Aging Suppresses Skin-Derived Circulating SDF1 to Promote Full-Thickness Tissue Regeneration

Abstract

SUMMARY Physicians have observed that surgical wounds in the elderly heal with thinner scars than wounds in young patients. Understanding this phenomenon may reveal strategies for promoting scarless wound repair. We show that full-thickness skin wounds in aged but not young mice fully regenerate. Exposure of aged animals to blood from young mice by parabiosis counteracts this regenerative capacity. The secreted factor, stromal-derived factor 1 (SDF1), is expressed at higher levels in wounded skin of young mice. Genetic deletion of SDF1 in young skin enhanced tissue regeneration. In aged mice, enhancer of zeste homolog 2 (EZH2) and histone H3 lysine 27 trimethylation are recruited to the SDF1 promoter at higher levels, and pharmacologic inhibition of EZH2 restores SDF1 induction and prevents tissue regeneration. Similar age-dependent EZH2-mediated SDF1 suppression occurs in human skin. Our findings counter the current dogma that tissue function invariably declines with age and suggest new therapeutic strategies in regenerative medicine.

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…The authors elucidated that aging induced the suppression of keratinocyte-derived SDF1 as the underlying mechanism. This idea is further corroborated by enhanced tissue regeneration in young skin in response to genetic deletion of SDF-1 [91].…”

Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7

“…Cell senescence is a form of cell cycle arrest characterized by the activation of tumor suppressor networks including p53, p16, and p21, and production of SASP factors. Cellular senescence is regarded as detrimental for tissue repair and regeneration since it induces replicative aging in cells, which directly contributes to their loss of regenerative capacity in tissue repair . Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner .…”

Single cell sequencing identifies serine proteases as regulators of myofibroblast differentiation

“…Although DPP4 inhibition has previously been demonstrated to directly inhibit canonical TGFβ signaling via Smad2 in renal fibrosis 60 and TGFβ-mediated myoFB-differentiation by interfering with ERKsignaling 61 , we were not able to confirm these mechanisms in skin FBs. Possible explanations for alternative the anti-fibrotic action of sitagliptin could be interactions with CXCL12/SDF1 (Stromal derived factor 1), a substrate of DPP4 62 which was found to promote scar formation 63 , or with components of the ECM, such as fibronectin , which have been shown to bind latent TGFβ 19 , or DPP4 induced cleavage of growth factors or receptors 62 . Deciphering these interactions will be the scope of further mechanistic studies.…”

“…In accordance with human scar tissue, 8 weeks old mouse scars contained a higher proportion of murine FBs (mFBs) (32,6%) compared to 6 weeks old scars (17,39%), and more DCs (9,6 versus 6,3%). In contrast, less pericytes and endothelial cells (2,8 versus 1,5%) and less keratinocytes (63,3 vs 45%) were present ( Figure 4E, F,). We next calculated up-and downregulated genes for FBs, PCs, ECs, T-cells, DCs and KCs, comparing weeks to 6-week-old scars ( Figure S5A-F).…”