:2322–2332.
120. Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006;5:91–116.
121. Zhu M, Kohan E, Bradley J, Hedrick M, Benhaim P, Zuk P. The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. J Tissue Eng Regen Med. 2009;3:290–301.
122. Jin Y, Yang L, Zhang Y, et al. Effects of age on biological and functional characterization of adipose-derived stem cells from patients with endstage liver disease. Mol Med Rep. 2017;16:3510–3518.
123. Wu W, Niklason L, Steinbacher DM. The effect of age on human adipose-derived stem cells. Plast Reconstr Surg. 2013;131:27–37.
124. Liu M, Lei H, Dong P, et al. Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties. Cell Transplant. 2017;26:1505–1519.
125. Efimenko A, Dzhoyashvili N, Kalinina N, et al. Adipose-derived mesenchymal stromal cells from aged patients with coronary artery disease keep mesenchymal stromal cell properties but exhibit characteristics of aging and have impaired angiogenic potential. Stem Cells Transl Med. 2014;3:32–41.
126. Dufrane D. Impact of age on human adipose stem cells for bone tissue engineering. Cell Transplant. 2017;26:1496–1504.
127. Devitt SM, Carter CM, Dierov R, Weiss S, Gersch RP, Percec I. Successful isolation of viable adipose-derived stem cells from human adipose tissue subject to long-term cryopreservation: positive implications for adult stem cell-based therapeutics in patients of advanced age. Stem Cells Int. 2015;2015:146421.
128. Maredziak M, Marycz K, Tomaszewski KA, Kornicka K, Henry BM. The influence of aging on the regenerative potential of human adipose derived mesenchymal stem cells. Stem Cells Int. 2016;2016:2152435.
129. van Harmelen V, Skurk T, Rohrig K, et al. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int J Obes Relat Metab Disord. 2003;27:889–895.
130. Wu LW, Wang YL, Christensen JM, et al. Donor age negatively affects the immunoregulatory properties of both adipose and bone marrow derived mesenchymal stem cells. Transpl Immunol. 2014;30:122–127.
131. De Barros S, Dehez S, Arnaud E, et al. Aging-related decrease of human ASC angiogenic potential is reversed by hypoxia preconditioning through ROS production. Mol Ther. 2013;21:399–408.
132. Zhang M, Wang Z, Zhao Y, et al. The effect of age on the regenerative potential of human eyelid adipose-derived stem cells. Stem Cells Int. 2018;2018:5654917.
133. Neuber GA. Fett transplantation. Verl Dtsch Ges Chir. 1893;22:66.
134. Fontdevila J, Serra-Renom JM, Raigosa M, et al. Assessing the long-term viability of facial fat grafts: an objective measure using computed tomography. Aesthet Surg J. 2008;28:380–386.
135. Philips BJ, Grahovac TL, Valentin JE, et al. Prevalence of endogenous CD34+ adipose stem cells predicts human fat graft retention in a xenograft model. Plast Reconstr Surg. 2013;132:845–858.
136. Gerth DJ, King B, Rabach L, Glasgold RA, Glasgold MJ. Long-term volumetric retention of autologous fat grafting processed with closed-membrane filtration. Aesthet Surg J. 2014;34:985–994.
137. Kim HY, Jung BK, Lew DH, Lee DW. Autologous fat graft in the reconstructed breast: fat absorption rate and safety based on sonographic identification. Arch Plast Surg. 2014;41:740–747.
138. Delay E, Garson S, Tousson G, Sinna R. Fat injection to the breast: technique, results, and indications based on 880 procedures over 10 years. Aesthet Surg J. 2009;29:360–376.
139. Zocchi ML, Zuliani F. Bicompartmental breast lipostructuring. Aesthetic Plast Surg. 2008;32:313–328.
140. Wolf GA, Gallego S, Patron AS, et al. Magnetic resonance imaging assessment of gluteal fat grafts. Aesthetic Plast Surg. 2006;30:460–468.
141. Coleman SR. Long-term survival of fat transplants: controlled demonstrations. Aesthetic Plast Surg. 1995;19:421–425.
142. Coleman S. Structural fat grafting. Aesthet Surg J. 1998;18:386–388.
143. Gause TM II, Kling RE, Sivak WN, Marra KG, Rubin JP, Kokai LE. Particle size in fat graft retention: a review on the impact of harvesting technique in lipofilling surgical outcomes. Adipocyte. 2014;3:273–279.
144. Conde-Green A, Wu I, Graham I, et al. Comparison of 3 techniques of fat grafting and cell-supplemented lipotransfer in athymic rats: a pilot study. Aesthet Surg J. 2013;33:713–721.
145. Khouri RK Jr, Khouri RK. Percentage augmentation: the more meaningful index of success in fat grafting. Plast Reconstr Surg. 2015;135:933e–935e.
146. Khouri RK Jr, Khouri RK. Current clinical applications of fat grafting. Plast Reconstr Surg. 2017;140:466e–486e.
147. Neuhof HH, Hirshfeld S. The Transplantation of Tissues. New York: Appleton; 1923.
148. Peer LA. Loss of weight and volume in human fat graft, with postulation of a cell survival theory. Plast Reconstr Surg. 1950;5:217–230.
149. Peer LA. Cell survival theory versus replacement theory. Plast Reconstr Surg. 1955;16:161–168.
150. Eto H, Kato H, Suga H, et al. The fate of adipocytes after nonvascularized fat grafting: evidence of early death and replacement of adipocytes. Plast Reconstr Surg. 2012;129:1081–1092.
151. Khouri RK Jr, Khouri RE, Lujan-Hernandez JR, Khouri KR, Lancerotto L, Orgill DP. Diffusion and perfusion: the keys to fat grafting. Plast Reconstr Surg Glob Open. 2014;2:e220.
152. Khouri RK, Rigotti G, Cardoso E, Khouri RK Jr, Biggs TM. Megavolume autologous fat transfer: part I. Theory and principles. Plast Reconstr Surg. 2014;133:550–557.
153. Khouri RK, Rigotti G, Cardoso E, Khouri RK Jr, Biggs TM. Megavolume autologous fat transfer: part II. Practice and techniques. Plast Reconstr Surg. 2014;133:1369–1377.
154. Khouri RK, Smit JM, Cardoso E, et al. Percutaneous aponeurotomy and lipofilling: a regenerative alternative to flap reconstruction?. Plast Reconstr Surg. 2013;132:1280–1290.
155. Kølle S-FT, Fischer-Nielsen A, Mathiasen AB, et al. Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. Lancet. 2013;382:1113–1120.
156. Garza RM, Rennert RC, Paik KJ, et al. Studies in fat grafting: part IV. Adipose-derived stromal cell gene expression in cell-assisted lipotransfer. Plast Reconstr Surg. 2015;135:1045–1055.
157. Koh KS, Oh TS, Kim H, et al. Clinical application of human adipose tissue-derived mesenchymal stem cells in progressive hemifacial atrophy (Parry-Romberg disease) with microfat grafting techniques using 3-dimensional computed tomography and 3-dimensional camera. Ann Plast Surg. 2012;69:331–337.
158. Tanikawa DY, Aguena M, Bueno DF, Passos-Bueno MR, Alonso N. Fat grafts supplemented with adipose-derived stromal cells in the rehabilitation of patients with craniofacial microsomia. Plast Reconstr Surg. 2013;132:141–152.
159. Topcu A, Aydin OE, Unlu M, Barutcu A, Atabey A. Increasing the viability of fat grafts by vascular endothelial growth factor. Arch Facial Plast Surg. 2012;14:270–276.
160. Jiang A, Li M, Duan W, Dong Y, Wang Y. Improvement of the survival of human autologous fat transplantation by adipose-derived stem-cells-assisted lipotransfer combined with bFGF. ScientificWorldJournal. 2015;2015:968057.
161. Butala P, Hazen A, Szpalski C, Sultan SM, Coleman SR, Warren SM. Endogenous stem cell therapy enhances fat graft survival. Plast Reconstr Surg. 2012;130:293–306.
162. Billon N, Iannarelli P, Monteiro MC, et al. The generation of adipocytes by the neural crest. Development. 2007;134:2283–2292.
163. Gesta S, Bluher M, Yamamoto Y, et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci USA. 2006;103:6676–6681.
164. Billon N, Dani C. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Stem Cell Rev Rep. 2012;8:55–66.
165. Berry DC, Stenesen D, Zeve D, Graff JM. The developmental origins of adipose tissue. Development. 2013;140:3939–3949.
166. Kouidhi M, Villageois P, Mounier CM, et al. Characterization of human knee and chin adipose-derived stromal cells. Stem Cells Int. 2015;2015:592090.
167. Foissac R, Villageois P, Chignon-Sicard B, Georgiou C, Camuzard O, Dani C. Homeotic and embryonic gene expression in breast adipose tissue and in adipose tissues used as donor sites in plastic surgery. Plast Reconstr Surg. 2017;139:685e–692e.
168. Procino A, Cillo C. The HOX genes network in metabolic diseases. Cell Biol Int. 2013;37:1145–1148.
169. Sanchez-Gurmaches J, Hung CM, Guertin DA. Emerging complexities in adipocyte origins and identity. Trends Cell Biol. 2016;26:313–326.
170. Dani C, Foissac R, Ladoux A, Chignon-Sicard B. Autologous fat grafts: can we match the donor fat site and the host environment for better postoperative outcomes and safety?. Curr Surg Rep. 2017;5:14.
171. Chon SH, Pappas A. Differentiation and characterization of human facial subcutaneous adipocytes. Adipocyte. 2015;4:13–21.
172. Strong AL, Cederna PS, Rubin JP, Coleman SR, Levi B. The current state of fat grafting: a review of harvesting, processing, and injection techniques. Plast Reconstr Surg. 2015;136:897–912.
173. Montenegro CF, Flacco J, Chung NN, et al. Fat graft retention decreases with recipient age. J Am Coll Surg. 2017;225:e144–e145.
174. Yuan YI, Gao J, Lu F. Effect of exogenous adipose-derived stem cells in the early stages following free fat transplantation. Exp Ther Med. 2015;10:1052–1058.
175. Herly M, Orholt M, Glovinski PV, et al. Quantifying long-term retention of excised fat grafts: a longitudinal, retrospective cohort study of 108 patients followed for up to 8.4 years. Plast Reconstr Surg. 2017;139:1223–1232.
176. Mok H, Feng J, Hu W, Wang J, Cai J, Lu F. Decreased serum estrogen improves fat graft retention by enhancing early macrophage infiltration and inducing adipocyte hypertrophy. Biochem Biophys Res Commun. 2018;501:266–272.
177. Kokai L, Johngrass MG, Schroth RN, Gusenoff JA, Rubin JP. Molecular mechanisms of fat graft failure: exploring pathways that confer hypoxia-induced apoptosis resistance in adipose tissue. Paper presented at: IFATS; November 30–December 3, 2017; Miami, FL.
178. Phipps KD, Gebremeskel S, Gillis J, Hong P, Johnston B, Bezuhly M. Alternatively activated M2 macrophages improve autologous fat graft survival in a mouse model through induction of angiogenesis. Plast Reconstr Surg. 2015;135:140–149.
179. Wang S, Gusenoff JA, Rubin JP, Kokai L. Molecular mechanisms of adipose tissue survival during severe hypoxia: implications for autologous fat graft performance. Plast Reconstr Surg Glob Open. 2019;7:e2275.
180. Gir P, Brown SA, Oni G, Kashefi N, Mojallal A, Rohrich RJ. Fat grafting: evidence-based review on autologous fat harvesting, processing, reinjection, and storage. Plast Reconstr Surg. 2012;130:249–258.
181. Massa M, Gasparini S, Baldelli I, et al. Interaction between breast cancer cells and adipose tissue cells derived from fat grafting. Aesthet Surg J. 2016;36:358–363.
182. Ejaz A, Yang KS, Venkatesh KP, Chinnapaka S, Kokai LE, Rubin JP. The impact of human lipoaspirate and adipose tissue-derived stem cells contact culture on breast cancer cells: implications in breast reconstruction. Int J Mol Sci. 2020;21:9171.
183. Krastev T, van Turnhout A, Vriens E, Smits L, van der Hulst R. Long-term follow-up of autologous fat transfer vs conventional breast reconstruction and association with cancer relapse in patients with breast cancer. JAMA Surg. 2019;154:56–63.