BMI1 is required for melanocyte stem cell maintenance and hair pigmentation

Abstract

The epigenetic repressor BMI1 plays an integral role in promoting the self‐renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16Ink4a and p19Arf. However, in cutaneous melanoma, BMI1 drives epithelial‐mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (McSC) biology. Here, we demonstrate that murine melanocyte‐specific Bmi1 deletion causes premature hair greying and gradual loss of melanocyte lineage cells. Depilation enhances this hair greying defect, accelerating depletion of McSCs in early hair cycles, suggesting that BMI1 acts to protect McSCs against stress. RNA‐seq of McSCs, harvested before onset of detectable phenotypic defects, revealed that Bmi1 deletion derepresses p16Ink4a and p19Arf, as observed in many other stem cell contexts. Additionally, BMI1 loss downregulated the glutathione S‐transferase enzymes, Gsta1 and Gsta2, which can suppress oxidative stress. Accordingly, treatment with the antioxidant N‐acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical function for BMI1 in McSC maintenance that reflects a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.

Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study

“…Preservation of normal melanin distribution in the current study could be explained by the antioxidant properties of NAC that enhances the survival of melanocyte stem cells that differentiate into melanocytes (Wilson et al. 2023 ) as melanocytes are vulnerable to oxidative stress owing to their reduced antioxidant capability compared with other cells present in the skin (Enkhtaivan & Lee 2021 ).…”

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

“…Recently, Wilson et al reported that BMI1 is an essential molecule for maintaining the stemness of MSCs. 63 BMI1 is a key molecule that regulates the self-renewal of multiple adult stem cells, and its deletion leads to the progressive depletion of MSCs. 63 These studies show that the crosstalk between follicular MSCs and their niche microenvironment plays an important regulatory role in the quiescent maintenance, proliferative differentiation and regenerative capacity of MSCs.…”

“… 63 BMI1 is a key molecule that regulates the self‐renewal of multiple adult stem cells, and its deletion leads to the progressive depletion of MSCs. 63 These studies show that the crosstalk between follicular MSCs and their niche microenvironment plays an important regulatory role in the quiescent maintenance, proliferative differentiation and regenerative capacity of MSCs. HFSCs can precisely regulate the quiescent maintenance and proliferation differentiation of MSCs through specific molecular signals.…”