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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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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Acknowledgements

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

Contributions

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.

Corresponding authors

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). https://doi.org/10.1007/s13770-022-00470-4

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  • DOI: https://doi.org/10.1007/s13770-022-00470-4

Keywords

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