1429 VEGF mediates rejuvenation of aged human skin xenografts in young mice

Abstract

Previously we have shown that transplantation of aged human skin onto young SCID mice results in a rejuvenated human epidermal phenotype. Here, we demonstrate that the rejuvenation of old human skin xenotransplants onto young SCID/beige mouse skin well extends beyond the epidermis and leads to statistically significant improvements in multiple skin aging-associated read-outs assessed by quantitative histomorphometry, which showed e.g. thickening of the epidermis, along with basal layer keratinocyte proliferation, increased vascularization, significantly more collagen type I and III and elastic fibers, and number of epidermal melanocytes in aged human skin xenotransplants.Gene expression RNA-Seq analyses of DEGs showed in 1week versus pre-transplant numerous transcripts related to hypoxia, VEGF and angiogenesis, inflammation, the Notch, TGF-β and IGF pathways, genes related to reinnervation, as well as keratins and epidermal regulators. qRT-PCR confirmed an upregulation of VEGFA and HIF1A, as well as angiogenesis-related genes. Proinflammatory infiltrates expressing CXCL1 and CXCL5 were also confirmed by these data. Skin rejuvenation was primarily mediated by the angiogenesis-promoting growth factor, VEGF, since injection of anti-VEGF blocking antibodies alone, but not of TGF-ß, IGF-1- or HGF-neutralizing antibodies, sufficed to prevent the rejuvenation of old human skin in vivo. Conversely, intradermal injection of VEGF-loaded nanoparticles reversed the aged human skin phenotype when aged human skin was grafted onto old mice. Our study shows that a remarkable degree of rejuvenation of aged human skin is possible in vivo and that VEGF-mediated signaling i a key pathway in this process.