Innate immune cell-mediated regeneration of acellular vascular grafts in aged hosts

Previously we reported on engineering cell-free vascular grafts that harnessed the potential of the innate immune system to remain patent and regenerate into functional neo-arteries in small and large, preclinical animal models. However, the performance of these grafts in aged hosts—the predominant patient demographic in need of vascular graft replacement—remains elusive. To address this gap, we evaluated graft patency and regenerative potential in aged mice and characterized the cellular phenotypes arising within the grafts using the CX3CR1-confetti mouse model, which we previously developed to trace the fate of cells contributing to graft repopulation. Much like in young mice, these grafts remained patent in aged mice throughout the 4-week implantation period and regenerated endothelial and underlying smooth muscle layers, resembling native arteries. Lineage-tracing analysis revealed that the grafts were repopulated by fluorescently-labeled host monocytes/macrophages that expressed both M1 and M2 macrophage markers, with a bias toward a pro-inflammatory phenotype when implanted in aged hosts. Additionally, cells populating the grafts in aged mice exhibited increased markers of cellular senescence compared with those in young hosts. Nevertheless, the grafts remained patent and developed distinct luminal and medial layers resembling native arteries, underscoring their potential suitability for geriatric recipients.