title: Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds.
abstract: Diabetic foot ulcers (DFU) are a major, debilitating complication of diabetes mellitus. Unfortunately, many DFUs are refractory to existing treatments and frequently lead to amputation. The development of more effective therapies has been hampered by the lack of predictive in vitro methods to investigate the mechanisms underlying impaired healing. To address this need for realistic wound-healing models, we established patient-derived fibroblasts from DFUs and site-matched controls and used them to construct three-dimensional (3D) models of chronic wound healing. Incorporation of DFU-derived fibroblasts into these models accurately recapitulated the following key aspects of chronic ulcers: reduced stimulation of angiogenesis, increased keratinocyte proliferation, decreased re-epithelialization, and impaired extracellular matrix deposition. In addition to reflecting clinical attributes of DFUs, the wound-healing potential of DFU fibroblasts demonstrated in this suite of models correlated with in vivo wound closure in mice. Thus, the reported panel of 3D DFU models provides a more biologically relevant platform for elucidating the cell-cell and cell-matrix-related mechanisms responsible for chronic wound pathogenesis and may improve translation of in vitro findings into efficacious clinical applications.
authors.affiliation: 1 Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University , Boston, Massachusetts.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Maione
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Brudno
authors.forename: Olivera
authors.initials: O
authors.lastname: Stojadinovic
authors.forename: Lara K
authors.initials: LK
authors.lastname: Park
authors.forename: Avi
authors.initials: A
authors.lastname: Smith
authors.forename: Ana
authors.initials: A
authors.lastname: Tellechea
authors.forename: Ermelindo C
authors.initials: EC
authors.lastname: Leal
authors.forename: Cathal J
authors.initials: CJ
authors.lastname: Kearney
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic-Canic
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Garlick
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D017719:Diabetic Foot / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D023822:Tissue Engineering / Q000379:methods*; D014945:Wound Healing
chemical_list: D016207:Cytokines