Aging, Environment, & DiseaseChromatin StructureHistone Modifications

Aging Promotes Tissue Regeneration and Less Scar Formation

Aging Promotes Tissue Regeneration and Less Scar FormationIf Harry Potter had been older during his confrontation with Voldemort, he may not have even gotten his famous scar. Dermatologists have long noted that skin wounds in elderly patients tend to heal with less scarring than those in younger patients [1]. Recent work from Nishiguchi et al shows that epigenetic repression of the gene SDF1 in older mammals leads to reduced scarring and greater tissue regeneration than in the young.

Working with both young and aged mice, Nishiguchi et al poked holes in their ears and assessed how well the mice healed. They found that after allowing the mice to heal for four weeks, the older, 18 month old mice’s wounds had closed completely, while those of the 1 month old mice remained open. In fact, the older mice had already started to regenerate normal ear tissue consisting of fat cells and hair follicles while younger mice exhibited scar tissue around the edges of the wound. The researchers saw the same results when they looked at skin injuries on the back of both old and young mice, indicating that this phenomenon is not specific to ear injuries.

In fact, when the researchers surgically joined young and aged mice together so that any circulating factors in their blood could mix, they found that now, the aged mouse did not heal skin wounds as quickly and had more scar tissue than before, thus looking more like a young mouse. The young mouse in the pair still showed the same amount of scar tissue and slow wound healing as before, indicating that a factor circulating in the blood of young mice represses the tissue regeneration seen in older mice.

Looking to published RNA-sequencing data of skin cells at the edge of wounds in old versus young mice, they identified the secreted protein, stromal-derived factor 1 (SDF1) which is associated with signaling in mouse ear tissue regeneration [2], as a potential candidate for this circulating factor. When the researchers looked at SDF1 expression, they found that its expression increased in injured skin tissue and in circulating blood in young mice significantly more than in older mice. Furthermore, they showed that young mice that lost expression of SDF1 now looked more like aged mice with faster wound closing, less scar tissue formation, and the return of hair follicles.

The researchers next asked how aging regulates the differences in expression of SDF1. Using tiled chromatin immunoprecipitation, they found that after injury, repressive H3K27me3 and enhancer of zeste homolog 2 (EZH2) were enriched at the promoter region and transcription start site of SDF1 in aged mice but not young mice. These same regions also showed a decrease in activating H3K4me3 after injury in aged mice. When the researchers inhibited EZH2 activity in old mice, they saw an increase in SFD1 expression and less wound healing, indicating that epigenetic repression of SDF1 leads to less scarring and more tissue regeneration in older mice.

Finally, to ask if this same process of SDF1 repression occurs in human skin, Nishiguchi et al probed published microarray data and found that after injury, young people expressed significantly more SDF1 than older people. To test this further, the researchers then made 3D organoids of young and old human skin, and saw the same results after injury: SDF1 expression increased and EZH2 expression decreased in young human skin compared to older human skin, demonstrating that the same age-dependent repression of SDF1 seen in mice also regulates human skin tissue regeneration and scar formation.

When it comes to scar formation and tissue regeneration, the outcome actually improves with age. The findings of this study hold potential for the development of new therapies targeting SDF1 or its regulation to treat scarring in humans.

 

References:

Original article: Nishiguchi MA*, Spencer CA*, Leung DH, and Leung TH (2018). Aging Suppresses Skin-Derived Circulating SDF1 to Promote Full-Thickness Tissue Regeneration. Cell Rep, 24 (13): 3383-3392.e5. DOI: 10.1016/j.celrep.2018.08.054. *co-first authors

[1] Bayat A, Arscott G, Ollier WE, McGrouther DA, and Ferguson MW (2005). Keloid disease: clinical relevance of single versus multiple site scars. Br. J. Plast. Surg. 58, 28–37. DOI: 10.1016/j.bjps.2004.04.024

[2] King BL and Yin VP (2016). A Conserved MicroRNA Regulatory Circuit Is Differentially Controlled during Limb/Appendage Regeneration. PLoS ONE, 11 (6): e0157106. DOI: 10.1371/journal.pone.0157106.

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Stephanie DeMarco

Stephanie DeMarco