Category Archives: Mayumi Ito

The Sonic Hedgehog Pathway: An Unrealized Dream

Humans have three Hedgehog (Hh) genes: Sonic (SHH), Desert (DHH) and Indian (IHH). Of these three, Sonic Hedgehog is the most studied.

Update: July 1, 2022 —  A new study finds that a signaling molecule (SCUBE3) stimulates hair growth significantly. The hedgehog pathway is also involved.

Update: March 17, 2020 — A new study concluded that coordinated hedgehog signaling induces new hair follicle generation in adult skin. The activation of Hedgehog (Hh) signaling in adjacent epithelial and stromal cells in adult mice created de novo follicles.

Not surprisingly, the new hair follicles were also accompanied with skin tumors. However, treatment with Hedgehog-pathway inhibitor Vismodegib restricted tumor growth. At the same time, the new follicles remained intact.

This post was originally written in July 2017. Then updated in December 2018 with the latest major developments summarized at the bottom.

The Sonic Hedgehog Pathway and Hedgehog Signaling

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).

It 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. He remains in practice even today.

These authors injecting balding mice hair cells with the sonic hedgehog gene using an adenovirus. They then discovered that resting hair follicles in the mice started growing robust hair of 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 when it came androgenetic alopecia. They hoped 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. Their aim was 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. Even a very minimal risk of developing cancer is not worth it for treating cosmetic problems such as hair loss. At least in the eyes of government. Below is an 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, read my post from earlier this year regarding ear hair regeneration and possible links with scalp hair regeneration. There is some controversy in that analogy if you read the comments to that post.

Hedgehog Pathway 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. This in turn ensures hair follicle neogenesis. The experiment 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.

Brief Items of Interest, May 2016

Hair loss news first:

There have been a huge amount of hair loss related news items of interest in the past month.  Several of them probably deserved their own blog posts.

— I did not realize that GSK was launching Dutasteride in Japan via the brand name Zagallo (to treat male pattern hair loss) and that this plan was delayed in late 2015.  I did, however, cover the favorable Japanese clinical trial results last year that are mentioned in that first link.  Now comes word that Catalent’s French plant has been cleared to restart production.  So there is a very high chance that Dutasteride will finally be approved to treat hair loss in 2016 (one year later than I was hoping), 14 years after being approved to treat enlarged prostates in men. (Edit: in fact the drug was already approved for hair loss treatment in Japan on September 28th 2015, and even approved in South Korea around 2010!  Hopefully the US and EU will finally follow suit in 2016.).  It would be the third ever drug to be approved to treat hair loss, almost 20 years after the second one (Finasteride/Propecia) was approved and almost 30 years after the first one (Minoxidil/Rogaine) was approved.  Make sure to read the Dutasteride testimonials post and related comments.  FYI — If you are worried about Finasteride (Propecia) side effects, do not even consider taking Dutasteride. The side effects from the latter are guaranteed to be worse for most people.

— Since quite a few of the reader comments to my past few posts have mentioned Kerastem, I am giving high importance to Christopher1’s thread on hairsite regarding his Kerastem treatment in Switzerland.  He had the treatment in early February of this year for $8,000.  Unlike his well covered failed experiment with topical JAK inhibitor tofactinib, this time he went to a professional clinic (more reliable in my opinion) to get the Kerastem treatment. Per his latest post from three days ago (which has surprisingly still not received any replies), he has good news to share and I quote:  “After having brought you some bad news about my Jak inhibitor trial, I finally have some good news for you. It’s not great, but it’s very good.  My hair has stopped falling out. It stopped about three weeks ago, which was a bit over 2 months after my Kerastem treatment.”  Note that this is only one data point and there has been no regrowth and we do not know how long this cessation in hair loss will last.  The rest of his post indicates that this is the first time in 15 years that his hair has stopped falling out.  I find Chrisopher1 to be a highly reliable and sincere person, or else I would not mention him to start off a blog post.

— Scientists at NYU Langone Medical Center in New York recently 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, with 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.

— A new paper from China titled “Wnt/β-catenin signaling pathway activates melanocyte stem cells in vitro and in vivo.”  Research was done in mice.

— An update on research at Japan’s Yokohama University under the leadership of Dr. Junji Fukuda.  Translation required, and yes, it is in mice only for now.  Short interview with Dr. Fukuda in there that is partially lost in translation.  Thanks yet again to our wonderful Japanese blog reader and commentator “nosyu” who updates me regularly about developments in Japan that are not covered by the English media.  The Fukuda Lab lists hair regrowth as one of its key areas of research.

— Update on Thorn Medical’s further plans in the Bahamas.

Topical methyl vanillate (a plant derived natural ingredient) increases hair count and hair mass index by inducing Wnt10b mRNA expression in the scalp.  According to the study, methyl vanillate has recently been shown to activate the Wnt/β-catenin signaling pathway, which has become a key target in the treatment of androgenic alopecia by numerous researchers in recent years.

— I was not planning to cover this public relations type piece on Dr. James Harris, but I liked the ending: “And when Harris predicts the future of his profession, he sees stem cells and growth factors – not plucking and planting.

More good publicity for Samumed and its CEO Osman Kibar.

— I am always impressed by hair loss sufferers who go through impressive regimens and post regular updates.  The latest example is “westonci” on HLT who is supposedly going through the whole of SwissTemple’s prostaglandin protocol that I have mentioned on this blog several times before.

— Talking about PGD2, an interesting new study from South Korea just came out today and provides yet more evidence that prostaglandin D2 (PGD2) and its nonenzymatic metabolite, 15-deoxy-Δ-prostaglandin J2, inhibit hair growth.

— For those in the United Kingdom, Dr. Steven Edgar is now prescribing topical Finasteride in the UK (his e-mail address is in that thread).

— An interesting new hair product from a company named “Reason to Believe” will soon be produced in North Carolina, based on the Alpha Keratin 60ku patent.  Hard to tell how good this product will be and how long it will last (I doubt it is permanent).

Can protein shakes lead to hair loss?

— “Baldy Viking” has some videos on dermaroller and onion juice!  I just saw only part of one of those…seems interesting and not entirely crazy.  I have become more of a believer in natural treatments for hair loss having at least some minor benefit.

— An interesting story of an Irish woman’s battle with alopecia cicatricial related hair loss since age 21.

Yet one more distraction for Dr. George Cotsarelis.

— In celebrity news, Rosie O’Donnell discusses her hair loss; it seems like golfer Jordan Speith may have had a hair transplant; and Charles Barkley has asked basketball superstar Lebron James to stop painting on his hair.  Search this blog for my past mentions of Lebron James if you are interested in this kind of news.

And now on to medical items of interest:

CRISPR breakthrough is most clever yet, and increasingly relevant to humans.

Scientist turn skin cells into heart cells and brain cells just using drugs.

Regenerating brains of the dead.  A more interesting take from my favorite Daily Mail.

Japan OK’s gene editing of eggs.  As long-time blog readers know, the Japanese have already fast tracked clinical trials for newer regenerative medicine and stem cell treatments, and earlier in this post I mentioned that Japan could be the first country to approve Dutasteride for hair loss treatment.  Everything is moving along fast over there and I am glad that we have both Shiseido and Dr. Takashi Tsuji based in that country.

— As expected, the first ever penis transplant in the US got widespread global news coverage yesterday.  I first heard about it via the radio in my car yesterday, then via a text message from a friend (wonder why?), and then again today via my yahoo homepage. Bill Gates must be horrified at global priorities.

— Now just imagine if this really happens in 2017?  I doubt it, but it would be absolutely ridiculous if that came to fruition before a hair loss cure.

— Alzheimer’s cure getting closer:

— Five-year update on face transplant recipient.

— MIT scientists and others create an artificial second skin:

— Histogen is also involved in skin care products via its growth factor technology in case people forgot.  Here is an update.

Doubling lifespan of embryos in petri dishes.

Maybe vitamin supplements are useful after all?

Biohacking in Brooklyn.

— I am a bit skeptical about Liz Parrish and Bioviva, but since I have mentioned her a few times before, here is an update and some reddit comments on the subject.

Rapamycin and more to make your dogs live forever.