Targeting senescent dermal fibroblasts responsible for hyperactive melanocytes in melasma

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.^[1] 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.^[2] 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.^[2]

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.^[3] 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.^[4] Indeed, immunohistochemical analysis by Kim et al^[5] assessed the distribution profile of senescent cells in lesional melasma skin and in perilesional normal skin from 38 patients using a monoclonal antibody against p16^INK4A, a cell senescence marker. Their results showed that the number of p16^INK4A-positive cells in the dermis of lesional skin was higher than in perilesional skin. Most p16^INK4A-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 p16^INK4A-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.^[5] 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^[6] and the non-classical MHC molecule HLA-E.^[7] 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.^[10] 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.^[11] A study by Kim et al^[12] 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.^[13] 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,^[15] which might be partially explained by reducing the number of mast cells in melasma lesional skin.^[16]

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.^[17] 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.^[18]

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.

Figure 1: Diagram demonstrating pathological changes in lesional melasma skin. In the papillary dermis of lesional melasma, senescent fibroblasts might be responsible for inciting melanocytes to be in a hyperactive state through the secretion of SASP factors, such as: (1) the release of VEGF to induce neovascularization, (2) the release of SCF to recruit c-KIT-positive mast cells, (3) the release of MMPs to disrupt the overlying basement membrane, and eventually, (4) the production of ET-1 by the nascent microvascular endothelial cells also, all of which directly or indirectly stimulate melanocytes. ET-1: Endothelin-1; FBs: Fibroblasts; HS: Heparan sulfate; MC: Melanocyte; MMPs: Matrix metalloproteinases; SASP: Senescence-associated secretory phenotype; SCF: Stem cell factor; VEGF: Vascular endothelial growth factor.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81972919, 82273513).

Conflicts of interest

None.