Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation

Abstract

Vitiligo is an autoimmune skin disease caused by cutaneous melanocyte loss. Although phototherapy and T cell suppression therapy have been widely used to induce epidermal re-pigmentation, full pigmentation recovery is rarely achieved due to our poor understanding of the cellular and molecular mechanisms governing this process. Here, we identify unique melanocyte stem cell (McSC) epidermal migration rates between male and female mice, which is due to sexually dimorphic cutaneous inflammatory responses generated by ultra-violet B exposure. Using genetically engineered mouse models, and unbiased bulk and single-cell mRNA sequencing approaches, we determine that manipulating the inflammatory response through cyclooxygenase and its downstream prostaglandin product regulates McSC proliferation and epidermal migration in response to UVB exposure. Furthermore, we demonstrate that a combinational therapy that manipulates both macrophages and T cells (or innate and adaptive immunity) significantly promotes epidermal melanocyte re-population. With these findings, we propose a novel therapeutic strategy for repigmentation in patients with depigmentation conditions such as vitiligo.

Melanocyte stem cells in the skin: Origin, biological characteristics, homeostatic maintenance and therapeutic potential

“…3 Moreover, two-photon microscopy with high depth penetration, low invasiveness and precise spatial point focusing has recently been used for MSCs lineage tracking. 101 Single-cell RNA sequencing (scRNA-seq) has created new opportunities for research in various fields due to its crucial role in the discovery of new cell populations, dynamic observation of developmental processes and revelation of gene regulatory mechanisms in recent years. 102,103 Utilising 3D imaging and scRNA-seq to track the process of cellular senescence and movement within each HF in real…”

“…106 The development of practical models of MSCs has provided researchers with tools to study MSCs in vitro and in vivo (Table 2). These models include genetically engineered mouse models, 18,30,31,33,48,66,91,94,96,97,101 zebrafish models, 107 human vitiligo skin biopsies 22 and human pluripotent stem cell models. 24 These models serve as important tools for studying the biological properties, differentiation potential, disease mechanisms and potential therapeutic strategies of MSCs.…”

“…Compared with tissue sections that only show the status of MSCs at a specific moment in time, 3D in vivo imaging can track the migration and differentiation of MSCs in real time, providing an excellent tool for defining the migration pathways of MSCs in vivo 3 . Moreover, two‐photon microscopy with high depth penetration, low invasiveness and precise spatial point focusing has recently been used for MSCs lineage tracking 101 …”

“… 3 Moreover, two‐photon microscopy with high depth penetration, low invasiveness and precise spatial point focusing has recently been used for MSCs lineage tracking. 101 …”