The effect of DPP-4 inhibitor on angiogenic regeneration by bone marrow mesenchymal stem cell in hind limb ischemia injury model

Abstract

Background: Mesenchymal stem cells (MSCs) are known to have a therapeutic potential for severe limb ischemia. However, poor survival of implanted MSCs in the target tissue remains as an important factor that attenuates the angiogenic potential of the cell therapy.

Thus, we investigated whether sitagliptin, a DPP-4 inhibitor, may enhance the angiogenic efficacy of MSC in a hind limb ischemia murine model by increasing production of SDF-1.

Methods and Results: Mice with induced hind limb ischemia were devided into 4 groups; group 1 treated with oral saline and local injection of saline, group 2 treated with oral sitagliptin and local injection of saline, group 3 treated with oral saline and local injection of MSCs, and group 4 treated with oral sitagliptin and local injection of MSCs. Angiogenic responses were measured by laser-Doppler perfusion imaging, muscle capillary density, and protein and mRNA expression of SDF-1, CXCR4, and vascular endothelial growth factor VEGF growth factors and compared among the treatment groups.

The combined treatment of oral sitagliptin and local injection of MSCs achieved more effective angiogenic response than oral sitagliptin administration or local MSC transplantation alone in a mouse hind limb ischemia model. The combination therapy also demonstrated increased expression of VEGF, SDF-1 and CXCR4 in hind limb ischemia models.

Conclusion: The combination therapy of oral sitagliptin and local transplantation of MSCs was more effective in enhancing angiogenic responses to ischemia than oral sitagliptin or local transplantation of MSCs alone possibly due to up-regulation of SDF-1.