Temporal Activation of Senescence Associated Secretory Proteins in a Post Burn Hypertrophic Scarring Model

Background: Hypertrophic scarring is the most debilitating factor that impedes the quality of life of burn survivors. While cellular senescence was reported in burn patient skin, the temporal activation of cellular senescence in scar development and maintenance is unexplored. Epigenetic modifications and cellular senescence can occur prematurely following major stress including burns.

Methods and Results: To determine the role of senescence activation in the development and maintenance of hypertrophic scars post-burn, we analyzed the temporal expression of the main senescence-associated secretory proteins (SASP) during scar development using the Red Duroc Pig (RDP) burn model. The RDP burn model closely mimics human hypertrophic scarring post burn. Red duroc skin biopsies were collected at 24 hours, and 1, 2, and 4 months post burn. The expression of mRNA transcripts for senescence-associated secretory proteins and epigenetic modulators were compared to non-burned control biopsies.  The expression of mRNA transcripts of various SASP components were upregulated at 24 hrs postburn; this includes the cell cycle proteins p21 (p< 0.01), and p16 (p<0.001), the inflammatory cytokines and chemokines IL-1b (p< 0.01), IL-6 (p< 0.01), IL-8 (p<0.001), MCP-1 (p<0.001), TGF-b (p<0.01), CXCL-10 (p<0.01), and TGF-b (p< 0.01). The expression of mRNA transcripts for other markers of cellular senescence involved in cell motility and actin polymerization was also upregulated 24 hrs postburn (CFL-1, p< 0.05) and PAI-1 (p< 0.01) before returning to basal levels at 1-month post-injury.  Loss of lamin B1 (LMB1) expression, characteristic of early senescence activation was also observed in our model 24 hours postburn (p< 0.01). Matrix metalloproteinase mRNA expression was upregulated early post-burn and stayed elevated for up to 4 months post burn compared to non-burn controls.

Conclusion: These data indicate that early activation of SASP contributes to the development and maintenance of hypertrophic scars postburn.