Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice

Diabetologia. 2011 Apr;54(4):945-53. doi: 10.1007/s00125-010-2007-2. Epub 2010 Dec 17.


Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology*
  • Cell Proliferation
  • Cell Survival / physiology
  • Diabetes Mellitus / therapy*
  • Mice
  • Stem Cell Transplantation
  • Stem Cells / cytology*
  • Stem Cells / physiology*
  • Wound Healing / physiology*