Human organ rejuvenation by VEGF-A: Lessons from the skin

Transplanting aged human skin onto young SCID/beige mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including beta-galactosidase, p16(ink4a), SIRT1, PGC1 alpha, collagen 17A, and MMP1. Angiogenesis-and hypoxia-related pathways, namely, vascular endothelial growth factor A (VEGF-A) and HIFI A, are most up-regulated in rejuvenated human skin. This rejuvenation cascade, which can be prevented by VEGF-A-neutralizing antibodies, appears to be initiated by murine VEGF-A, which then up-regulates VEGF-A expression/secretion within aged human skin. While intradermally injected VEGF-loaded nanoparticles suffice to induce a molecular rejuvenation signature in aged human skin on old mice, VEGF-A treatment improves key aging parameters also in isolated, organ-cultured aged human skin, i.e., in the absence of functional skin vasculature, neural, or murine host inputs. This identifies VEGF-A as the first pharmacologically pliable master pathway for human organ rejuvenation in vivo and demonstrates the potential of our humanized mouse model for clinically relevant aging research.

Automated summary

Transplanting aged human skin onto young SCID/beige mice can rejuvenate the skin and improve aging-related biomarkers. The rejuvenation cascade is initiated by murine VEGF-A, which up-regulates VEGF-A expression/secretion within aged human skin. VEGF-A is identified as the first pharmacologically pliable master pathway for human organ rejuvenation in vivo.