Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks

Abstract

Notwithstanding remarkable progress in vascular network engineering, implanted bioengineered microvessels largely fail to form anastomoses with the host vasculature. Here, we demonstrate that implants containing assembled human vascular networks (A-Grafts) fail to engraft due to their inability to engage non-inflammatory host neutrophils upon implantation into mice. In contrast, unassembled vascular cells (U-Grafts) readily engage alternatively polarized neutrophils, which in turn serve as indispensable mediators of vascular assembly and anastomosis. The depletion of host neutrophils abrogated vascularization in U-Grafts, whereas an adoptive transfer of neutrophils fully restored vascularization in myeloid-depleted mice. Neutrophil engagement was regulated by secreted factors and was progressively silenced as the vasculature matured. Exogenous addition of factors from U-Grafts reengaged neutrophils and enhanced revascularization in A-Grafts, a process that was recapitulated by blocking Notch signaling. Our data suggest that the pro-vascularization potential of neutrophils can be harnessed to improve the engraftment of bioengineered tissues.

Robust differentiation of human pluripotent stem cells into endothelial cells via temporal modulation of ETV2 with modified mRNA

“…5F). This high percentage of perivascular coverage is to be expected by day 7 in this model (25), and vessels formed by control ECFCs consistently displayed high coverage ( Fig. 5F).…”

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

“…On the other hand, neutrophils not only participate in inflammation but they can also promote vascularization by inducing angiogenesis via a proangiogenic phenotype [61,62]. In this regard, proteins such as LCN2 have been found to induce angiogenesis in several breast cancers [63] and upregulation of LCN2 has been shown to promote EC tube formation and migration via iron and ROSrelated pathways in rat's brain [64].…”

Localized Delivery of Cl-Amidine From Electrospun Polydioxanone Templates to Regulate Acute Neutrophil NETosis: A Preliminary Evaluation of the PAD4 Inhibitor for Tissue Engineering

“…Neutrophils secrete potent pro-angiogenic factors in large quantities, like inhibitor free matrix metalloproteinase 9 (MMP-9), to guide and direct the growth of new blood vessels (Ardi et al, 2007 ). Without neutrophils, Lin et al found vascularization of their biomaterial abrogated (Lin et al, 2017 ). Regulating NETosis and neutrophil invasion may work in tandem to enhance tissue integration and regeneration.…”