Gray Hair and Aging: Could ‘Stuck’ Stem Cells Be to Blame?

New research could change how experts think about graying hair and what can be done about it. Traditionally, experts thought that undifferentiated stem cells in the hair follicle get called to duty, transform to melanocytes, and then die off.

New evidence points more to a cycle wherein undifferentiated stem cells mature to perform their hair coloring duties and then transform back to their primitive form. To accomplish this, they need to stay on the move.

When these special stem cells get “stuck” in the follicle, gray hair is the result, according to a new study reported online April 19 in Nature.

The regeneration cycle of melanocyte stem cells (McSCs) to melanocytes and back again can last for years. However, McSCs die sooner than do other cells nearby, such as hair follicle stem cells. This difference can explain why people go gray but still grow hair.

“It was thought that melanocyte stem cells are maintained in an undifferentiated state, instead of repeating differentiation and de-differentiation,” said the study’s senior investigator Mayumi Ito, PhD, professor in the departments of Dermatology and Cell Biology at NYU Langone Health in New York City.

The process involves different compartments in the hair follicle — the germ area is where the stem cells regenerate, the follicle bulge is where they get stuck. A different microenvironment in each location dictates how they change. This “chameleon like” property surprised researchers.

Now that investigators figured out how gray hair might get started, a next step will be to search for a way to stop it.

The research has been performed in mice to date but could translate to humans. “Because the structure of the hair follicle is similar between mice and humans, we speculate that human melanocytes may also demonstrate the plasticity during hair regeneration,” Ito told Medscape Medical News.

Future findings could also lead to new therapies. “Our study suggests that moving melanocytes to a proper location within the hair follicle may help prevent gray hair,” Ito said.

Given the known effects of ultraviolet B (UVB) radiation on melanocytes, Ito and colleagues wanted to see what effect it might have on this cycle. So in the study, they exposed hair follicles of mice to UVB radiation and report it speeds up the process for McSCs to transform to color-producing melanocytes. They found that these McSCs can regenerate or change back to undifferentiated stem cells, so UVB radiation does not interrupt the process.

A Melanoma Clue?

The study also could have implications for melanoma. Unlike other tumors, melanocytes that cause cancer can self-renew even from a fully differentiated, pigmented form, the researchers note.

This makes melanomas more difficult to eliminate.

“Our study suggests normal melanocytes are very plastic and can reverse a differentiation state. Melanoma cells are known to be very plastic,” Ito said. “We consider this feature of melanoma may be related to the high plasticity of original melanocytes.”

The finding that melanocyte stem cells “are more plastic than maybe previously given credit for…certainly has implications in melanoma,” agreed Melissa Harris, PhD, associate professor, Department of Biology at the University of Alabama, Birmingham, when asked to comment on the study.

Small Technology, Big Insights?

The advanced technology used by Ito and colleagues in the study included 3D-intravital imaging and single cell RNA sequencing to track the stem cells in almost real time as they aged and moved within each hair follicle.

“This paper uses a nice mix of classic and modern techniques to help answer a question that many in the field of pigmentation biology have suspected for a long time. Not all dormant melanocyte stem cells are created equal,” Harris said.

“The one question not answered in this paper is how to reverse the dysfunction of the melanocyte stem cell ‘stuck’ in the hair bulge,” Harris added. “There are numerous clinical case studies in humans showing medicine-induced hair re-pigmentation, and perhaps these cases are examples of dysfunctional melanocyte stem cells becoming ‘unstuck.'”

‘Very Interesting’ Findings

The study and its results “are very interesting from a mechanistic perspective and basic science view,” said Anthony M. Rossi, MD, a private practice dermatologist and assistant attending dermatologist at Memorial Sloan Kettering Cancer Center in New York City, when asked to comment on the results.

The research provides another view of how melanocyte stem cells can pigment the hair shaft, Rossi added. “It gives insight into the behavior of stem cells and how they can travel and change state, something not well known before.”

Rossi cautioned that other mechanisms are likely taking place. He pointed out that graying of hair can actually occur after a sudden stress event, as well as with vitamin B12 deficiency, thyroid disease, vitiligo-related autoimmune destruction, neurofibromatosis, tuberous sclerosis, and alopecia areata.

The “standout concept” in this paper is that the melanocyte stem cells are stranded and are not getting the right signal from the microenvironment to amplify and appropriately migrate to provide pigment to the hair shaft, said Paradi Mirmirani, MD, a private practice dermatologist in Vallejo, California.

It could be challenging to find the right signaling to reverse the graying process, Mirmirani added. “But the first step is always to understand the underlying basic mechanism. It would be interesting to see if other factors such as smoking, stress…influence the melanocyte stem cells in the same way.”

Grants from the National Institutes of Health and the Department of Defense supported the study. Ito, Harris, Mirmirani, and Rossi had no relevant disclosures.

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