title: Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice.
abstract: OBJECTIVE
  Bone marrow (BM)-derived endothelial progenitor cells (EPC) promote tissue healing and angiogenesis, whereas altered EPC biology may favour diabetic complications. We tested the hypothesis that diabetes impairs the contribution of BM-derived cells at sites of wound healing.
  
  
  METHODS
  Four weeks after induction of diabetes in C57BL/6 mice, hindlimb skin wounds were created and monitored by digital imaging and histology. Circulating EPCs were quantified by flow cytometry before and after wounding. In separate experiments, bone marrow from C57BL/6 mice constitutively producing green fluorescent protein (GFP) was transplanted into myeloablated wild-type mice before induction of diabetes. We quantified proliferation, apoptosis and endothelial differentiation of tissue GFP(+) cells. Net recruitment of GFP(+) cells was estimated by correcting the number of tissue GFP(+) cells at each time point for basal levels, apoptosis and proliferation rates.
  
  
  RESULTS
  Diabetes delayed wound healing, with reduced granulation tissue thickness and vascularity, and increased apoptosis. Circulating EPC levels were not modified by 4 week diabetes and/or skin wounding. BM-derived EPCs (GFP(+)vWf(+) [von Willebrand factor] cells) within the granulation tissue were significantly reduced in diabetic compared with control mice. BM-derived GFP(+) cells showed increased apoptosis and decreased proliferation in diabetic versus non-diabetic wound tissues. Estimated net recruitment of BM-derived GFP(+) cells was reduced on day 1 after wounding in diabetic mice.
  
  
  CONCLUSIONS
  Diabetic-delayed wound healing was associated with defective recruitment, survival and proliferation of BM-derived progenitor cells. Local treatments aimed at restoring EPC homing and survival might improve tissue healing in diabetes.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova, Medical School, Via Giustiniani, 2. 35100 Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Albiero
authors.forename: L
authors.initials: L
authors.lastname: Menegazzo
authors.forename: E
authors.initials: E
authors.lastname: Boscaro
authors.forename: C
authors.initials: C
authors.lastname: Agostini
authors.forename: A
authors.initials: A
authors.lastname: Avogaro
authors.forename: G P
authors.initials: GP
authors.lastname: Fadini
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003920:Diabetes Mellitus / Q000628:therapy*; D051379:Mice; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*