Dipeptidyl Peptidase‐4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

Abstract

Background DPP4 (Dipeptidyl peptidase‐4)‐GLP‐1 (glucagon‐like peptide‐1) and its receptor ( GLP ‐1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3‐adrenergic receptor)/ CXCL 12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP 4‐ GLP ‐1/ GLP ‐1 and Adrβ3/CXCL12 signals in bone marrow ( BM ) hematopoietic stem cell ( HSC ) activation in response to chronic stress. Methods and Results Male 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP 4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP 4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP ‐1 levels and the brain GLP ‐1R and BM CXCL 12 expressions. These changes were reversed by DPP 4 inhibition. The stress activated BM sca‐1 high c‐Kit high CD 48 low CD 150 high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP 4 depletion and by GLP ‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL 12 gene expression in BM niche cells in response to chronic stress. Conclusions These findings suggest that DPP 4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/ CXCL 12‐dependent mechanism that is mediated by the GLP ‐1/ GLP ‐1R axis, suggesting that the DPP 4 inhibition or the GLP ‐1R stimulation may have applications for treating inflammatory diseases.