title: TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.
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.-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. TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Yong-Ung
authors.initials: YU
authors.lastname: Lee
authors.affiliation: Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Juan
authors.initials: J
authors.lastname: de Dios Ruiz-Rosado
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Nathan
authors.initials: N
authors.lastname: Mahler
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Best
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tara
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Sugiura
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Avione Y
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, Ohio, USA;
authors.forename: Frank
authors.initials: F
authors.lastname: Robledo-Avila
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Cardiothoracic Surgery-The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA; and.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Hibino
authors.affiliation: Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Cardiothoracic Surgery-The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA; and.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shinoka
authors.affiliation: Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, Ohio, USA; santiago.partida-sanchez@nationwidechildrens.org.
authors.forename: Santiago
authors.initials: S
authors.lastname: Partida-Sanchez
authors.affiliation: Tissue Engineering Program, Nationwide Children's Hospital, Columbus, Ohio, USA; christopher.breuer@nationwidechildrens.org.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Breuer
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D003251:Constriction, Pathologic; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023822:Tissue Engineering; D054457:Tissue Scaffolds
chemical_list: D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta
keywords: Fontan operation; cell seeding; congenital heart defect; inflammation; regenerative medicine