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Adenosine-Prefabricated Adipose Tissue Improves Fat Graft Survival by Promoting VEGF-Dependent Angiogenesis



Angiogenesis plays an important role in determining the fat graft survival. However, clinical preconditioning techniques that target angiogenesis during fat grafting have not been established so far. Adenosine has emerged as a regulator of angiogenesis under hypoxic conditions; therefore, the aim of this study was to investigate the effects and underlying mechanisms of adenosine prefabrication on fat graft survival.


In the first animal study, a total of 32 mice were transplanted with fat prefabricated with vehicle (Control, N = 16) or adenosine (Adenosine, N = 16). In the second animal study, 24 mice were divided into three groups based on the type of fat graft: Control (N = 8), Adenosine (N = 8), and Axitinib (cotreatment of adenosine with axitinib, N = 8). At 1- and 4-weeks post-transplantation, grafts were evaluated by histopathological and biochemical assessment. Adenosine-induced vascular endothelial growth factor (VEGF) production and angiogenesis were determined using cell cultures.


The retention volumes of fat grafts in the adenosine group were significantly increased until 4 weeks. Fat grafts from the adenosine group exhibited greater structural integrity, reduced fibrosis, and increased blood vessels. The expression levels of angiogenesis-related genes, Vegfa, Vegfr1, Vegfr2, and Vwf, were elevated in the adenosine group. Furthermore, adenosine upregulated VEGF production in preadipocytes, thereby enhancing the migration of endothelial cells. Treatment with the axitinib, VEGF receptor inhibitor, abrogated the adenosine-induced angiogenesis in the fat grafts.


Adenosine prefabrication in fat improved the graft survival by enhancing angiogenesis through the VEGF/VEGFR axis in the preadipocytes and endothelial cells. Therefore, this method may be used as a novel strategy to increase the retention rate in fat grafts.

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  1. Fredman R, Katz AJ, Hultman CS. Fat grafting for burn, traumatic, and surgical scars. Clin Plast Surg. 2017;44:781–91.

    Article  Google Scholar 

  2. Doornaert M, Colle J, De Maere E, Declercq H, Blondeel P. Autologous fat grafting: latest insights. Ann Med Surg (Lond). 2019;37:47–53.

    Article  Google Scholar 

  3. Kolle SF, Fischer-Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, Glovinski PV, 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;382:1113–20.

    Article  Google Scholar 

  4. Kerfant N, Albacete G, Guernec A, Inizan M, Amerand A, Hu W, et al. Fat grafting: early hypoxia, oxidative stress, and inflammation developing prior to injection. J Plast Reconstr Aesthet Surg. 2020;73:1775–84.

    Article  Google Scholar 

  5. Shim YH, Zhang RH. Literature review to optimize the autologous fat transplantation procedure and recent technologies to improve graft viability and overall outcome: a systematic and retrospective analytic approach. Aesthetic Plast Surg. 2017;41:815–31.

    Article  Google Scholar 

  6. Vyas KS, Vasconez HC, Morrison S, Mogni B, Linton S, Hockensmith L, et al. Fat graft enrichment strategies: a systematic review. Plast Reconstr Surg. 2020;145:827–41.

    CAS  Article  Google Scholar 

  7. Luo S, Hao L, Li X, Yu D, Diao Z, Ren L, et al. Adipose tissue-derived stem cells treated with estradiol enhance survival of autologous fat transplants. Tohoku J Exp Med. 2013;231:101–10.

    CAS  Article  Google Scholar 

  8. Park B, Kong JS, Kang S, Kim YW. The effect of epidermal growth factor on autogenous fat graft. Aesthetic Plast Surg. 2011;35:738–44.

    Article  Google Scholar 

  9. Shoshani O, Livne E, Armoni M, Shupak A, Berger J, Ramon Y, et al. The effect of interleukin-8 on the viability of injected adipose tissue in nude mice. Plast Reconstr Surg. 2005;115:853–9.

    CAS  Article  Google Scholar 

  10. Zhang T, Dai J, Xu Y, Yu L, Wang X. Liquid phase concentrated growth factor improves autologous fat graft survival in vivo in nude mice. Aesthetic Plast Surg. 2021;45:2417–22.

    Article  Google Scholar 

  11. Csóka B, Koscsó B, Töro G, Kókai E, Virág L, Németh ZH, et al. A2B adenosine receptors prevent insulin resistance by inhibiting adipose tissue inflammation via maintaining alternative macrophage activation. Diabetes. 2014;63:850–66.

    CAS  Article  Google Scholar 

  12. Ohta A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol. 2016;7:109.

    Article  Google Scholar 

  13. Gnad T, Scheibler S, von Kügelgen I, Scheele C, Kilić A, Glöde A, et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature. 2014;516:395–9.

    CAS  Article  Google Scholar 

  14. Ohisalo JJ. Effects of adenosine on lipolysis in human subcutaneous fat cells. J Clin Endocrinol Metab. 1981;52:359–63.

    CAS  Article  Google Scholar 

  15. Turpin BP, Duckworth WC, Solomon SS. Perifusion of isolated rat adipose cells. Modulation of lipolysis by adenosine. J Clin Invest. 1977;60:442–8.

    CAS  Article  Google Scholar 

  16. Merino M, Briones L, Palma V, Herlitz K, Escudero C. Role of adenosine receptors in the adipocyte-macrophage interaction during obesity. Endocrinol Diabetes Nutr. 2017;64:317–27.

    Article  Google Scholar 

  17. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6:263.

    CAS  Article  Google Scholar 

  18. Cha HG, Kim DG, Chang J, Song Y, Jeong S, Nam SM, et al. Fasting: an effective preconditioning method to increase fat graft survival. Aesthetic Plast Surg. 2021.

    Article  PubMed  Google Scholar 

  19. Yu F, Witman N, Yan D, Zhang S, Zhou M, Yan Y, et al. Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model. Stem Cell Res Ther. 2020;11:490.

    Article  Google Scholar 

  20. Du X, Ou X, Song T, Zhang W, Cong F, Zhang S, et al. Adenosine A2B receptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells. Exp Biol Med (Maywood). 2015;240:1472–9.

    CAS  Article  Google Scholar 

  21. Auchampach JA. Adenosine receptors and angiogenesis. Circ Res. 2007;101:1075–7.

    CAS  Article  Google Scholar 

  22. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2:1097–105.

    Article  Google Scholar 

  23. Kling RE, Mehrara BJ, Pusic AL, Young VL, Hume KM, Crotty CA, et al. Trends in autologous fat grafting to the breast: a national survey of the American society of plastic surgeons. Plast Reconstr Surg. 2013;132:35–46.

    CAS  Article  Google Scholar 

  24. Choi M, Small K, Levovitz C, Lee C, Fadl A, Karp NS. The volumetric analysis of fat graft survival in breast reconstruction. Plast Reconstr Surg. 2013;131:185–91.

    CAS  Article  Google Scholar 

  25. Coleman SR. Structural fat grafts: the ideal filler? Clin Plast Surg. 2001;28:111–9.

    CAS  Article  Google Scholar 

  26. Kaufman MR, Miller TA, Huang C, Roostaien J, Wasson KL, Ashley RK, et al. Autologous fat transfer for facial recontouring: is there science behind the art? Plast Reconstr Surg. 2007;119:2287–96.

    CAS  Article  Google Scholar 

  27. Report on autologous fat transplantation. ASPRS Ad-Hoc Committee on New Procedures, September 30, 1987. Plast Surg Nurs. 1987;7:140–1.

    Article  Google Scholar 

  28. Cronstein BN. Adenosine receptors and wound healing. ScientificWorldJournal. 2004;4:1–8.

    CAS  Article  Google Scholar 

  29. Adair TH. Growth regulation of the vascular system: an emerging role for adenosine. Am J Physiol Regul Integr Comp Physiol. 2005;289:R283–96.

    CAS  Article  Google Scholar 

  30. Desai A, Victor-Vega C, Gadangi S, Montesinos MC, Chu CC, Cronstein BN. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol. 2005;67:1406–13.

    CAS  Article  Google Scholar 

  31. Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, et al. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res. 2002;90:531–8.

    CAS  Article  Google Scholar 

  32. Tozzi M, Novak I. Purinergic receptors in adipose tissue as potential targets in metabolic disorders. Front Pharmacol. 2017;8:878.

    Article  Google Scholar 

  33. Gharibi B, Abraham AA, Ham J, Evans BA. Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J Bone Miner Res. 2011;26:2112–24.

    CAS  Article  Google Scholar 

  34. Kocherova I, Bryja A, Mozdziak P, Angelova Volponi A, Dyszkiewicz-Konwinska M, Piotrowska-Kempisty H, et al. Human Umbilical Vein Endothelial Cells (HUVECs) Co-Culture with Osteogenic cells: from molecular communication to engineering prevascularised bone grafts. J Clin Med. 2019;8:1602.

    CAS  Article  Google Scholar 

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This study was supported by the Soonchunhyang University Research Fund and the National Research Foundation of Korea (NRF) grant funded by the Korean government (2019R1A2C1084684).

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Authors and Affiliations



J.C., W.J.S, C.Y.C, and K.W.C. conceived the study and developed the study design; J.C., S.S., and S.S. generated data; W.J.S., Y.J.K., C.Y.C, and K.W.C interpreted the data; W.J.S., C.Y.C., and K.W.C. wrote the manuscript.

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Correspondence to Chang Yong Choi or Kae Won Cho.

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The authors have no financial conflicts of interest.

Ethical statement

The animal studies were performed after receiving approval from the Institutional Animal Care and Use Committee (IACUC) at Soonchunhyang University (IACUC Approval No. SCH20-U-104).

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Chang, J., Song, W.J., Soedono, S. et al. Adenosine-Prefabricated Adipose Tissue Improves Fat Graft Survival by Promoting VEGF-Dependent Angiogenesis. Tissue Eng Regen Med (2022).

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  • Adenosine
  • Vascular endothelial growth factor
  • Prefabrication
  • Fat graft