Emerging Roles of Dermal Fibroblasts in Hyperpigmentation and Hypopigmentation: A Review

Abstract

Background: Skin pigmentation disorders may increase patients' psychological burdens. Consequently, they are increasingly attracting attention. Dermal fibroblasts have been shown to regulate pigmentation by secreting soluble factors.

Aim: This study aimed to summarize recent findings on the effects of dermal fibroblasts on hyperpigmentation and hypopigmentation, enabling the discovery of new therapeutic targets.

Methods: PubMed was searched for literature on fibroblast factors, hyperpigmentation, and hypopigmentation, and a comprehensive summary and analysis were performed.

Results: Fibroblasts secrete both cytokines that promote pigmentation, including stem cell factor (SCF) and keratinocyte growth factor (KGF), and small amounts of those that inhibit pigmentation, such as Dickkopf1 (DKK1) and transforming growth factor (TGF)-β. Fibroblast-derived extracellular matrix (ECM) can also affect melanocyte tyrosinase activity and the transfer of melanosomes. In hyperpigmentation disorders, such as melasma and solar lentigines, the secretion of pigmentation-promoting factors increases, and the activity of key enzymes in melanin production is elevated. In hypopigmentation disorders, including vitiligo, the secretion of melanogenic factors decreases while the factors that inhibit pigmentation increase. Fibroblasts may serve as a new therapeutic target, providing new insights to precisely treat pigmentary disorders.

Conclusions: Fibroblasts synthesize and secrete various cytokines and proteins that modify melanin synthesis and transfer through different signaling pathways, playing prominent roles in pigmentary skin disorders, such as photoaging, melasma, solar lentigo, and vitiligo.

Keywords: cytokine; fibroblasts; melanocytes; pigmentation.

FIGURE 1

Cytokines secreted by fibroblasts that promote pigmentation. Akt, protein kinase B; bFGF, basic fibroblast growth factor; ECM, extracellular matrix; EDN1, Endothelin 1; EDNRB, endothelin receptor B; GDF15, growth differentiation factor15; HGF, hepatocyte growth factor; JNK, c‐Jun N‐terminal kinase; KGF, keratinocyte growth factor; KGFR, keratinocyte growth factor receptor; NRG1, Neuregulin1; PI3K, phosphoinositide 3‐kinase; SCF, stem cell factor; SDF1, stromal‐derived factor 1; sFRP2, secreted frizzled‐related protein 2; WIF‐1, Wnt inhibitory factor‐1.

FIGURE 2

Cytokines secreted by fibroblasts that inhibit pigmentation. CLU, clusterin; DKK1, Dickkopf1; MITF, microphthalmia‐associated transcription factor; PAR‐2, Peroxisome Activator Receptor‐2; PKA, protein kinase A; PTN, Pleiotrophin; TGF‐β, Transforming growth factor‐β.