Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing

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, Tgfb1, and a-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.

The adipose‐derived stem cell peptide ADSCP2 alleviates hypertrophic scar fibrosis via binding with pyruvate carboxylase and remodeling the metabolic landscape

“…The mouse skin wound model has been widely used in investigating hypertrophic scar 48,49 . Herein, we found that ADSCP2 promoted wound healing and attenuated collagen deposition in the mouse model.…”

“…The mouse skin wound model has been widely used in investigating hypertrophic scar. 48,49 Herein, we found that ADSCP2 promoted wound healing and attenuated collagen deposition in the mouse model. It has been reported that exosomes secreted from ADSCs promoted hair growth and that the Wnt/β-catenin signaling pathway was activated in ADSC-derived exosome-treated mice.…”

In vitro assessment of Neuronal PAS domain 2 mitigating compounds for scarless wound healing

“…Further studies have identified circadian control in larger areas of dermal physiology, such as the adequate hydration of the epidermis and stratum corneum ( 25 ), rather than the specific cell types present. In summary, although there is a few evidence in the current literature of Npas2- specific control of dermal wound healing ( 11 , 26 ), there is an extensive publication about the way elements of the circadian system interact with skin physiology to impact wound healing. As such, this study puts forth a novel mechanism by which the circadian system is able to impact cutaneous wounds in order to accelerate dermal wound healing while focusing on the mitigation of excess collagen deposition.…”

Therapeutic Potential of Adipose Stem Cell-Derived Conditioned Medium on Scar Contraction Model

“…After skin injury, the wound contracts strongly, thereby reducing the wound area. This contraction is caused by the action of myofibroblasts derived from skin fibroblasts and the extracellular matrix regulated by fibroblasts [ 1 , 2 ]. Excessive contraction often causes skin tightness called scar contracture [ 3 ].…”