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Newborns with severe congenital heart defects often require implantation of a graft to replace defective arteries and valves soon after birth. The current materials used for grafts all possess an inability to integrate and grow with the patient, resulting in repeated surgical interventions to replace failed grafts. Tissue engineering has aimed to address this limitation by seeding grafts with cells to create a biological “living” graft, however, the choice of cells is a critical aspect that is often not thoroughly explored, and thus limited success has been achieved. Here we identify and characterise a novel umbilical cord-derived pericyte (UCP) population with enhanced therapeutic potential for vascular tissue engineering in patients with CHD. Methods and results CD31-/NG2+ UCPs were isolated from the umbilical cord by explant outgrowth, and purified using magnetic activated cell sorting and flow cytometry. Doubling time and viability was quantified by counting cells on consecutive days for 1 week. UCPs maintained a viability of above 90% throughout culture and demonstrated a population doubling time of 50–70 hours. To assess angiogenic potential, endothelial-fibroblast cocultures were treated with UCP-conditioned medium and the cumulative tube network was measured. UCPs induced an increase of 9.9mm±2mm in tube length whereas mesenchymal stromal cells (MSCs) only induced a 1.8±1mm increase. The promigratory effect of UCPs on endothelial cells was tested using a scratch assay treated with conditioned medium. Endothelial cells treated with UCP conditioned medium demonstrated a 3.0±0.2-fold increase in migration compared with endothelial cells treated with MSC conditioned medium. Finally, the capability of UCPs to form functional vascular tissue was assessed using a differentiation and contraction assay. Differentiated cells demonstrated an increased expression of vascular smooth muscle markers alpha smooth muscle actin (aSMA; 7.1±1.6 protein fold change vs control), calponin (22.5±3.9 protein fold change vs control), Transgelin (7.4±1.6 protein fold change vs control) and smooth muscle myosin heavy chain (SM-MHC; 1.7±0.1 protein fold change vs control). Both differentiated and undifferentiated UCPs exhibited a contractile response to vasoactive peptide endothelin-1, however, differentiated UCPs demonstrated a 65.3±14.9% increase in contraction from the inhibited state, compared to 37.3±10.7% for undifferentiated UCPs. Conclusion UCPs are an ideal autologous cell population for vascular tissue engineering in newborns. They are capable of forming functional vascular tissue and can be expanded sufficiently within the surgical window for CHD treatment. Furthermore, UCPs hold distinct advantages over MSCs. Namely, UCPs induce a greater increase in endothelial migration and network formation, which is essential for endothelisation and perfusion of engineered tissue. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Heart Research UK

Umbilical cord-derived pericytes present an optimal cell population for vascular tissue engineering in newborns