Anuj Gupta

Background: Wound healing is a complex process that often can be impaired by various disease mechanisms, such as diabetes and cancer. This can result in chronic wounds that cannot heal and recover properly.¹ They can affect roughly 1% to 2% of the general population and can lead to infections as well as improper scarring of tissue.^1,2 Some chronic wounds take decades to heal, which can contribute to secondary conditions, such as depression and impaired mobility.² Expression of the circadian clock gene, neuronal PAS domain protein 2 (Npas2) in fibroblasts was found to interfere with skin homeostasis of aging human skin and amongst individuals with slow wound healing patterns.^3,4 These findings suggest a novel therapeutic target for the treatment of chronic wounds.

Objective: In this narrative review, we investigated the mechanisms by which Npas2 downregulation can elicit faster wound healing via dermal fibroblast migration and proliferation to the wound site.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “Npas2”, “chronic wounds”, “fibroblasts in wound healing”, “circadian rhythm”.

Results: Studies indicate that Npas2 deficient fibroblasts accelerated skin wound healing when the wound was created during the active phase of the circadian rhythm.^4,5 Dwn1 is a topical compound that downregulates expression of the clock gene, Npas2. Microarray analysis of human skin has shown that Npas2 is upregulated with aging and can cause scarring and impaired wound healing. Dwn1-mediated reduction of Npas2 expression in dermal fibroblasts can accelerate the healing of surgical wounds, with reduced scarring through the recruitment of dermal fibroblasts to the wound.^6,8

 Conclusions: Studies have found that downregulation of Npas2 leads to increased dermal fibroblast recruitment, which helps aid in wound healing. Even though the current research regarding Npas2 downregulation and the effects on chronic wounds is limited, there are many mechanistic qualities of Npas2 inhibition that are similar to studies conducted on chronic wound healing.^7,8,9 The use of Dwn1, an FDA-approved topical drug, has the therapeutic potential to prevent chronic wound formation in vulnerable patients, such as those with immune deficiencies or diabetes; however, clinical studies are lacking.⁹

 Works Cited 

1. Han G, Ceilley R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv Ther. 2017;34(3):599-610. doi:10.1007/s12325-017-0478-y
2. Bowers S, Franco E. Chronic Wounds: Evaluation and Management. Am Fam Physician. 2020;101(3):159-166.
3. Peng LU, Bai G, Pang Y. Roles of NPAS2 in circadian rhythm and disease. Acta Biochim Biophys Sin (Shanghai). 2021;53(10):1257-1265. doi:10.1093/abbs/gmab105
4. Cable EJ, Onishi KG, Prendergast BJ. Circadian rhythms accelerate wound healing in female Siberian hamsters. Physiol Behav. 2017;171:165-174. doi:10.1016/j.physbeh.2016.12.019
5. Sasaki H, Hokugo A, Wang L, et al. Neuronal PAS Domain 2 (Npas2)-Deficient Fibroblasts Accelerate Skin Wound Healing and Dermal Collagen Reconstruction. Anat Rec (Hoboken). 2020;303(6):1630-1641. doi:10.1002/ar.24109
6. Gharbia, F. Z., Abouhashem, A. S., Moqidem, Y. A., Elbaz, A. A., Abdellatif, A., Singh, K., Sen, C. K., & Azzazy, H. M. E. (2023). Adult skin fibroblast state change in murine wound healing. Scientific reports, 13(1), 886. https://doi.org/10.1038/s41598-022-27152-4
7. Taradaj J, Shay B, Dymarek R, et al. Effect of laser therapy on expression of angio- and fibrogenic factors, and cytokine concentrations during the healing process of human pressure ulcers. Int J Med Sci. 2018;15(11):1105-1112. Published 2018 Jul 13. doi:10.7150/ijms.25651
8. Sa Shibuya Y, Hokugo A, Okawa H, et al. Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing. Elife. 2022;11:e71074. Published 2022 Jan 18. doi:10.7554/eLife.71074
9. Bowers S, Franco E. Chronic Wounds: Evaluation and Management. Am Fam Physician. 2020;101(3):159-166.