Researchers here report on an investigation of mechanisms by which aged human skin is improved in function when transplanted onto young immunocompromised mice. They identified VEGF-A as a factor involved in this improvement, and showed that delivering VEGF-A to human skin models can reduce signatures of aging. This is interesting, as a number of skin conditions exhibit high levels of VEGF-A, and are treated by therapies that are shown to inhibit VEGF-A in addition to other effects. Thus more work is needed here in order to understand whether or not VEGF-A based treatments are a viable path to improving aged skin function.
Human skin is ideally suited as a preclinical aging research model but is rarely used by mainstream aging research for this purpose. Yet, aging of the human body becomes nowhere sooner and more immediately visible than in skin changes and hair graying. While massive industry efforts therefore cater to the ancient human desire to halt or reverse the phenotype of aging skin, success at this frontier has remained moderate at best, and many product claims of in vivo rejuvenation of human skin are typically insufficiently substantiated. Nevertheless, the molecular mechanisms that underlie extrinsic and intrinsic skin aging in vivo are becoming increasingly understood, albeit mostly in nonhuman animal models of uncertain clinical relevance.
Previously, we had shown that grafting aged human skin to immunocompromised young mice reverts several aging-associated parameters in the epidermis of the human xenotransplants. Yet, it is unknown whether the observed skin rejuvenation effects extend beyond the epidermis, and the molecular mechanisms that underlie this striking epidermal rejuvenation phenomenon have remained elusive. Examining this accessible, experimentally pliable, and clinically relevant model for human organ rejuvenation in vivo, the present study hoped to identify druggable targets for human organ rejuvenation.
Transplanting aged human skin onto young immunocompromised mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including ß-galactosidase, p16ink4a, SIRT1, PGC1α, collagen 17A, and MMP1. Angiogenesis- and hypoxia-related pathways, namely, vascular endothelial growth factor A (VEGF-A) and HIF1A, 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 transplanted onto 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.