Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats

J Diabetes Complications. 2014 Sep-Oct;28(5):588-95. doi: 10.1016/j.jdiacomp.2014.05.003. Epub 2014 May 22.


Aims/hypothesis: Although the initial healing stage involves a re-epithelialization in humans, diabetic foot ulceration (DFU) has been investigated using rodent models with wounds on the thigh skin, in which a wound contraction is initiated. In this study, we established a rodent model of DFU on the plantar skin and evaluated the therapeutic efficacy of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in this model.

Methods: The wounds made on the hind paws or thighs of streptozotocin induced diabetic or control rats were treated with BM-MSCs. Expression levels of phosphorylated focal adhesion kinase (pFAK), matrix metaroprotease (MMP)-2, EGF, and IGF-1, were evaluated in human keratinocytes, which were cultured in conditioned media of BM-MSCs (MSC-CM) with high glucose levels.

Results: Re-epithelialization initiated the healing process on the plantar, but not on the thigh, skin. The therapy utilizing BM-MSCs ameliorated the delayed healing in diabetic rats. In the keratinocytes cultured with MSC-CM, the decreased pFAK levels in the high glucose condition were restored, and the MMP2, EGF, and IGF-1 levels increased.

Conclusions/interpretation: Our study established a novel rat DFU model. The impaired healing process in diabetic rats was ameliorated by transplantation of BM-MSCs. This amelioration might be accounted for by the modification of keratinocyte functions.

Keywords: Cell therapy; Diabetic complication; Diabetic foot ulcer; Mesenchymal stem cell; Wound healing.

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental* / pathology
  • Diabetes Mellitus, Experimental* / physiopathology
  • Diabetic Foot / physiopathology*
  • Diabetic Foot / therapy*
  • Foot
  • Humans
  • Keratinocytes / pathology
  • Keratinocytes / physiology*
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Skin / pathology
  • Skin / physiopathology
  • Streptozocin
  • Wound Healing*


  • Streptozocin