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e-Article

Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
Document Type
article
Source
Subject
Biological Sciences
Biomedical and Clinical Sciences
Health Sciences
Development of treatments and therapeutic interventions
5.1 Pharmaceuticals
Skin
Animals
Basic Helix-Loop-Helix Transcription Factors
Cell Differentiation
Cell Line
Cell Movement
Cicatrix
Collagen Type I
Down-Regulation
Drug Discovery
Female
Fibroblasts
Granulation Tissue
High-Throughput Screening Assays
Humans
Mice
Mice
Inbred C57BL
Mice
Knockout
Nerve Tissue Proteins
Small Molecule Libraries
Wound Healing
clock gene
fibroblast
high‐throughput screening
medicine
mouse
regenerative medicine
skin
stem cells
wound healing
Biochemistry and Cell Biology
Biological sciences
Biomedical and clinical sciences
Health sciences
Language
Abstract
Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 (Npas2)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfβ1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.