Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds.
Transl Res
; 205: 51-63, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30452888
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.
Palabras clave
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
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Cicatrización de Heridas
/
Heridas y Lesiones
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Células Madre Hematopoyéticas
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Dipeptidil Peptidasa 4
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Diabetes Mellitus Experimental
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Inhibidores de la Dipeptidil-Peptidasa IV
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Neovascularización Patológica
Idioma:
En
Revista:
Transl Res
Asunto de la revista:
MEDICINA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Año:
2019
Tipo del documento:
Article