An international team of researchers funded in part by NIAMS sought to understand why skin nevi grow long hair. Nevi, which are a type of skin lesion, have an abundance of pigment-producing cells, called melanocytes, that have become aged (or senescent). The team determined that senescent melanocytes within nevi produce large quantities of several signaling molecules. One such molecule, called osteopontin, causes dormant hair stem cells to wake up, which increases hair growth.
The study, which appeared in the journal Nature on June 21, 2023, provides answers as to why nevi are hairy and also uncovers the unexpected growth-promoting potential of senescent cells, which are typically thought to be associated with inhibited tissue growth.
Hair growth is highly dependent on the activation of stem cells, which can divide and self-renew. Hair growth occurs in cycles, and each cycle starts with stem cell activation. A hair follicle will continue to grow for some time until its stem cells enter dormancy, in which they remain for many months until the next cycle begins.
In hairy nevi, this tightly controlled growth cycle is interrupted. Nevi occur when melanocytes develop a mutation that causes them to transition into a state of senescence, a type of cellular aging. Curiously, senescent cells produce inflammatory signaling molecules thought to reduce the body’s ability to replace aging cells.
Researchers understand how nevi develop, but they do not fully understand why nevi show excessive hair growth. In this study, the NIAMS-funded researchers and their international collaborators sought to understand if senescent melanocytes in nevi stimulate hair stem cells and enhance hair growth.
The researchers first studied mouse models with the same mutations seen in human nevi. They then tracked the activity of hair follicles over time and found that the excessive hair growth in the nevi of these mice was driven by a much shorter than typical timeframe between hair growth cycles. Further, they showed that hair stem cells in the nevi became hyperactive.
The researchers then focused on the senescent melanocytes to understand how they may be inducing hyperactivity in nearby hair stem cells. By analyzing the signals these aged cells release, the researchers identified one signaling molecule—osteopontin—that the senescent melanocytes produced more of than melanocytes from the skin of mice without nevi.
To confirm the importance of osteopontin in hair growth in nevi, the researchers studied two additional mouse models with the nevi-causing mutations but without either the gene needed to produce osteopontin or its receptor, CD44. The mice missing either osteopontin or CD44 exhibited well-regulated hair growth cycles, suggesting that osteopontin has a direct influence on excessive hair growth.
The researchers then confirmed these findings in samples of human hairy nevi. Like in the mouse models, increased levels of osteopontin were found in hairy nevi samples when compared to adjacent skin. To test this functionally, small doses of osteopontin were applied to human follicles, which induced new hair growth.
“Senescent cells are typically viewed as detrimental to the regenerative potential of tissue. But our work showed that there are contexts in which senescent cells can have positive effects on tissues. As we learn more about these contexts, we can potentially harness that information for regenerative therapies,” said the study’s senior author, Maksim Plikus, Ph.D., a professor in the department of developmental and cell biology at the University of California, Irvine.
Future studies in Plikus’ lab will focus on learning more about the mechanism controlling hair growth in pigmented nevi. “Of the signals released by senescent melanocytes, osteopontin has the greatest effect on hair growth, but we are eager to study other signals as well,” said Xiaojie Wang, Ph.D., the study’s first author. Work is ongoing to fully understand this fascinating natural hair growth phenomenon.
The research was supported in part by NIAMS (under award numbers U01AR073159, R01AR079470, R01AR079150, R21AR078939 and P30AR075047), the National Science Foundation. the LEO Foundation, the Chan Zuckerberg Initiative, the W.M. Keck Foundation, the Simons Foundation and the California Institute for Regenerative Medicine.
Wang, X., Ramos, R., Phan, A.Q. et al. Signalling by senescent melanocytes hyperactivates hair growth. Nature 618, 808–817 (2023). DOI: 10.1038/s41586-023-06172-8