Category Archives: Mayumi Ito

The Sonic Hedgehog Pathway — An Unrealized Dream

This post was originally written on July 5, 2017. Now updated with the latest major developments from last week summarized at the bottom.

Perhaps the most important area of hair loss research that I have not yet covered on this blog relates to the Sonic Hedgehog (SHH) protein and signaling pathway.  This Shh pathway is used by cells to communicate with each other. While the sonic hedgehog protein has numerous critical effects on a developing human embryo (brain, craniofacial, lungs, teeth and more), it also continues to be important in adulthood when it controls certain stem cell division activities.

Getting into too much more detail about this would go beyond the scope of this blog. Shh was named after SEGA’s famous video game character, Sonic the Hedgehog.

Sato, Leopold and Crystal (1999)

In the initial decade after the first identification of the hedgehog gene around 1980, there was almost no research devoted to the impact of the SHH pathway upon human hair. However, this started to change in the mid-1990s (e.g., this from 1998) and culminated in the seminal work on this subject that was published in the US in 1999: “Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog“.

Dr. Ronald Crystal: Sonic Hedgehog

Of the three authors of the above study, the most cited was Cornell based Dr. Ronald Crystal who remains in practice even today.

What these authors discovered was that after injecting balding mice hair cells with the sonic hedgehog gene using an adenovirus, resting hair follicles in the mice started growing robust hair of the mouse’s native hair color. They dyed all the existing fur blonde so as to differentiate it from the newly growing hair.

Moreover, upon final analysis, the team found that the SHH gene was active in the injected areas of the skin, but not elsewhere. A very humorous as well as highly informative article on this subject from 1999 can be read here.

Curis-Procter & Gamble Partnership RIP

After the groundbreaking 1999 study on mice, some researchers were mildly optimistic that SHH activation could also have positive implications on human hair growth in balding men and women. A new company that was formed in 2000 called Curis partnered with Procter & Gamble in 2005 to try and develop a topical Hedgehog agonist product for scalp hair growth.

However, this partnership ended in 2007 due to potential safety issues since SHH can potentially also cause basal cell carcinoma cancer. P&G was not willing to continue with the drug development work, since even a very minimal risk of developing cancer is not worth it for treating a cosmetic problem such as hair loss (at least in the eyes of government). Interesting comment from the at-the-time CEO of Curis:

“We are obviously disappointed that the collaboration with Procter & Gamble will come to an end. We believe that our topically administered Hedgehog agonists have demonstrated encouraging efficacy in preclinical hair growth models and we were hopeful that one of our Hedgehog agonist drug candidates under the program would have progressed.”

Current Status

While the initial excitement of a SHH based cure for hair loss has long ended, sporadic research activity in this area continues (e.g, this in 2016). Moreover, in 2013, scientists even found that SHH signaling regenerates ear hair cells.

On a related note, also make sure to read my post from earlier this year regarding ear hair regeneration and possible links with scalp hair regeneration (some controversy in that analogy if you read the comments to that post).

November 2018 Update

On November 21st 2018, an important new study related to the Sonic Hedgehog (Shh) pathway and hair growth in mice was published in Nature Communications:

“Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing.”

The lead author of this study is the famous Dr. Mayumi Ito, who I have covered numerous times on this blog. The research was led by Dr. Ito and her team from the NYU School of Medicine. Other well known co-authors include Dr. George Cotsarelis, Dr. Maksim Plikus and Dr. Sarah Millar.

For some reason, a number of newspapers around the world only covered these results a week after publication. Even Dr. Ito’s own university only discussed the findings on November 28th. More here.

The study authors claim to have shown that activation of the Sonic hedgehog (Shh) pathway regenerates dermal papilla cells, which in turn ensures hair follicle neogenesis. This was done on wounded and damaged skin that was previously unable to grow hair.

Moreover, the authors have found a way to prevent cancerous tumor growth upon Shh pathway activation:

“To bypass the risk of tumors reported in other experiments that turned on the sonic hedgehog pathway, the NYU Langone team turned on only fibroblasts located just beneath the skin’s surface where hair follicle roots (dermal papillae) first appear.”

The study also has some very interesting discussion about the interplay with Shh signaling and Wnt signaling (and activation).

The Cure for Grey Hair

Note that this grey hair cure post was first published on Jan 4, 2016.  Now updated on July 8, 2018 due to new research on grey hair reversal.

Over the past few years I have collected quite a few interesting links related to a cure for grey hair. I kept delaying writing this post because a permanent reversal of grey hair is obviously far less important than a cure for hair loss. However, there are some interesting ideas in reversing graying hair that are also relevant to reversing hair loss. Both problems also seem to have some common pathways and genetics.

Moreover, whenever we get back a full head of hair, the vast majority of us will no doubt prefer that the new hair is pigmented. At that point, grey hair will be deemed to be a significant problem unless one prefers the salt and pepper distinguished look. Finally, for younger people who are both balding and prematurely graying, it is a double whammy.

Why Does Hair Turn Grey?

A person’s hair color is determined by his/her pigment producing stem cells known as melanocytes working in conjunction with his/her hair follicle stem cells. Hair color depends on the presence and ratios of two types of melanins: eumelanins (brown and black pigments) and pheomelanins (red and yellow pigments). As people age, a natural buildup of hydrogen peroxide occurs in their hair follicles, which in turn causes oxidative stress, melanocyte destruction and subsequent graying (side note: many women use hydrogen peroxide solutions to go blonde).

In 2009, a team of scientists from Germany and the UK figured out why this hydrogen peroxide buildup occurs in people as they age and why hydrogen peroxide is to blame for graying hair. Basically, in younger people an enzyme called catalase breaks down hydrogen peroxide into water and oxygen. However, as people get older, they often have lower levels of this enzyme as well as lower levels of other enzymes called MSR A and B that repair hydrogen peroxide related damage to hair follicles. The combination of high levels of hydrogen peroxide and low levels of MSR A and B also disrupts the formation of an enzyme called tyrosinase, which is important to melanin production in hair follicles. Scientists think that something similar is at play in the skin condition called vitiligo. Link to actual study.

Anti–interleukin (IL)-17 Therapy Reverses Grey Hair

In May 2018, Italian scientists reported a complete reversal of grey hair in one 61-year old patient. He first started getting white hair around the age of 45. He was undergoing interleukin-17 therapy with secukinumab to treat scalp psoriasis. The below before and after photo after 6 months of treatment is truly astounding. The 10-month follow up showed maintenance of results.

Note that this patient also saw new hair growth. The conclusion of the scientists is especially motivating: “hair whitening and thinning caused by the aging process might be reversible”.

Grey Hair Anti–Interleukin-17

Minoxidil could Reverse Grey Hair

In 2017, Dr. Wilma Bergfeld told the New York Times that:

“In early testing of the anti-hair-loss drug minoxidil, she and other researchers noticed the drug sometimes also restored hair color, suggesting it was rejuvenating the melanocytes”.

This is very surprising since Minoxidil has been in use for decades. Make sure to read my post on how Minoxidil works to regrow hair for more on this important FDA approved hair loss drug.

Hair Repigmentation after Immunotherapy

Grey Hair Becomes Dark Again

In 2017, scientists were able to reverse grey hair in 14 patients using a new immunotherapy based cancer treatment. The before and after picture of one of the patients is extraordinary. In recent years, research has found a connection between immune system involvement in both hair loss and hair premature greying of the hair.

Stem Cell Factor Protein, Krox20 and Hair Color

In 2017, scientists at UT Southwestern Center in the US led my Dr. Lu Le found that a protein called stem cell factor (SCF) was essential for hair pigmentation. Full study here. They found that the mice without SCF in Krox20 lineage cells developed grey hair early in life.

Is PC-KUS (a modified pseudocatalase) a False Flag?

In 2013, the same Germany and UK based team that was discussed earlier in this post came out with a potential way to reverse grey hair. According to the article:

The researchers found that this massive build up of hydrogen peroxide can be reversed with a UVB-activated compound called PC-KUS, a modified pseudocatalase. The research team developed this new proprietary treatment.

PC-KUS was also supposed to cure vitiligo. However, according to the UK’s NHS, the research and subsequent publicity on PC-KUS curing grey hair was a bit of a sham.

I am not sure if this avenue of work is definitely over, and perhaps these same scientists will surprise us and come out with better news in the future.

L’Oréal: A Pill to Prevent Grey Hair Forever

During the past decade, France’s cosmetics behemoth  L’Oréal has led global research in the private sector when it comes to a search for a cure for grey hair. The company’s head of the “Hair Biology Group”, Mr. Bruno Bernard, is a co-inventor of a topical product to protect and/or regenerate the melanocytes of hair follicles. The patent for this product was filed in 2009.

Moreover, In 2011, L’Oreal announced that it was developing a pill that would prevent grey hair forever — as long as you continued to take the pill once a day permanently! The medicine contains an undisclosed fruit extract that mimics the chemical tyrosinase-related protein (TRP-2), an enzyme that protects pigment production. Unfortunately, this pill will not cause existing grey hairs to darken, but instead, just prevent new grey hairs from forming. The pill was supposed to become available in 2015, but now we are now well past that year.

Dr. Mayumi Ito, Wnt Signaling and Hair Pigmentation

Dr. Mayumi Ito is a renowned Japanese hair loss research scientist who got her Ph.D from Nagoya University in 2003. She now does research and teaching at New York University. She has co-authored numerous papers on the impact of Wnt signaling on hair follicle growth and regeneration. On this blog you can find many posts that discuss this important subject matter.

In 2011, Dr. Ito found that Wnt signaling also explains hair losing its pigmentation. Her team even restored hair color in mice in 2011 via manipulating the Wnt pathway. It remains to be seen when they will experiment in humans (via stem cell injection or gene therapy) and see a successful reversal of grey hair.

Update: Also in April 2016, scientists (led by Dr. Ito) at NYU Langone Medical Center in New York found the molecular pathways responsible for creating the color of skin and hair. They found that a signaling pathway known as Edn/EdnrB interacts with other pathways (in particular, the Wnt signaling pathway), which in turn causes the proliferation of melanocyte stem cells (McSCs) that are involved in the earliest stages of skin and hair pigmentation. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote hair pigmentation retention.

Is Dr. Cotsarelis also Working on Hair Pigmentation?

Interestingly, in December 2011, the renowned Dr. George Cotsarelis and Dr. Mayumi Ito co-filed for a patent titled: “Methods for generating new hair follicles, treating baldness, and hair removal.” This patent was approved in December 2015. In the description to the patent, it ends with “The present invention also provides methods for hair removal and inducing hair pigmentation.” Incredible. A three-in-one solution (hair regrowth, body hair removal, and grey hair reversal). If only Dr. Cotsarelis’ predictions and optimism would be realized faster than he thinks or claims.

Can Finasteride Make Grey Hair Darker?

Over the years, I have read quite a few testimonials on hair loss forums where Finasteride users have claimed that their hair darkened while on Finasteride (which reduces DHT levels). The majority of these patients had very limited quantities of grey hair to begin with, so it was hard for me to tell from their before and after photos (when available) if this phenomenon was true or not.

However, in 2014, forum member “bverotti” who is a hair transplant clinic representative in Belgium posted a stunning now deleted before and after image of one of the clinic’s patients on Finasteride. While it shows blonde hair turning brown, I think of that as the same as grey hair turning brown or black. Also, see this hair darkening on finasteride post on Reddit.

I think that DHT, besides making many people go bald, also makes some of them go grey much sooner. I do not know if this has ever been shown to be true in any kind of study, and I could be wrong in my observation.

Using similar logic as in the above paragraph regarding Finasteride, I think that the much stronger Dutasteride can also reverse grey hair. Moreover, a few of the commentators in my post on Dutasteride Testimonials mention that the drug darkened their hair.

Could Platelet-Rich Plasma (PRP) Darken Hair?

I have covered PRP to treat hair loss many times on this blog. While the results are never guaranteed and PRP will not bring back hair in totally bald areas of the scalp, there are now numerous doctors who believe in the product. I am skeptical, but willing to listen to them.

More relevant to this blog post’s subject matter, in November 2015, Dr. Carlos Wesley started an interesting thread on the BTT forums with a photo showing PRP and ACell mesotherapy darkening some previously transparent scalp hair. This was very surprising to me. Moreover, he states that “An additional finding that has also been observed by other practices throughout the world is that PRP can help return some of the original hair color to follicles.” It seems like PRP could be stimulating melanocytes in hair follicles.

Update: A number of other doctors have confirmed this phenomenon of PRP darkening hair color in rare instances.

Grey Hair Reversal PRP

Stem Cell Transplants to Cure Grey Hair

I have discussed Dr. Takashi Tsuji on this blog numerous times in the past. Several of his old videos have shown black pigmented hair growing on a mouse after stem cell transplantation. Moreover, this article on his work has the following sentence in it: “He combined a number of stem cells to adjust the density and color of the hair, raising the possibility of a cure to graying strands.

Will Telomerase Activation Therapy Reverse Grey Hair?

There are a number of online testimonials regarding telomarase therapy via the ingestion of the TA-65 supplement reversing grey hair and/or growing new hair. There are also many opinions to the contrary. I cover all this and more in my post titled “TA-65. telomerase activation and hair regrowth“.

Cancer Treatments that lead to Hair Repigmentation

There have been various reports of drugs that treat cancer being able to repigment hair in rare instances. For example:

Hair Benefits of Fo-Ti Root

Several studies as sell as numerous online anecdotal reports suggest that Fo-Ti root can darken grey hair. Fo-Ti is also knows as Fallopia multiflora and Polygonum multiflorum. Make sure to read reviews and search for user experiences in relation to hair color changes before purchasing Fo-Ti.

Fluoxetine (SSRI)

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs) have been known to cause hair loss. However, in 2017, a report from Germany discussed how Fluoxetine promoted hair follicle pigmentation. However, the work was done in dissected sample hair from two females and not on actual scalps.

Grey Hair Cure Scams

While not as proliferate as in the hair loss cure industry, the grey hair reversal market is still full of scams. Moreover, while some products have been FDA approved and proven to reverse hair loss in numerous patients, nothing of that sort can be said for products that are touted to reverse grey hair to pigmented hair. Most of these products are natural supplements that will do nothing for your hair color.

In 2015, the US government went after various companies that were making fraudulent claims about their products being able to treat grey hair successfully. Prior to that, in 2013, a nutritional supplement  company called “Rise-N-Shine” promised a pill that would permanent cure grey hair. Wonder if that pill ever came into stores, and if so, how many gullible people purchased it?

Proctor & Gamble’s ME+ Molecule Hair Dye

Until a cure for grey hair does come out, people will have to accept their graying locks, or continue to use hair dyes. In 2013, Proctor & Gamble came out with a supposed permanent hair dye based on a new proprietary ME+ molecule. The new molecule (chemical name 2-Methoxymethyl-p-Phenylenediamine) was apparently a result of 20 years of research. Proctor & Gamble’s website also raved about ME+ in early 2014, but it does not seem like all this early optimism has led to any kind of new blockbuster permanent dye product.

Stress and Plucking will not Cause Grey Hair

Most of the articles I have read on this subject seem to indicate that for the vast majority of people, stress will not cause early premature graying of hair. Plucking hair will definitely not cause it to go grey. Both of these myths are old wives’ tales.

Some articles suggest that US presidents have grayed a lot while in office, but in my opinion, these presidents’ parents are also usually fully grey haired in their old age — so it is not surprising to see more white hairs appearing on the presidents’ heads when they are in office in their 50s and 60s. In all likelihood, it is grey hair genes rather than stress for most people.

Grey Hair is not Always a Sign of Ageing

Since grey hair usually only affects people in their mid-30s and aftermath (and a full head of white hair is almost never seen in those below the age of 50), most people assume that it is a sign of ageing. However, this is not always the case. There is no shortage of celebrities on TV that have grayed at a very early age.

Perhaps the two most famous examples here in the US are Anderson Cooper and Jay Leno, who both look very young for their age in that video despite graying in their 20s. Cooper started to go grey at just 20 and Leno at 29 according to his statement in that video. Neither of them seem to have any health issues despite now having been grey for decades. If anything, both seem to be aging at slower pace then the average human.

Grey Hair in Men versus in Women

Grey hair is a far greater concern for women than for men. For the former, it represents a sign of aging and an almost certain end to careers in acting and modeling unless the hair is dyed all the time. For the latter, this is not true, and some men are even purposely buying grey hair dye in order to look like George Clooney. Humans are nature’s strangest creation indeed.

Update: In March 2016, researchers in the UK discovered key genes for grey hair and more.

Update: In April 2016, a Forbes magazine cover story on Samumed suggested that the company’s SM04554 hair regrowth product that targets the Wnt pathway could also cure grey hair.

Update: In May 2018, researchers from the NIH and the University of Alabama discovered a connection between hair color and immune system activity.

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