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

12 Citations (Scopus)

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

Fingerprint

Blood Vessel Prosthesis
Phagocytes
Grafts
Monocytes
Pathologic Constriction
Chemical activation
Tissue
Transplants
Vascular Patency
Inferior Vena Cava
Interleukin-12
Inbred C57BL Mouse
Interleukin-6
Cytokines
Control Groups
Infiltration
Cells

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Lee, Y. U., De Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., ... 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

TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation. / Lee, Yong Ung; De Dios Ruiz-Rosado, Juan; Mahler, Nathan; Best, Cameron A.; Tara, Shuhei; Yi, Tai; Shoji, Toshihiro; Sugiura, Tadahisa; Lee, Avione Y.; Robledo-Avila, Frank; Hibino, Narutoshi; Pober, Jordan S.; Shinoka, Toshiharu; Partida-Sanchez, Santiago; Breuer, Christopher K.

In: FASEB Journal, Vol. 30, No. 7, 01.01.2016, p. 2627-2636.

Research output: Contribution to journalArticle

Lee, YU, De Dios Ruiz-Rosado, J, Mahler, N, Best, CA, Tara, S, Yi, T, Shoji, T, Sugiura, T, Lee, AY, Robledo-Avila, F, Hibino, N, Pober, JS, Shinoka, T, Partida-Sanchez, S & Breuer, CK 2016, 'TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation', FASEB Journal, vol. 30, no. 7, pp. 2627-2636. https://doi.org/10.1096/fj.201500179R
Lee, Yong Ung ; De Dios Ruiz-Rosado, Juan ; Mahler, Nathan ; Best, Cameron A. ; Tara, Shuhei ; Yi, Tai ; Shoji, Toshihiro ; Sugiura, Tadahisa ; Lee, Avione Y. ; Robledo-Avila, Frank ; Hibino, Narutoshi ; Pober, Jordan S. ; Shinoka, Toshiharu ; Partida-Sanchez, Santiago ; Breuer, Christopher K. / TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation. In: FASEB Journal. 2016 ; Vol. 30, No. 7. pp. 2627-2636.
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AU - Lee, Yong Ung

AU - De Dios Ruiz-Rosado, Juan

AU - Mahler, Nathan

AU - Best, Cameron A.

AU - Tara, Shuhei

AU - Yi, Tai

AU - Shoji, Toshihiro

AU - Sugiura, Tadahisa

AU - Lee, Avione Y.

AU - Robledo-Avila, Frank

AU - Hibino, Narutoshi

AU - Pober, Jordan S.

AU - Shinoka, Toshiharu

AU - Partida-Sanchez, Santiago

AU - Breuer, Christopher K.

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