Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds

Transl Res. 2019 Mar:205:51-63. doi: 10.1016/j.trsl.2018.10.006. Epub 2018 Nov 2.

Abstract

In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.

Keywords: BM-MPC = bone marrow-derived mesenchymal progenitor cell; DMEM = Dulbecco's Modified Eagle Medium; DPP-4 = dipeptidyl peptidase-4; FBS = fetal bovine serum; MPC = mesenchymal progenitor cell; NIH = National Institute of Health; PBS = phosphate buffered saline; SDF-1 = stromal cell-derived factor-1; VEGF = vascular endothelial growth factor; WT = wild type; qRT-PCR = quantitative reverse transcription polymerase chain reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CXCL12 / metabolism
  • Diabetes Mellitus, Experimental / complications*
  • Dipeptidyl Peptidase 4 / drug effects*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Glipizide / pharmacology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic*
  • Triazoles / pharmacology
  • Wound Healing / drug effects*
  • Wounds and Injuries / physiopathology*

Substances

  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Dipeptidyl-Peptidase IV Inhibitors
  • MK0626
  • Triazoles
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse
  • Glipizide