Upregulating CXCR7 accelerates endothelial progenitor cell-mediated endothelial repair by activating Akt/Keap-1/Nrf2 signaling in diabetes mellitus

Abstract

Background Endothelial progenitor cell (EPC) dysfunction contributes to vascular disease in diabetes mellitus. However, the molecular mechanism underlying EPC dysfunction and its contribution to delayed reendothelialization in diabetes mellitus remain unclear. Our study aimed to illustrate the potential molecular mechanism underlying diabetic EPC dysfunction in vivo and in vitro. Furthermore, we assessed the effect of EPC transplantation on endothelial regeneration in diabetic rats. Methods Late outgrowth EPCs were isolated from the bone marrow of rats for in vivo and in vitro studies. In vitro functional assays and Western blotting were conducted to reveal the association between C-X-C chemokine receptor type 7 (CXCR7) expression and diabetic EPC dysfunction. To confirm the association between cellular CXCR7 levels and EPC function, CXCR7 expression in EPCs was upregulated and downregulated via lentiviral transduction and RNA interference, respectively. Western blotting was used to reveal the potential molecular mechanism by which the Stromal-Derived Factor-1 (SDF-1)/CXCR7 axis regulates EPC function. To elucidate the role of the SDF-1/CXCR7 axis in EPC-mediated endothelial regeneration, a carotid artery injury model was established in diabetic rats. After the model was established, saline-treated, diabetic, normal, or CXCR7-primed EPCs were injected via the tail vein. Results Diabetic EPC dysfunction was associated with decreased CXCR7 expression. Furthermore, EPC dysfunction was mimicked by knockdown of CXCR7 in normal EPCs. However, upregulating CXCR7 expression reversed the dysfunction of diabetic EPCs. The SDF-1/CXCR7 axis positively regulated EPC function by activating the AKT-associated Kelch-like ECH-associated protein 1 (keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, which was reversed by blockade of AKT and Nrf2. Transplantation of CXCR7-EPCs accelerated endothelial repair and attenuated neointimal hyperplasia in diabetes mellitus more significantly than transplantation of diabetic or normal EPCs. However, the therapeutic effect of CXCR7-EPC transplantation on endothelial regeneration was reversed by knockdown of Nrf2 expression. Conclusions Dysfunction of diabetic EPCs is associated with decreased CXCR7 expression. Furthermore, the SDF-1/CXCR7 axis positively regulates EPC function by activating the AKT/keap-1/Nrf2 axis. CXCR7-primed EPCs might be useful for endothelial regeneration in diabetes-associated vascular disease.

Dapagliflozin restores diabetes-associated decline in vasculogenic capacity of endothelial progenitor cells via activating AMPK-mediated inhibition of inflammation and oxidative stress

“…Normal level and function of circulating EPCs have been considered to be an endogenous protective factor of vascular diseases [33]. Studies have shown that patients from T2DM endure a reduced number and ability of EPCs [22,34]. In this study, we not only demonstrated T2DM patients had a lower level of circulating EPCs, but also first discovered the number of EPCs was well-correlated with decreased capillary density and increased non-perfused areas in retina.…”

Incoherent collective cell chemotaxis underlies organ dysmorphia in a model of branchio-oto-renal syndrome

“…Given that the causative mutation for over 50% of BOR cases is not yet known, we predict that the lateral line of zebrafish will remain a powerful model to validate genomic polymorphisms from GWAS studies of BOR patients, and generate novel cellular and molecular insights with translational potential. On this regards, our findings raise the possibility that augmenting residual CXCR7 activity may improve the outcome of Eya1 mutations in humans (Jiang et al, 2021; Hughes and Nibbs, 2018). It also encourages the development of tissue engineering approaches to control collective cell migration aimed at clinical applications (Manivannan et al, 2012).…”

CXCL12/CXCR7/β-arrestin1 biased signal promotes epithelial-to-mesenchymal transition of colorectal cancer by repressing miRNAs through YAP1 nuclear translocation

“…Highly expressed CXCR7 activated MAPK/ERK signaling through ligand-independent but β-arr2-dependent mechanisms [ 32 ]. Recent studies uncovered a novel role of β-arrestins in guiding receptor-mediated extracellular signals from cell membrane and transmitting through the cytoplasm to the nucleus by a complicated signaling network [ 33 , 34 ]. In the present study, we revealed that CXCL12/CXCR7 biased signal transmitted predominantly through β-arr1 to facilitate YAP1 nuclear translocation.…”