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BackgroundDPP4 (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)/CXCL12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4‐GLP‐1/GLP‐1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress.Methods and ResultsMale 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 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 CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca‐1highc‐Kithigh CD48low CD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP4 depletion and by GLP‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress.ConclusionsThese findings suggest that DPP4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12‐dependent mechanism that is mediated by the GLP‐1/GLP‐1R axis, suggesting that the DPP4 inhibition or the GLP‐1R stimulation may have applications for treating inflammatory diseases.

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Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.