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.

86 thoughts on “The Sonic Hedgehog Pathway: An Unrealized Dream”

  1. @admin

    I think it’s time for you to enroll in some biology classes and start your medical career.

    Or become an author of “history of hairloss”.
    A book about history of cancer titled “emperor of all maladies” won the Pulitzer.

    Or may be start an ice bucket challenge to collect funding for hair loss research. We should actually have bald dudes breaking various things on their head to show how frustrated they are. The bigger the object, the bigger the donation. We can start with an egg.


  2. Ha..ha..ha…
    Frustated, but cmnt like this makes me laugh and frustration goes away…

    Thanks a lot Admin for this blog.

  3. Hi Admin, just wanna to say that very impressed with your finding & research on hairloss history and information. Kudos to you and keep up the good job. wish one day you will announce you closing the site down because no longer needed anymore to keep us posted about hairloss because the cure/treatment is out there for us.

  4. Admin, your dedication to this research and keeping everything grouped together and updated is truly invaluable. Thank you. I really do believe medicine is on the cusp of some amazing new treatments for everything and that we’ll see something big (crispr, hair regeneration, cancer cure) within the next decade which will unleash the floodgates to enormous possibilities.

  5. @PaulPheonix there is no evidence that a truly effective cure or treatment is forthcoming. These incidental news items – while interesting – are proof of nothing. All the news just repeats itself. Sad but true.

  6. @hanginginthewire don’t forget Tsuji, man. The cure is in sight. Maintenance in the forms of follica, possibly polichem are even closer. Brotzu is anybody’s guess at this moment I suppose, but there are certainly new treatments coming.

    1. Agreed. I think Tsuji’s work is the greatest case for optimism but still needs to be proven further it can work on mass scale.

  7. as someone from pharma company, safety is the first and foremost topic on our agenda. no one in pharma wants to be associated with products causing cancer and such. So I cna obviously understand why P&G withdrawn.

    My opinion, SHH is indeed the cure for hairloss. I dont think any other treatments can even come close. Same logic, you can also try developing spidey skills by getting biten by an irradiated spider. Most probably you will be dead within next few hours.
    this is very much same logic otherwise P&G would have stayed and continued working on it. Because hairloss is a chicken laying golden eggs… no one denies it

    1. @Paulpheonix I admire your optimism but I don’t share it. Yes hair loss is going to be cured. No it’s not gonna be anytime soon, or soon enough to benefit us.

      1. I find it hard to believe that DHT has so many critical benefits in adults. That source Netshed posted sells DHT and other blood tests FYI and I would not count it as unbiased.

        Women live longer than men and have drastically less DHT and testosterone (and much more estrogen).

        To really believe all that stuff, you would need to find a few reputable studies for each item they list there —

        e.g., studies that show low DHT levels lead to higher stroke rates. Similar one for heart disease. Similar one for diabetes. Similar one for depression etc…really doubt any of those are true (except of course things such as less sex drive, gyno etc…) that have been noted many times in an assortment of reputable studies.

    1. Admin is right, they are selling stuff. hmm
      Either way, there are ‘indications’ that they might be right about:

      Male Development
      Prostate Health
      Cognitive Function
      Because we all know what studies there are about a certain hair loss drug. But let’s not get into a discussion again about that Merck thing. Some hate it, some love it :)

  8. IMHO hair is a very important condition…It’s beoming more relevant in this society. We will have a new treatment soon. The big 3 will be the past…Is strange all people with MPB thinks 2018 is the year!!!!

  9. Any cure for baldness will provide a great boost to the world economy. Older men have more money and if their confidence and optimism rises so will their spending on entertainment, clothes, holidays etc.

  10. Oxidative stress management in the hair follicle: Could targeting NRF2 counter age-related hair disorders and beyond?

    Small molecule activators of NRF2 may therefore be useful in the management of HF pathologies associated with redox imbalance, ranging from HF greying and HF ageing via androgenetic alopecia and alopecia areata to chemotherapy-induced hair loss

  11. Generation of Human Hair Cells In Vitro: Is It
    All about How the Wnt Blows?

    In humans, and all other mammals, hearing
    and balance are dependent on a
    shockingly small number of mechanosensory
    hair cells. At birth, each of our ears
    contains approximately 75,000 of these
    magnificently sensitive mechanosensors:
    15,000 in the cochlea and 60,000 in the
    vestibular system. However, with age,
    and in response to various environmental
    insults, these cells are gradually lost,
    potentially leading to an isolating hearing
    impairment or debilitating vertigo. While
    recent results suggest that some vestibular
    hair cells may spontaneously regenerate,
    the numbers seem to be too
    small to be clinically relevant

  12. This comment is completely unrelated to this thread but I think it’s worth sharing as I’m sure there are a lot of readers in the same boat as I was.

    So, this weekend I shaved my head. Well, my barber did. We’ve always had an agreement that he will tell me when it’s time to bite the bullet and buzz it down. Every time I would go in expecting him to tell me that today is the day. But for the last year or so I’ve been walking out with hair. Well, some hair. But today I walked in there knowing that it was time. I sat down, pulled off my cap, and said, “today is the day. Let’s do it.” He ran his fingers through what was left and asked if I was sure. I nodded my head, closed my eyes, and the clippers did their thing.

    Now, I’m not going to pretend it wasn’t traumatic. I’m not going to pretend I haven’t caught my reflection in storefronts and car windows over the last couple of days and been a little shocked at what was staring back at me. But the relief I now feel – the weight that has been lifted off my shoulders – is palpable.

    No more wearing a cap every single day.
    No more around in the mirror, fashioning interesting shapes and comb-overs to make some sort of style work with what was left.
    No more Toppik.
    No more fearing downlights.
    No more fearing the slightest breeze.
    No more asking the Uber driver to put up the car window.
    No more avoiding swimming, even when it’s hot as balls.
    No more checking this blog twice a day (I’ll still probably check in weekly ;)

    For anyone else out there thinking of shaving their head, maybe this post will help you take the plunge.

    Just do it and own it.
    I wish I did it sooner.

  13. Charablaze, hanginginthewire, pimmler….do not feed the troll. They know we will have new alternatives and more treatments for mpb the next year…that’s life…

    1. @newerah, I am no troll. My depression over hair loss is unspeakable. I hope and pray that there is a new (effective) treatment or cure soon. My future looks mighty bleak without one. This will be my last post repeating it cause I don’t want o spam the thread, but I know what false hope looks like, hope born out of wishful thinking and desperation. There’s no evidence that 2018 is gonna be some kind of gamechanger. And when 2018 comes and goes and we are still suffering, the positivity brigade will move the goalposts and start amping everyone up for 2019…2020…no 2021. On and on it goes. Some of us are not mentally equipped to deal with the inevitable disappointment.

    87% of people said they’d do this fat injection deal I did the vote at bottom. I personally would not do it and feel like it’s these half a** treatments that are hindering the real progress in hair loss research. People waste their money on this stuff and companies and doctors think “hehe jackpot! but it doesn’t do anything in fact one photo I think the guys bald spot definately got bigger.

      1. But don’t some people who suffer from AA also suffer from mpb? So what if 100% of the male subjects fully recover hair? This trial may actually verify more than just its itended purpose.

        1. They claim topical may work for AGA, but not oral. Need topical trial once correct topical formulation is created.

          Plus needs to be selective JAK 3 inhibitor.

      1. C’mon egghead with all that regrowth in those pictures though ;) I’m gonna stop running and stock up on fat

        1. You shave ur head take a picture grow it out an inch take a shot in the right lighting it looks like an amazing before and after. Go ahead go for it man just saying there’s no regrowth there and if there is its peach fuzz

  15. Why do people think Shiseido will release something in 2018? They’re not even half way don’t their 3 year trial, unless I missed something?

    1. Shiseido and replicel have both said they will be at market in 2018… then it turned into they will have finished all trials and made major announcements at end 18 and thus be at market 2019….

  16. I agree with egghead those before after treatment is a joke. They can’t say they can cure mpb when their before after pics show otherwise. I see no difference. You should loOK at a before after and be like “sht! That is amazing, his whole hairline is restored or oh man! His crown is completely filled in! Amazing! Not us zooming into the picture to find a stray new hair sprouting out lol. Sad just sad they still pull these scams on us.

  17. Curis Inc was another company that had it on their product pipeline, I even got stocks from them. Same problem, they decide to not enter into phase 2 cause side effects from phase 1. Basically, forget about Sonic

  18. Funny seeing all these comments from a year ago looking to 2018 for a cure. Hold onto that hope gents, the cure is only 5 years away…

    *Come back to this comment in 2023. Don’t worry guys, the cure is only 5 years away…

    Then in 2028. Don’t worry guys, the cure is only 5 years away…

    1. We’re literally 4 months away from the beginning of Tsuji’s human trial, with it all still on track to be launched in less than two years’ time or so. A therapy which has already used human cells to grow hair with no ill effects in subjects, so it’s basically a formality at this point.

      Yeah, some of the things that could’ve potentially been out this year didn’t come out, but it’s not like their progress is stagnant.

      Just keep looking for more reasons to whine, though.

      1. On track for a treatment that you yourself say virtually no one will be able to access or afford for years and years to come. That’s IF it works. Why wouldn’t people “whine” in that case?

        There doesn’t appear to be a realistic solution to this problem in the foreseeable future and it makes people unhappy. It’s not because we’re weak or stupid.

        1. So what? It is literally the only thing that will likely be a legit cure all the way around.

          This is like being angry about the fact that nice cars exist just because we can’t all afford them right off the lot.

    2. 3 years later…at the heart of a pandemic, we know now that we can cure any disease, quickly if necessary. Humans are self-centered. Therefore, a good way to find a cure for AGA would be to fund a task force of young bald scientists in a country without medical regulatory approval process (like the Bahamas) … et voilà!

  19. I am hoping that when the cure comes out, it is prohibitively expensive, so the sad coward from this forum that left anti-Semitic remarks on my YouTube channel can’t afford it :-)

    I guess some losers deserve to be bald.

    I am happy with hair, but I am also happy without. That kind of makes me untouchable, in addition to being the bad guy.

    1. you say you’re happy “without hair”, yet you stick a wig on your head 24/7 which costs maintenance and quite frankly… is utterly ridiculous … shave your head if you truly feel good not having hair …

      1. Nobody is truly happy without hair.

        Even among the guys who don’t mind shaving or buzzing their head, they all still want to at least have the choice.

  20. @Egghead. A hairloss doc I was a patient of stopped using apidose injections for baldness because, guess why?…… didn’t work! Ha.
    Those ‘regrowth’ pics are a worry!

    1. lol.

      boycott Peachfuzz products, throw your money at scientist not scam artist if your gonna throw your money away at all.
      Can’t stand thinking of Jeff Bezos and Alexey Terskikh at the same time I start getting a head ache.

      I read these old post of mine i dont even remember writing.

      I Grew up on Sonic The Hedgehog, 2 had some good music, chemical plant zone was so the jam back in the day.

  21. ^Admin, I recently posted a comment about if Trinov is available for purchase in the U.S.? Also it appears that Trinov is unavailable on the italian websites that you listed in one of your earlier posts about Trinov.

    1. The company behind Trinov said it would be available from december 2018. Then they gave a date,4 of december.
      Some companies never hold their promises. Have mentioned many times that there is only one company in this business that always have hold their promises. Clue: A Nordic company.

  22. Pepperpot…it’s in mice aND have done no trials. This is at least 10 years away if they even pursue it. Best to eat a healthy Mediterranean diet haha. If you are in your teens then this might come out when you are late 30s. I remember I went to a ht doc when I was 20. He told me to hop on Propecia. I asked him if any new better treatments would hit the market that can cure hair loss. He told me Propecia will keep your hair till your 40 and by then cloning of hair should be available. Well 3 years to go …haha let’s see if he was right all along. Tsuji it’s up to you now haha.

  23. Hello Admin,

    In this study they tested Chitosan on HDPCs and mice, and found an increase in sonic hedgehog activity, among other pro-hair growth parameters such as FGF-7 and VEGF.
    As you mention it is also supposed to promote follicle neogenesis. Perhaps combining it with wounding could activate some serious hair growth. Chitosan is available as a powder and could quite easily be made into a home topical if anyone is inclined to try it.

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