TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation

Yong Ung Lee, Juan De Dios Ruiz-Rosado, Nathan Mahler, Cameron A. Best, Shuhei Tara, Tai Yi, Toshihiro Shoji, Tadahisa Sugiura, Avione Y. Lee, Frank Robledo-Avila, Narutoshi Hibino, Jordan S. Pober, Toshiharu Shinoka, Santiago Partida-Sanchez, Christopher K. Breuer

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Stenosis is a critical problem in the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-β receptor 1 (TGF-βR1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-βR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-βR1 inhibitor systemic treatment for the first 2 wk. The TGF-βR1 inhibitor treatment effectively improved TEVG patency at 6 mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-β to LPS/IFN-γ-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-α, IL-12, and IL-6; this effect was blocked by TGF-βR1 inhibition (P < 0.0001). These findings suggest that the TGF-β signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-βR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining neotissue formation.

Original languageEnglish (US)
Pages (from-to)2627-2636
Number of pages10
JournalFASEB Journal
Volume30
Issue number7
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • Cell seeding
  • Congenital heart defect defect
  • Fontan operation
  • Inflammation
  • Regenerative medicine

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Lee, Y. U., De Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., & Breuer, C. K. (2016). TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation. FASEB Journal, 30(7), 2627-2636. https://doi.org/10.1096/fj.201500179R