%0 Journal Article
%T YAP/TAZ Drive Agrin-Matrix Metalloproteinase-12 Mediated Diabetic Skin Wound Healing.
%A Yu Lin MO
%A Sampath D
%A Bosykh DA
%A Wang C
%A Wang X
%A Subramaniam T
%A Han W
%A Hong W
%A Chakraborty S
%J J Invest Dermatol
%V 0
%N 0
%D 2024 May 27
%M 38810954
%F 7.59
%R 10.1016/j.jid.2024.05.005
%X Macroscopic loss of extracellular matrix (ECM) can lead to chronic defects in skin wound healing, but supplementation of ECM holds promise for facilitating wound closure, particularly in diabetic wound healing. We recently showed that the ECM proteoglycan agrin accelerates cutaneous wound healing by improving mechanoperception of migrating keratinocytes and allowing them to respond to mechanical stresses via matrix metalloproteinase-12 (MMP12). RNA-sequencing analysis revealed that in addition to a disorganized ECM, agrin-depleted skin cells have impaired YAP/TAZ transcriptional outcomes, leading us to hypothesize that YAP/TAZ, as central mechanosensors, drive the functionality of agrin-MMP12 signaling during cutaneous wound repair. Herein, we demonstrate that agrin activates YAP/TAZ during migration of keratinocytes post-wounding in vitro and in vivo. Mechanistically, YAP/TAZ sustain agrin and MMP12 protein expression during migration post-wounding through positive feedback. YAP/TAZ silencing abolishes agrin-MMP12 mediated force-recognition and geometrical constraints. Importantly, soluble agrin (sAgrin) therapy accelerates wound closure in diabetic mouse models by engaging MMP12-YAP. Because patients with diabetic foot ulcers and impaired wound healing have reduced expression of agrin-MMP12 that correlates with YAP/TAZ inactivation, we propose that timely activation of YAP/TAZ by sAgrin therapy can accentuate mechanobiological microenvironments for efficient wound healing, under normal and diabetic conditions.