Wound Healing Society

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Caveolin-1 Promotes Bacterial Colonization And Inhibition Of Wound Closure In Aged Human Skin
Ivan Jozic, Irena Pastar, Cheyanne R. Head, Robert S. Kirsner, Marjana Tomic-Canic.
University of Miami Miller School of Medicine, Miami, FL, USA.

Aging, together with age-related co-morbidities, such as weakening of the immune system, diabetes and peripheral vascular disease, compromise skin integrity resulting in skin breakdown and increased susceptibility to infections, thus leading to development of non-healing chronic wounds. Regardless of clinical signs of infection, every chronic wound is colonized by opportunistic pathogens (both intra- and extra-cellular), which contributes to compromised ability to heal a wound and restore barrier. We have recently identified a structural membrane protein caveolin-1 (cav1) as a potential therapeutic target of non-healing chronic wounds commonly observed in the elderly population. Cav1 plays important roles in multiple cellular process fundamental for wound healing by: 1) being linked with age-associated immunity resulting in increased production of pro-inflammatory cytokines, i.e. chronic inflammation; 2) being associated with cellular senescence; 3) playing a role in facilitating evasion of lysosomal degradation of a common colonizer of chronic wounds Pseudomonas aeruginosa, thus allowing persistence inside the host cells. Using human tissue biopsies, we observed induction of cav1 expression in elderly skin as well as in chronic non-healing wounds on both mRNA and protein levels. Furthermore, we found that upregulation of cav1 in human keratinocytes regulates colonization of Staphylococcus aureus (a common chronic wound colonizer) in vitro, which can be reversed by CRISPR/Cas9-mediated knockdown of cav1 or perturbation membrane cholesterol by MβCD. Additionally, using wound scratch assays, we found that disruption of cav1 in primary human keratinocytes isolated from aged human skin rescues the retarded directional cell migration observed in these cells due to reorganization of cytoskeletal machinery and promoted wound closure in 3D organotypic skin equivalents assembled using aged keratinocytes. Together, our data provide evidence for a novel molecular mechanism by which upregulation of cav1 expression observed in elderly individuals inhibits wound re-epithelialization by targeting two processes considered as “hallmarks” of non-healing: 1) promotion of bacterial colonization/persistence and 2) inhibition of directional cell migration necessary for wound epithelialization.


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