Adipose-derived stem cells promote lymphangiogenesis in response to VEGF-C stimulation or TGF-Β1 inhibition

Alan Yan, Tomer Avraham, Jamie C. Zampell, Yosef S. Haviv, Evan Weitman, Babak J. Mehrara

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Aims: Recent studies have demonstrated that augmentation of lymphangiogenesis and tissue engineering hold promise as a treatment for lymphedema. The purpose of this study was to determine whether adipose-derived stem cells (ASCs) can be used in lymphatic tissue-engineering by altering the balance between pro- and anti-lymphangiogenic cytokines. Materials & methods: ASCs were harvested and cultured in media with or without recombinant VEGF-C for 48 h. ASCs were then implanted in mice using Matrigel plugs. Additional groups of animals were implanted with ASCs transfected with a dominant-negative TGF-Β1 receptor-II adenovirus with or without VEGF-C stimulation, since TGF-Β1 has been shown to have potent antilymphangiogenic effects. Lymphangiogenesis, lymphatic differentiation and cellular proliferation were assessed. Results: Stimulation of ASCs with VEGF-C in vitro significantly increased expression of VEGF-A, VEGF-C and Prox-1. ASCs stimulated with VEGF-C prior to implantation induced a significant (threefold increase) lymphangiogenic response as compared with control groups (unstimulated ASCs or empty Matrigel plugs; p < 0.01). This effect was significantly potentiated when TGF-Β1 signaling was inhibited using the dominant-negative TGF-Β1 receptor-II virus (4.5-fold increase; p < 0.01). Stimulation of ASCs with VEGF-C resulted in a marked increase in the number of donor ASCs (twofold; p < 0.01) and increased the number of proliferating cells (sevenfold; p < 0.01) surrounding the Matrigel. ASCs stimulated with VEGF-C expressed podoplanin, a lymphangiogenic cell marker, whereas unstimulated cells did not. Conclusion: Short-term stimulation of ASCs with VEGF-C results in increased expression of VEGF-A, VEGF-C and Prox-1 in vitro and is associated with a marked increase lymphangiogenic response after in vivo implantation. This lymphangiogenic response is significantly potentiated by blocking TGF-Β1 function. Furthermore, stimulation of ASCs with VEGF-C markedly increases cellular proliferation and cellular survival after in vivo implantation and stimulated cells express podoplanin, a lymphangiogenic cell marker.

Original languageEnglish
Pages (from-to)1457-1473
Number of pages17
JournalFuture Oncology
Volume7
Issue number12
DOIs
StatePublished - 1 Jan 2011
Externally publishedYes

Keywords

  • TGF-Β
  • VEGF-C
  • adipose-derived stem cells
  • antilymphangiogenic
  • lymphangiogenesis

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