Humans accumulate scars over their lifetime, however, as one ages, the likelihood a thick, ugly scar forms from a wound is reduced. In fact, dermatologists and plastic surgeons have routinely observed that older patients heal from surgical wounds with thinner scars compared to younger individuals. How then does aging affect scar formation? A new study reveals suppression of a circulating factor in the blood of older mice actually promotes tissue regeneration and reduces scar formation, revealing a rare example of the mammalian body functioning better with age.
Wound repair occurs through a combination of two processes: scarring and tissue regeneration. Scarring is a result of deposition of fibrous tissue that disrupts the normal tissue structure whereas tissue regeneration involves returning the original tissue architecture without any scar formation. In order to understand how aging affects scar formation, scientists utilized the technique of parabiosis, in which two different mice were surgically joined to share a common circulatory system. Following joining the mice together, the ear of each mouse was injured to observe wound closure. Recently published in Cell Reports, the study found that wounds on older mice that were joined to younger mice formed visible scars compared to the absence of scar formation in older, unjoined mice, suggesting the presence of a scar promoting circulating factor in the blood of young mice.
Genomic studies comparing injured young and old mouse skin identified the factor as stromal cell-derived factor 1 (SDF1), which was previously shown to play a role in tissue regeneration in the skin, lung, and liver. Genetic deletion of SDF1 in the skin of young mice enhanced skin regeneration without scar formation and the joining of young SDF1-deficient mice with older mice showed no scar formation in either mouse following skin wounding.
Scientists found that older mice have enhanced recruitment of methyltransferase, EZH2, to the SDF1 promoter, which prevents SDF1 gene expression and thus inhibits scar formation. Interestingly, pharmacological inhibition of EZH2 in older mice induced SDF1 and promoted scar formation. Moreover, wounded human skin organoids exhibited age-dependent expression of SDF1 and EZH2 like in the mice, suggesting inhibition of SDF1 can be useful in reducing scar formation following surgery in humans. Currently, SDF1 inhibitors are on the market being utilized to mobilize hematopoietic stem cells. Future studies will focus on utilizing these inhibitors to determine their potential use in preventing scar formation in many types of human tissue injuries, including those suffering from epidermolysis bullosa or in burn victims.
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