Melasma (chloasma) is a highly prevalent and cosmetically disfiguring pigmented skin disease that mainly manifests as bilateral irregular brown macules on sun-exposed areas of the face. Although melasma causes no physical discomfort, it poses a significant psychological burden on patients due to distressing cosmetic concerns. The sustained epidermal hypermelanization is a prominent pathological feature of melasma, which is usually considered to result from melanin overproduction by hyperactive melanocytes. However, existing therapeutic interventions that suppress melanocytes and tyrosinase, the rate-limiting enzyme in the synthetic pathway of melanin pigments, fail to achieve satisfactory outcomes, especially for recalcitrant melasma patients whose lesions tend to rebound.
In recent years, it has been demonstrated that melasma is not simply a pigmentary disorder only attributable to overactive melanocytes but may also involve senescent dermal fibroblasts and dysfunctional vascular endothelial cells as well as subtle inflammation mediated by activated mast cells. Therefore, we summarize the most up-to-date literature to explore the roles of senescent dermal fibroblasts in the pathogenesis of melasma and also highlight several novel concept-directed treatments for melasma.
It has long been recognized that sun exposure, genetic predisposition, and circulating estrogens are the leading risk factors and maintainers of melasma. Recent studies have shown that senescent dermal fibroblasts resulting from chronic solar ultraviolet radiation (UVR) secrete soluble senescent-associated secretory phenotype factors, such as pro-inflammatory cytokines, angiogenic factors, and matrix metalloproteinases (MMPs), that incite melanocytes to drive epidermal hyperpigmentation in melasma. Indeed, immunohistochemical analysis by Kim et al assessed the distribution profile of senescent cells in lesional melasma skin and in perilesional normal skin from 38 patients using a monoclonal antibody against p16INK4A, a cell senescence marker. Their results showed that the number of p16INK4A-positive cells in the dermis of lesional skin was higher than in perilesional skin. Most p16INK4A-positive cells were observed in the upper (papillary) dermis near the epidermal–dermal junction, not in the lower (reticular) dermis. There was no change in the number of p16INK4A-positive cells in the epidermis of lesional skin compared to that in perilesional normal skin. They concluded that the accumulation of senescent fibroblasts in the papillary dermis supports the idea that solar UVR-induced senescent fibroblasts might be a critical player during the pathogenesis of melasa. Under normal physiological conditions, the timely clearance of senescent cells is required to maintain tissue homeostasis. However, several research studies have presented strong evidence that senescent dermal fibroblasts in melasma may evade immune cell clearance by the upregulation of lysophospholipids and the non-classical MHC molecule HLA-E. Encouragingly, recent studies have shown that the elimination of accumulated senescent fibroblasts using a non-invasive radiofrequency (RF) device or senolytic drugs significantly improves melasma and photoaging-related skin hyperpigmentation.[8,9]
The sub-clinical telangiectatic erythema confined to melasma lesions is more often observed in certain patients [Supplementary Figure 1, https://links.lww.com/CM9/B342], which represents an indicator that those patients are prone to rebound following treatment. Senescent dermal fibroblasts have been reported to secrete vascular endothelial growth factor (VEGF) that directly stimulates neovascularization, and eventually these nascent endothelial cells release endothelin-1 that can upregulate the melanogenesis pathway in melanocytes. A study by Kim et al found that VEGFR2, a functional receptor for VEGF, was also expressed on the surface of melanocytes. Although the exact role of the increased vascularity in melasma remains to be determined, any stimulation of angiogenesis in the treatment of melasma should always be avoided. In the clinical setting, vascular-targeted laser therapy or oral tranexamic acid have been proven to be promising adjunctive treatments via the downregulation of VEGF and its cognate receptor VEGFR2 in melasma lesional skin.[13,14]
Earlier studies revealed that the number of mast cells was increased in the dermis of lesional melasma skin compared with that in perilesional skin. Increased paracrine secretion of stem cell factor by senescent dermal fibroblasts is thought to be the cause of the recruitment and proliferation of c-KIT+ mast cells. Although the use of glucocorticoids in the treatment of facial melasma has been highly controversial, it has been noted that the skin lightening efficacy of hydroquinone is significantly increased by a combination of topical glucocorticoids in the Kligman formula, which might be partially explained by reducing the number of mast cells in melasma lesional skin.
Senescent dermal fibroblasts have also been found to secrete MMPs that degrade the collagen matrix and disrupt the basement membrane. Recent studies have shown that the presence of pendulous melanocytes, which protrude into the dermis from the epidermis in melasma lesional skin, strongly suggests that the disrupted basement membrane cannot support melanocytes firmly in place where they reside in the basal layer. More recently, several pilot studies have reported that restoration of the basement membrane using carbon dioxide lasers and RF significantly improves the clinical outcome of melasma patient treatments.
In summary, melasma is a heterogeneous disease with a high rebound rate and a relative resistance against existing treatment regimens. In addition to classical skin lightening agents that reduce tyrosinase activity, several novel concept-directed treatments aimed at the removal of senescent dermal fibroblasts, the suppression of neovascularization, the inhibition of mast cell-involved inflammation, and the restoration of impaired basement membrane have emerged over the years, such as RF microneedling, intensive pulsed light, and oral tranexamic acid and senolytics, etc, all of which show beneficial results. Senescent fibroblasts might be responsible for inciting melanocytes to be in a hyperactive state [Figure 1]. Tailored treatment regimens based on individual clinical characteristics are needed to achieve successful outcomes in patients with melasma.
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81972919, 82273513).
Conflicts of interest
1. Wang RF, Ko D, Friedman BJ, Lim HW, Mohammad TF. Disorders of hyperpigmentation. Part I. Pathogenesis and clinical features of common pigmentary disorders. J Am Acad Dermatol 2022;88:271–288. doi: 10.1016/j.jaad.2022.01.051.
2. Neagu N, Conforti C, Agozzino M, Marangi GF, Morariu SH, Pellacani G, et al. Melasma treatment: a systematic review. J Dermatolog Treat 2022;33:1816–1837. doi: 10.1080/09546634.2021.1914313.
3. Phansuk K, Vachiramon V, Jurairattanaporn N, Chanprapaph K, Rattananukrom T. Dermal pathology in melasma: an update review. Clin Cosmet Investig Dermatol 2022;15:11–19. doi: 10.2147/CCID.S343332.
4. Bellei B, Picardo M. Premature cell senescence in human skin: dual face in chronic acquired pigmentary disorders. Ageing Res Rev 2020;57:100981. doi: 10.1016/j.arr.2019.100981.
5. Kim M, Kim SM, Kwon S, Park TJ, Kang HY. Senescent fibroblasts in melasma pathophysiology. Exp Dermatol 2019;28:719–722. doi: 10.1111/exd.13814.
6. Narzt MS, Pils V, Kremslehner C, Nagelreiter IM, Schosserer M, Bessonova E, et al. Epilipidomics of senescent dermal fibroblasts identify lysophosphatidylcholines as pleiotropic senescence-associated secretory phenotype (SASP) factors. J Invest Dermatol 2021;141:993–1006.e15. doi: 10.1016/j.jid.2020.11.020.
7. Pereira BI, Devine OP, Vukmanovic-Stejic M, Chambers ES, Subramanian P, Patel N, et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun 2019;10:2387. doi: 10.1038/s41467-019-10335-5.
8. Kwon SH, Na JI, Huh CH, Park KC. A clinical and biochemical evaluation of a temperature-controlled continuous non-invasive radiofrequency device for the treatment of melasma. Ann Dermatol 2021;33:522–530. doi: 10.5021/ad.2021.33.6.522.
9. Park JH, Yoon JE, Kim YH, Kim Y, Park TJ, Kang HY. The potential skin-lightening candidate, senolytic drug ABT263, for photoageing pigmentation. Br J Dermatol 2022;186:740–742. doi: 10.1111/bjd.20893.
10. Geddes ER, Stout AB, Friedman PM. Retrospective analysis of the treatment of melasma lesions exhibiting increased vascularity with the 595-nm pulsed dye laser combined with the 1927-nm fractional low-powered diode laser. Lasers Surg Med 2017;49:20–26. doi: 10.1002/lsm.22518.
11. Regazzetti C, De Donatis GM, Ghorbel HH, Cardot-Leccia N, Ambrosetti D, Bahadoran P, et al. Endothelial cells promote pigmentation through endothelin receptor B activation. J Invest Dermatol 2015;135:3096–3104. doi: 10.1038/jid.2015.332.
12. Kim EJ, Park HY, Yaar M, Gilchrest BA. Modulation of vascular endothelial growth factor receptors in melanocytes. Exp Dermatol 2005;14:625–633. doi: 10.1111/j.0906-6705.2005.00345.x.
13. Iranmanesh B, Khalili M, Mohammadi S, Amiri R, Aflatoonian M. The efficacy of energy-based devices combination therapy for melasma. Dermatol Ther 2021;34:e14927. doi: 10.1111/dth.14927.
14. Zhu JW, Ni YJ, Tong XY, Guo X, Wu XP, Lu ZF. Tranexamic acid inhibits angiogenesis and melanogenesis in vitro by targeting VEGF receptors. Int J Med Sci 2020;17:903–911. doi: 10.7150/ijms.44188.
15. Nasimi M, Ghiasi M, Lajevardi V, Nasiri F, Shakoei S. A split-face comparison of fractional erbium: YAG laser plus Kligman's formula vs. Kligman's formula monotherapy for facial melasma. Arch Dermatol Res 2022;314:791–797. doi: 10.1007/s00403-021-02294-z.
16. Finotto S, Mekori YA, Metcalfe DD. Glucocorticoids decrease tissue mast cell number by reducing the production of the c-KIT ligand, stem cell factor, by resident cells: In vitro and in vivo evidence in murine systems. J Clin Invest 1997;99:1721–1728. doi: 10.1172/JCI119336.
17. Gautam M, Patil S, Nadkarni N, Sandhu M, Godse K, Setia M. Histopathological comparison of lesional and perilesional skin in melasma: a cross-sectional analysis. Indian J Dermatol Venereol Leprol 2019;85:367–373. doi: 10.4103/ijdvl.IJDVL_866_17.
18. Gulfan MCB, Wanitphakdeedecha R, Wongdama S, Jantanapornchai N, Yan C, Rakchart S. Efficacy and safety of using non-insulated microneedle radiofrequency alone versus in combination with polynucleotides for the treatment of melasma: a pilot study. Dermatol Ther (Heidelb) 2022;12:1325–1336. doi: 10.1007/s13555-022-00728-8.