Mechanism causing age-related reductions in wound healing discovered
Researchers from The Rockefeller University (NY, USA) have demonstrated that impaired wound healing in aged skin is a result of dendritic T cell activation, and that epidermally expressed Skints mediate keratinocyte– dendritic epithelial T cell crosstalk.
Researchers from The Rockefeller University (NY, USA), led by Elain Fuchs – the Rebecca C. Lancefield Professor and head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology, have revealed the age-related bodily alterations that result in slower wound healing. By studying aging mouse skin, the group has uncovered novel mechanisms involved in wound healing, which could be utilized to enhance healing in the elderly in the future.
Wound healing is a highly complex process that involves a wide number of cells, molecular pathways and signaling systems. It is well known that wounds to aged skin heal at a reduced rate compared with younger skin, resulting in an increased susceptibility to infection. This highlights the importance of a better understanding of the age-related changes that occur at each stage of the process.
The study involved assessing molecular alterations in aging mouse skin, more specifically the stage in which keratinocytes travel to the wound site under the forming scab. They assessed the difference in keratinocyte migration in 2- versus 24-month-old mice, which is thought to represent the difference between 20- and 70-year-old humans.
The team discovered that aging caused intrinsic defects and disruption in the communication between keratinocytes and nearby immune cells through Skint3/9 proteins, resulting in a reduced the rate of skin cell migration and wound closure.
Aged keratinocytes at the wound edge were also demonstrated to have a reduced ability to activate dendritic epithelial T cells, key mediators of re-epithelialization post-injury, and reduced STAT3 activation. Upon silencing Skint genes, Stat3 and dendritic epithelial T cells in young skin, the researchers in fact demonstrated that re-epithelialization following wounding was perturbed. Together, the findings highlight epithelial–immune crosstalk reductions in general, and Skint genes more specifically, as critical mediators in the age-related decline observed in wound repair. Moreover, STAT3 signaling was indicated as regulating Skint expression.
In an attempt to enhance Skint signaling in aged skin, the researchers also applied a protein normally released by immune cells following injury to the tissue, which resulted in enhanced keratinocyte migration. “Our work suggests it may be possible to develop drugs to activate pathways that help aging skin cells to communicate better with their immune cell neighbors, and so boost the signals that normally decline with age,” stated Fuchs.
Sources: Keyes BE, Liu S, Asare A et al. Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin. Cell 167(5), 1323–1338.e14 (2016); http://newswire.rockefeller.edu/2016/11/17/new-research-clarifies-why-wounds-heal-more-slowly-with-age/