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Continuous NPWT regulates fibrosis in murine diabetic wound healing

Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this stu...

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Main Authors: Wu, Mengfan (Author) , Matar, Dany Y. (Author) , Yu, Zhen (Author) , Chen, Ziyu (Author) , Knoedler, Samuel (Author) , Ng, Brian (Author) , Darwish, Oliver A. (Author) , Sohrabi, Sadaf (Author) , Friedman, Leigh (Author) , Haug, Valentin (Author) , Murphy, George F. (Author) , Rinkevich, Yuval (Author) , Orgill, Dennis P. (Author) , Panayi, Adriana C. (Author)
Format: Article (Journal)
Language:English
Published: 6 October 2022
In: Pharmaceutics
Year: 2022, Volume: 14, Issue: 10, Pages: 1-15
ISSN:1999-4923
DOI:10.3390/pharmaceutics14102125
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/pharmaceutics14102125
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1999-4923/14/10/2125
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Author Notes:Mengfan Wu, Dany Y. Matar, Zhen Yu, Ziyu Chen, Samuel Knoedler, Brian Ng, Oliver A. Darwish, Sadaf Sohrabi, Leigh Friedman, Valentin Haug, George F. Murphy, Yuval Rinkevich, Dennis P. Orgill and Adriana C. Panayi

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520 |a Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, −125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP (p = 0.04) but decreased En1 (p = 0.0001) and CD26 (p < 0.0001). The pro-fibrotic factors Vimentin (p = 0.04), α-SMA (p = 0.04) and HSP47 (p = 0.0008) were decreased with NPWT. Fibronectin was higher (p = 0.01) and collagen deposition lower in the NPWT group (p = 0.02). NPWT increased cellular proliferation (p = 0.002) and decreased apoptosis (p = 0.03). Western blotting demonstrated increased YAP (p = 0.02) and RhoA (p = 0.03) and decreased Caspase-3 (p = 0.03) with NPWT. NPWT uncouples YAP from EPF activation, through downregulation of Caspace-3, a pro-apoptotic factor linked to keloid formation. Mechanotransduction decreases multiple pro-fibrotic factors. Through this multifactorial process, NPWT significantly decreases fibrosis and offers promising potential as a mode to improve scar appearance. 
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