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Improved Wound Healing With A Novel Chemical Compound That Modulates Neuronal Pas Domain 2(npas2) Gene: In Vitro And In Vivo Studies
Akishige Hokguo, DDS, PhD1, Yoichiro Shibuya, MD1, Lixin Wang, DDS1, Daniel G. Khalil, MD2, Hodaka Sasaki, DDS3, Hiroko Okawa, DDS3, Ichiro Nishimura, DDS3, Reza Jarrahy, MD1.
1Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, 2Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Huntington Beach, CA, USA, 3Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.

PURPOSE: Attempts to modulate the wound healing process to minimize scarring remain among the most basic yet difficult challenges facing plastic surgeons. In this study, we focused on a new medical agent that has the potential to modulate the wound healing process to facilitate rapid healing of an incisional dermal wound with minimal scarring. This agent modulates the neuronal PAS domain 2 (Npas2) gene, which is integral to circadian rhythm function. In a previous study, we reported that Npas2 was associated to some degree in the modulation of wound healing. In this study, we performed high-throughput screening (HTS) to identify the compounds that suppress Npas2 and accelerate fibroblast migration to the wound site and have analyzed the effect of Npas2 on fibroblast behavior using one of Npas2 suppressor molecules on in vitro and in vivo wound healing. METHODS: Primary fibroblasts were isolated from WT and Npas2 heterozygous knockouts with reporter gene (Npas2+/-) mice. Npas2+/- fibroblasts were seeded on 384 plates, treated with 1,120 FDA-approved compounds and we then observed reporter gene expression. We also tested cell migration under the 1,120 compounds using Oris Cell Migration Assay. Then, WT fibroblast behaviors were characterized using scratch tests and floating collagen gel culture under one of hit compounds, named Dwn1. The effects of Dwn1 on fibroblast migration in vitro and in the full-thickness dorsal skin punched-out wound healing model in vivo were tested. RESULTS: Several hit compounds were discovered to simultaneously suppress Npas2 and thus increase fibroblast migration. Fibroblasts treated with Dwn1 showed increased cell migration and contraction capabilities relative to untreated FB. Furthermore, gross imaging of Dwn1-treated dermal wounds show statistically significant accelerated wound healing vs non-treated wounds. CONCLUSIONS: This study demonstrates that in vitro cultures of primary FBs treated with Dwn1 show greater migration and contractility. In addition, dorsal punch wounds treated with Dwn1 show similarly enhanced wound healing versus non-treated models. Our observations suggest that the down-regulation of the Npas2 gene might contribute to more efficient dermal wound healing. The clinical ramifications of these in vitro findings warrant further investigation.


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