Ultrasonic stimulation of mouse skin reverses the healing delays in diabetes and aging by activation of Rac1

Roper, James A., Williamson, Rosalind C., Bally, Blandine, Cowell, Christopher A. M., Brooks, Rebecca, Stephens, Phil ORCID: https://orcid.org/0000-0002-0840-4996, Harrison, Andrew J. and Bass, Mark D. 2015. Ultrasonic stimulation of mouse skin reverses the healing delays in diabetes and aging by activation of Rac1. Journal of Investigative Dermatology 135 (11) , pp. 2842-2851. 10.1038/jid.2015.224

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	R Medicine > RK Dentistry
Additional Information:	Supplementary information available from links on Official URL
Publisher:	Elsevier
ISSN:	0022-202X
Date of Acceptance:	5 June 2015
Last Modified:	03 May 2023 22:25
URI:	https://orca.cardiff.ac.uk/id/eprint/75136

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