Stem cells are totipotent and can remain dormant or become active to regenerate cells of a specific tissue. Either of these actions is the result of niche signals. In melanocytes, such niche signals may be altered to direct stem cells in the hair follicles of the skin into a hyperactive state, causing hair to grow in excess.

Study: Signalling by senescent melanocytes hyperactivates hair growth. Image Credit: hermen30 / Shutterstock.com

Introduction

Congenital melanocytic nevi (CMN), which may also be referred to as human skin nevi, are noncancerous skin lesions that typically present at birth or within the first few weeks of life. These nevi are dark in color due to the prevalence of melanocytes and frequently exhibit excessive hair growth, the latter of which may be due to the hyperactivity of hair stem cells in these nevi.

Stem cells can be found in various areas of the skin, including hair follicles. Here, hair stem cells exhibit cyclic shedding and hair growth, which is initiated by the cyclic renewal of progenitors in the follicle.

This is in response to signaling between follicle and non-hair cells, including skin adipocytes and adipose progenitors in the niche, characterized by specialized fibroblasts in the dermal papilla. These cells occur in proximity and utilize common regulatory pathways to facilitate hair growth. Various immune cells within the skin also produce signals that modify hair growth.

A new study published in the journal Nature investigated the mechanism responsible for the excessive hair growth often observed in hairy-pigmented nevi. Nevi arise as a result of oncogene mutations in the Braf pathway within skin melanocytes. These mutated cells first expand but soon thereafter enter oncogene-induced senescence (OIS).

The end of this process is a circumscribed lesion with relatively higher numbers of senescent melanocytes. These cells exhibit a distinct pattern of secretion forming the senescence-associated secretory phenotype (SASP), which includes a number of inflammatory cytokines and growth factors that are key to normal developmental pathways, repair processes, cellular reprogramming, and tumor progression.

What did the study show?

Clusters of senescent melanocytes, but not normal melanocytes, in a hairy nevus produced signals to epithelial hair stem cells, subsequently inducing excessive hair growth. Melanocyte OIS was crucial for producing increased hair growth rates in hairy pigmented nevi in mouse models.

Signaling by senescent melanocytes caused stem cells to transition from quiescent to hyperactive. The loss of quiescence was associated with the expression of senescence by melanocytes, which was reflected in the transcriptional and compositional profile of the stem cells that ultimately contributed to the overgrowth of hair.

Melanocytes in a nevus secreted a unique set of factors that included higher-than-expected levels of signaling factors. The main component of this change in the secretome was a marked rise in osteopontin production in clusters of dermal melanocytes associated with the nevus. Osteopontin is required for hair growth and induces this process, even in the absence of other factors, both in pigmented hairy nevi and during wound healing.

For example, an injection of osteopontin in mice causes hair to grow rapidly and thickly. The same effect is observed following the manipulation of the rate of transcription of this hormone.

Osteopontin is recognized by the CD44 receptor on epithelial hair stem cells, which mediates the effect of osteopontin in the hyperactivation of hair growth in the nevus. When either this hormone or its receptor is knocked out, the hair growth occurring in response to the signaling by dermal melanocytes is reversed.

Hairy nevi in humans were found to overexpress osteopontin, thus leading to the formation of new hair follicles and hair growth activation.

What are the implications?

Although broad accumulation of senescent cells is detrimental for the regenerative capacity of tissue, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal.”

Senescent cells contribute to the aging and death of tissues; however, they also have beneficial effects on the growth of tissues. For example, senescent cells occur in embryonic tissues and may regulate or direct growth. Similarly, these cells may be observed in injured adult tissues, where they promote repair processes.

Signaling by senescent cells is a physiological growth-promoting pathway, as observed in the current study, where hair growth occurs in response to melanocyte senescence within a hairy pigmented nevus. The result of senescence may depend on the SASP and varies with the cell of origin or mechanism of senescence. Osteopontin is the major SASP component secreted by senescent dermal melanocytes that is responsible for excessive hair growth.

Future studies are needed to understand the interaction between stem cells in hair follicles and senescent dermal melanocytes within the nevi. This type of research will answer critical questions, such as why oncogene mutations produce senescence in dermal melanocytes adjacent to the hair follicles in mice but not within the follicle. Does the hair follicle counteract the effects of senescent cells?

The study findings indicate a peculiar pathway of regulation of hair growth by hair stem cells that is mediated by dermal melanocytes in senescence. This points to the potential for using senescent cells and their secretomes to correct regenerative disorders.

Journal reference:

• Wang, X., Ramos, R., Phan, A. Q., et al. (2023). Signalling by senescent melanocytes hyperactivates hair growth. Nature. doi:10.1038/s41586-023-06172-8.