title: Ultrasonic Stimulation of Mouse Skin Reverses the Healing Delays in Diabetes and Aging by Activation of Rac1.
abstract: Chronic skin-healing defects are one of the leading challenges to lifelong well-being, affecting 2-5% of populations. Chronic wound formation is linked to age and diabetes and frequently leads to major limb amputation. Here we identify a strategy to reverse fibroblast senescence and improve healing rates. In healthy skin, fibronectin activates Rac1 in fibroblasts, causing migration into the wound bed, and driving wound contraction. We discover that mechanical stimulation of the skin with ultrasound can overturn healing defects by activating a calcium/CamKinaseII/Tiam1/Rac1 pathway that substitutes for fibronectin-dependent signaling and promotes fibroblast migration. Treatment of diabetic and aged mice recruits fibroblasts to the wound bed and reduces healing times by 30%, restoring healing rates to those observed in young, healthy animals. Ultrasound treatment is equally effective in rescuing the healing defects of animals lacking fibronectin receptors, and can be blocked by pharmacological inhibition of the CamKinaseII pathway. Finally, we discover that the migration defects of fibroblasts from human venous leg ulcer patients can be reversed by ultrasound, demonstrating that the approach is applicable to human chronic samples. By demonstrating that this alternative Rac1 pathway can substitute for that normally operating in the skin, we identify future opportunities for management of chronic wounds.
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Roper
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Rosalind C
authors.initials: RC
authors.lastname: Williamson
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Blandine
authors.initials: B
authors.lastname: Bally
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Christopher A M
authors.initials: CAM
authors.lastname: Cowell
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brooks
authors.affiliation: Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Stephens
authors.affiliation: Bioventus LLC, Durham, North Carolina, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Harrison
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol, UK; Centre for Membrane Interactions and Dynamics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, UK. Electronic address: mark.bass@sheffield.ac.uk.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bass
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000503:physiopathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D013997:Time Factors; D014464:Ultrasonic Therapy / Q000379:methods*; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000473:pathology / Q000628:therapy*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D020830:rac1 GTP-Binding Protein