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 language | English (US) |
|---|---|
| Pages (from-to) | 2627-2636 |
| Number of pages | 10 |
| Journal | FASEB Journal |
| Volume | 30 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2016 |
| Externally published | Yes |
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Keywords
- Cell seeding
- Congenital heart defect defect
- Fontan operation
- Inflammation
- Regenerative medicine
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
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 journal › Article
}
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.
PY - 2016/1/1
Y1 - 2016/1/1
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
UR - http://www.scopus.com/inward/record.url?scp=84978034194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978034194&partnerID=8YFLogxK
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 -