title: Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling.
abstract: BACKGROUND
  Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial-mesenchymal interaction during embryonic development. Recent observations indicate that exogenous administration of Shh can induce angiogenesis and may accelerate repair of ischemic myocardium and skeletal muscle. Because angiogenesis plays a pivotal role in wound repair, we hypothesized that activation of the hedgehog pathway may promote a favorable effect on microvascular remodeling during cutaneous wound healing and thereby accelerate wound closure. Because diabetes is associated with impaired wound healing, we tested this hypothesis in a diabetic model of cutaneous wound repair.
  
  
  RESULTS
  In Ptc1-LacZ mice, cutaneous injury resulted in LacZ expression, indicating that expression of the Shh receptor Patched was induced and therefore that the Shh signaling pathway was intact postnatally and upregulated in the process of wound repair. In diabetic mice, topical gene therapy with the use of naked DNA encoding for Shh resulted in significant local gene expression and acceleration of wound recovery. The acceleration in wound healing was notable for increased wound vascularity. In bone marrow transplantation models, the enhanced vascularity of the wound was shown to be mediated, at least in part, by enhanced recruitment of bone marrow-derived endothelial progenitor cells. In vitro, Shh promoted production of angiogenic cytokines from fibroblasts as well as proliferation of dermal fibroblasts. Furthermore, Shh directly promoted endothelial progenitor cell proliferation, migration, adhesion, and tube formation.
  
  
  CONCLUSIONS
  These findings suggest that a simple strategy of topically applied Shh gene therapy may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as occurs in diabetes.
authors.affiliation: Division of Cardiovascular Research and Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
authors.forename: Hideya
authors.initials: H
authors.lastname: Takenaka
authors.forename: Kengo F
authors.initials: KF
authors.lastname: Kusano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Corinne
authors.initials: C
authors.lastname: Luedemann
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eaton
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwakura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hamada
authors.forename: Saburo
authors.initials: S
authors.lastname: Kishimoto
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods; D053823:Hedgehog Proteins; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D042501:Angiogenic Proteins; D017931:DNA Primers; D053823:Hedgehog Proteins; D015534:Trans-Activators