title: Tumor necrosis factor improves vascularization in osteogenic grafts engineered with human adipose-derived stem/stromal cells.
abstract: The innate immune response following bone injury plays an important role in promoting cellular recruitment, revascularization, and other repair mechanisms. Tumor necrosis factor-α (TNF) is a prominent pro-inflammatory cytokine in this cascade, and has been previously shown to improve bone formation and angiogenesis in a dose- and timing-dependent manner. This ability to positively impact both osteogenesis and vascular growth may benefit bone tissue engineering, as vasculature is essential to maintaining cell viability in large grafts after implantation. Here, we investigated the effects of exogenous TNF on the induction of adipose-derived stem/stromal cells (ASCs) to engineer pre-vascularized osteogenic tissue in vitro with respect to dose, timing, and co-stimulation with other inflammatory mediators. We found that acute (2-day), low-dose exposure to TNF promoted vascularization, whereas higher doses and continuous exposure inhibited vascular growth. Co-stimulation with platelet-derived growth factor (PDGF), another key factor released following bone injury, increased vascular network formation synergistically with TNF. ASC-seeded grafts were then cultured within polycaprolactone-fibrin composite scaffolds and implanted in nude rats for 2 weeks, resulting in further tissue maturation and increased angiogenic ingrowth in TNF-treated grafts. VEGF-A expression levels were significantly higher in TNF-treated grafts immediately prior to implantation, indicating a long-term pro-angiogenic effect. These findings demonstrate that TNF has the potential to promote vasculogenesis in engineered osteogenic grafts both in vitro and in vivo. Thus, modulation and/or recapitulation of the immune response following bone injury may be a beneficial strategy for bone tissue engineering.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: Hutton
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Renu
authors.initials: R
authors.lastname: Kondragunta
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Moore
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ben P
authors.initials: BP
authors.lastname: Hung
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Material Sciences and Engineering, Johns Hopkins University School of Engineering, Baltimore, Maryland, United States of America.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Grayson
mesh_terms: D000818:Animals; D016025:Bone Transplantation / Q000379:methods; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D011923:Rats, Nude; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D017154:Stromal Cells / Q000187:drug effects*; D050151:Subcutaneous Fat / Q000166:cytology* / Q000187:drug effects; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014409:Tumor Necrosis Factor-alpha