Society largely agrees that having hair on your head is desirable. Hair in your moles, though? Not so much, despite the fact that it’s generally harmless.
But as it turns out, the same molecule that drives mole hair growth might be the key to reversing hair loss on your scalp. In the results of a study published June 21 in Nature, scientists from the University of California, Irvine described how they used a protein found in hairy moles—also known as hairy nevi—to stimulate new hair follicle growth in mice and human skin grafts. San Diego startup Amplifica is now in the process of turning the compound into a treatment for androgenetic alopecia, or pattern baldness, one of the most common types of hair loss.
“Nature essentially performed the most important experiment for us already: In millions of people, there are hairy moles that have increased osteopontin,” Maksim Plikus, Ph.D., study leader and co-founder of Amplifica, told Fierce Biotech Research in an interview. “I see what we did as reverse-engineering nature’s experiment, and for this reason I’m pretty excited that osteopontin really could be relevant to hair loss therapy.”
Clinicians have only a handful of FDA-approved treatments for androgenetic alopecia, which affects up to half of adults in the U.S. There’s the over-the-counter vasodilator minoxidil, commercialized in 1988 as Rogaine by Johnson & Johnson, and Merck & Co.’s prostate drug finasteride, trade name Propecia, which was approved to treat hair loss in 1997. Women may also be treated with the potassium-sparing diuretic spironolactone, sold by Pfizer as Aldactone.
Despite a dearth of options and an enormous market, the past few decades have seen little progress in developing novel treatments for androgenetic alopecia. That’s partly because getting to the root of the problem is more challenging than it looks, explained Plikus, who is also chief scientific officer at Amplifica.
“You don’t really die from hair loss, so it’s been underestimated,” he said. "People think, ‘How hard could it be?’, but the reality is that it’s actually very hard.”
Of mouse fur and mole hair
As is often the case with preclinical research, reversing hair loss in mice doesn’t necessarily mean reversing hair loss in men. Many high-quality studies in animal models have failed to successfully transfer to humans because of inherent differences in their hair, Plikus said.
“Human scalp hair is where the money is, but mouse fur is very different,” he said. “What we learn about mouse fur is applicable to mouse fur—it may not translate at all to human hair biology.”
The human body has roughly 5 million hair follicles, only half a million of which are on the scalp, Plikus said. While the hairs in most of them are so short that they’re practically invisible, they aren’t hairless. That can become apparent when a mole grows on the skin where tiny hair follicles happen to be—in some cases, it sprouts long, thick hair, resulting in a hairy nevus.
“Our interpretation was that whatever molecules are in that mole must be very potent activators of hair growth,” Plikus recalled. “Our goal became to find the biology behind the difference between normal skin and mole skin.”
Senescent cells, activate!
The team started by creating a mouse model with the same genetic changes that cause moles to form in human skin. They then tracked how hair growth cycles in mole skin differed from those in non-mole skin, finding that excessive hair growth in the moles was driven by shorter breaks between growth cycles and was stimulated by molecules coming from senescent, or non-dividing, cells. Unlike regular skin, mole skin is packed with senescent melanocytes, pigmented cells that give moles their color, Plikus explained.
“The only addition to that skin [compared to normal skin] is a ton more senescent cells,” he said. A hallmark feature of these cells is the senescent secretome, which produces many proteins with various signaling functions, he said. Somewhere within it was the molecule his team was looking for.
To find it, they performed single-cell RNA sequencing on mole skin samples from both the mice and from humans to identify which signaling molecules within the hairy nevi triggered hair growth. The top hit was the protein osteopontin, a molecule already known to biologists for its involvement in wound healing, tissue remodeling and bone remineralization, among many other functions. This was the first time it had been shown to be involved in hair growth.
“We showed that osteopontin directly goes to hair follicle stem cells and ‘awakens’ them, essentially triggering them to divide. That’s the onset of new hair growth,” Plikus explained. “Hairs are growing from moles because osteopontin from the senescent cells is overstimulating them.”
Despite the fact that osteopontin hadn’t previously come up as a hair growth stimulator, its function makes sense when you consider how it acts in wound healing, he noted. Hair growth is triggered not only by normal hormone cycles but also by biological stress signals. It will often sprout around the edges of a wound as a protection mechanism, a process that’s driven by a burst of osteopontin, as some of the lab’s experiments showed.
“What I think happens is that in mole skin, it gets sort of repurposed to cause this hairy nevi,” Plikus said. “If you’re studying normal hair growth without adding any stress, you might not come across osteopontin. I think that’s why it escaped people’s attention.”
A decade of research
Amplifica’s researchers took over next to see whether osteopontin could work as a hair growth stimulator in humans. Injecting the protein into the hair follicles of human skin grafts caused them to sprout hair, just as it had in mole skin.
The results were robust enough to help the company close an $11.8 million series A funding round in October 2022, which gives Amplifica enough runway to transition AMP-203 and a couple other compounds in the company’s pipeline from preclinical to early-stage clinical trials, CEO Frank Fazio told Fierce. His confidence in the product is bolstered by how much research Plikus’ team put into it.
“One of the pivotal factors is the length of time Max and his team took to get here,” Fazio said. “They did nearly a decade’s worth of quite laborious and very technical studies to understand what those signaling mechanisms may be in the animal model and how they would translate to the human model.”
The team still has many unknowns to address, including the question of duration. While a short burst of osteopontin activates a self-sustaining signaling cascade in the hair follicle, that follicle won’t stay “awake” forever, Plikus pointed out. Patients will likely require occasional top-offs to keep the effects going, and it’s not yet clear how often they’ll need them. That will likely be influenced by the patient’s age, which is linked to the duration of their hair growth cycle. The older a person gets, the shorter their hair growth cycle becomes.
“At some point the hair follicle will complete the cycle and reenter a state of dormancy, so periodically they’ll have to be restimulated, though that shouldn’t happen very often,” Plikus said. “Ideally in my mind that would be every six months, which is doable for many people because it’s a low commitment.”
Amplifica will also need to figure out the optimal way to deliver the drug into the scalp. They initially plan to study injections with a very fine-gauge needle similar to the one that’s used for aesthetic neuromodulators like Botox, but will likely spend some future dollars on developing their own injection system, Fazio said.
“We’ll need to standardize the experience for a patient and also ensure that the compounds are being delivered at the right level within the scalp,” he explained. It will also be vital that patients go to skilled injectors for treatment, just as they should with Botox and fillers like Juvederm, Fazio added.
Beyond hair
The findings aren’t just a potentially big deal for treating androgenetic alopecia. They also have implications for how scientists understand the biology of senescent cells in aging and for regenerative medicine more broadly.
“The dominant concept in this field is that as people get older, tissues inevitably accumulate senescent cells, so senescent cells are portrayed negatively in that context,” Plikus explained. Both the cells themselves and the signaling molecule they secrete have been associated with tissue and immune dysfunction, prompting scientists to look at ways to clear them out as means of rejuvenation.
But moles are present even in the young, Plikus said—and, given that they harbor molecules with the ability to grow hair, it’s clear that their role in aging is more nuanced.
“There are contexts where even young tissues that are otherwise normal and healthy have plenty of senescent cells,” he said. “So that really means that these cells aren’t always detrimental. In some cases, with the help of signaling molecules, they’re nurturing endogenous stem cells for regeneration, like in the case of hair growth.”
This isn’t to say that scientists should throw out what they know about senescent cells and begin injecting them into patients, of course, Plikus said. But it does suggest that they shouldn’t be approached in a totally negative light.
“By studying their biology, I think we can tease out individual molecules that we didn’t know about before and convert them into new molecular therapies for regenerative disorders,” he said. “The bottom line is that we shouldn’t approach senescent cells as categoricallyharmful. They need to be evaluated on a case-by-case basis.”