Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of
secondary lymphedema
摘要
Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunctionleading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, weidentified apelin (APLN) as a powerful molecule for regenerating lymphatic functionin LD. We identified the loss of APLN expression in the lymphedematous arm comparedto the normal arm in patients. The role of APLN in LD was confirmed in APLN knockoutmice, in which LD is increased and associated with fibrosis and dermal backflow.This was reversed by intradermal injection of APLN-lentivectors. Mechanistically,APLN stimulates lymphatic endothelial cell gene expression and induces the bindingof E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-Cprocessing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphaticcollector pumping. Our results show that APLN represents a novel partner for VEGF-Cto restore lymphatic function in both initial and collecting vessels. As LD appearsafter cancer treatment, we validated the APLN-VEGF-C combination using a novel classof nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phaseI/IIa clinical trial.