TY - JOUR
T1 - TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation
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.
N1 - Funding Information:
The authors acknowledge J. Reinhardt, E. Heuer, A. Singh, E. Clark, and E. Onwuka (Tissue Engineering Program, Nationwide Children's Hospital) for their contributions to the preparation of histologic samples and surgical procedures. This research was supported by R01-HL098228 (to C.K.B.). S.P.-S. is supported by the U.S National Institutes of Health, National Institute of Allergy and Infectious Diseases (Grant R01AI092117). C.K.B. and T.S. have received grant support from the Pall Corporation and Gunze Ltd. None of the work presented in this article was funded by the Pall Corporation or Gunze Ltd.
Publisher Copyright:
© FASEB.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Cell seeding
KW - Congenital heart defect defect
KW - Fontan operation
KW - Inflammation
KW - Regenerative medicine
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U2 - 10.1096/fj.201500179R
DO - 10.1096/fj.201500179R
M3 - Article
C2 - 27059717
AN - SCOPUS:84978034194
VL - 30
SP - 2627
EP - 2636
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 7
ER -