754 A crosstalk between the alpha and beta adrenergic receptors regulates keratinocyte migration

Abstract

Chronic venous leg ulcers (VLUs) are an increasingly prevalent unmet clinical challenge. Despite their high associated morbidity and mortality, the bioengineered bilayered living cellular construct (BLCC) remains the only VLU therapy FDA-approved for efficacy in 15 years, yet its healing-promoting mechanisms are not well-understood. We hypothesized that signals of the BLCC reverse the non-healing into healing-like phenotype by targeting cellular processes recognized as hallmarks of healing impairment in VLUs: unresolved chronic inflammation and fibrosis. To dissect the BLCC's in vivo mechanisms of action, we conducted a prospective randomized controlled clinical study (ClinicalTrials.gov NCT01327937) in which patients with non-healing VLUs were assigned to receive standard-care compression therapy (n¼8) or standard care plus a single BLCC application (n¼11). Biopsies were obtained from two distinct locations (the wound edge and ulcer bed) at baseline and 1 week after treatment. Specimens underwent transcriptome profiling followed by comprehensive bioinformatics pathway analysis and in vivo validation through QPCR, Western blotting, and immunofluorescence of prospectively collected VLUs. We found that the BLCC modulated key inflammatory and growth factor signals at the VLU edge (IL1B, CXCLs, and many others), orchestrating a dramatic shift in the ulcer microenvironment which reinstated immune features of the acute wound phenotype to convert it to a healing milieu. We further identified a distinct role for the BLCC in remodeling the non-healing VLU matrix, through coordinated induction of metallothioneins and MMP8, to reverse the fibrosis of the ulcer bed. Taken together, the BLCC provided integral activation and remodeling signals to chronic VLU keratinocytes and fibroblasts to promote successful wound closure.

Circadian rhythm affects the magnitude of contact hypersensitivity response in mice

“…Previous reports showed that circadian oscillation of leukocyte distribution disappears in Adrb2 −/− mice, 12,17 and not only immune cells but also keratinocytes and fibroblasts express this receptor. 26,27 This issue should be addressed using cell-specific targeting of Adrb2 in future.…”