title: Tissue-engineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel.
abstract: We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Hibino
authors.forename: Gustavo
authors.initials: G
authors.lastname: Villalona
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pietris
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Duncan
authors.forename: Adam
authors.initials: A
authors.lastname: Schoffner
authors.forename: Jason D
authors.initials: JD
authors.lastname: Roh
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Dobrucki
authors.forename: Dane
authors.initials: D
authors.lastname: Mejias
authors.forename: Rajendra
authors.initials: R
authors.lastname: Sawh-Martinez
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Harrington
authors.forename: Albert
authors.initials: A
authors.lastname: Sinusas
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
authors.forename: Themis
authors.initials: T
authors.lastname: Kyriakides
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shin'oka
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Breuer
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D001808:Blood Vessels / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D005260:Female; D048091:Guided Tissue Regeneration / Q000379:methods*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054457:Tissue Scaffolds; D014185:Transplantation, Isogeneic