Atypical chemokine receptor ACKR3/CXCR7 controls postnatal vasculogenesis and arterial specification by mesenchymal stem cells via Notch signaling

Abstract

Mesenchymal stem cells (MSCs) are known to play a role in postnatal vasculogenesis and hold great promise for vascular regeneration. However, the mechanisms by which the endothelial differentiation and specification of MSCs remain unclear. We examined the potential role and molecular mechanisms of atypical chemokine receptor ACKR3/ CXCR7 in MSC-mediated endothelial cell differentiation and specification. Here, we showed that vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) activate CXCR7 expression on MSCs through PDGF receptors, PDGFRα and PDGFRβ-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling. Genetic and pharmacologic blockage of CXCR7 on MSCs suppressed the VEGF or stromal cell-derived factor 1 (SDF)-1-induced the capacity for vasculogenesis in vitro and in vivo. Moreover, CXCR7 gain of function markedly promoted vasculogenesis by MSCs in vitro and in vivo and induced endothelial differentiation along the arterial endothelial cell lineage via upregulation of Notch signaling. However, blockade of Notch signaling inhibited CXCR7-induced vasculogensis by MSCs. These results indicate CXCR7 is a critical regulator of MSC-mediated postnatal vasculogenesis and arterial specification via Notch signaling.

CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor

“…Although CXCR7 seemed to promote cell survival under the ischemic condition in vitro , it is unclear whether the upstream of CXCR7 regulation is shared with other cardioprotective molecules, such as NPPA, NPPB, or SLC6A6. CXCR7 expression reportedly is increased upon tissue hypoxia via VEGF 45 or in the inflammatory response via NF-kB induction 46 and therefore, it is plausible that both hypoxia and an inflammatory response occur within the border zone of the infarcted heart, thereby enhancing CXCR7 expression to attenuate cell death (Fig. 4 a).…”

Emerging Roles of the Atypical Chemokine Receptor 3 (ACKR3) in Cardiovascular Diseases

“…In addition, ACKR3 is a critical regulator of mesenchymal stem cells-mediated postnatal vasculogenesis and arterial specification in vitro and in vivo via Notch signalling. These effects have been associated with the activation of ACKR3 expression on mesenchymal stem cells by VEGF and PDGF ( 41 ). Alternatively, several studies showed that ACKR3 governs the survival and proliferation of endothelial progenitor cells (EPCs) and their adhesion onto the endothelium contributing to angiogenesis ( 92 , 93 ).…”

Single-cell RNA sequencing reveals resident progenitor and vascularization-associated cell subpopulations in rat annulus fibrosus

“…Angptl1 encodes angiopoietin-like 1, a member of the vascular endothelial growth factor family [ 53 ]. Atypical chemokine receptor CXCR7 (ACKR3) promotes developmental and pathological angiogenesis [ 54 ]. PDGFRα also mediates angiogenesis and connective tissue remodeling [ 55 ].…”