Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71074 |
| _version_ | 1811253431168401408 |
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| author | Yoichiro Shibuya Akishige Hokugo Hiroko Okawa Takeru Kondo Daniel Khalil Lixin Wang Yvonne Roca Adam Clements Hodaka Sasaki Ella Berry Ichiro Nishimura Reza Jarrahy |
| author_facet | Yoichiro Shibuya Akishige Hokugo Hiroko Okawa Takeru Kondo Daniel Khalil Lixin Wang Yvonne Roca Adam Clements Hodaka Sasaki Ella Berry Ichiro Nishimura Reza Jarrahy |
| author_sort | Yoichiro Shibuya |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:50:46Z |
| format | Article |
| id | doaj.art-5ee0957360374def8fdaa907b1ffb4d7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:50:46Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5ee0957360374def8fdaa907b1ffb4d72022-12-22T03:24:24ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.71074Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healingYoichiro Shibuya0https://orcid.org/0000-0002-0558-5154Akishige Hokugo1https://orcid.org/0000-0002-7097-3364Hiroko Okawa2Takeru Kondo3Daniel Khalil4Lixin Wang5Yvonne Roca6Adam Clements7Hodaka Sasaki8Ella Berry9Ichiro Nishimura10https://orcid.org/0000-0002-3749-9445Reza Jarrahy11https://orcid.org/0000-0003-2518-4697Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United States; Weintraub Center for Reconstructive Biotechnology, Los Angeles, United States; Department of Plastic and Reconstructive Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United States; Weintraub Center for Reconstructive Biotechnology, Los Angeles, United StatesWeintraub Center for Reconstructive Biotechnology, Los Angeles, United States; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Miyagi, JapanWeintraub Center for Reconstructive Biotechnology, Los Angeles, United States; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Miyagi, JapanRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesWeintraub Center for Reconstructive Biotechnology, Los Angeles, United StatesRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesWeintraub Center for Reconstructive Biotechnology, Los Angeles, United StatesRegenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, Los Angeles, United StatesAttempts 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.https://elifesciences.org/articles/71074wound healingskinclock genefibroblasthigh‐throughput screening |
| spellingShingle | Yoichiro Shibuya Akishige Hokugo Hiroko Okawa Takeru Kondo Daniel Khalil Lixin Wang Yvonne Roca Adam Clements Hodaka Sasaki Ella Berry Ichiro Nishimura Reza Jarrahy Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing eLife wound healing skin clock gene fibroblast high‐throughput screening |
| title | Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing |
| title_full | Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing |
| title_fullStr | Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing |
| title_full_unstemmed | Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing |
| title_short | Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing |
| title_sort | therapeutic downregulation of neuronal pas domain 2 npas2 promotes surgical skin wound healing |
| topic | wound healing skin clock gene fibroblast high‐throughput screening |
| url | https://elifesciences.org/articles/71074 |
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