DWAT: Dermal White Adipose Tissue Hypothesis

[Armando Jose]

Yeah, model studies don't include sebaceous gland, a pitty

Towards developing an organotypic model for the preclinical study and manipulation of human hair matrix-dermal papilla interactions - Archives of Dermatological Research

Organ culture of microdissected scalp hair follicles (HFs) has become the gold standard for human ex vivo hair research; however, availability is becoming very limited. Although various simplistic “HF-equivalent” in vitro models have been developed to overcome this limitation, they often fail to...

link.springer.com

 

[balda]

Following threads about Setipiprant and other PGD2 "blockers", can say that they are undervalued or not fully investigated as treatment pathway. Seti is pretty pricey and hard to delivery. But the effect it produces on the skin is very important, if i get it right.

PGD2/DP2/CRTH2 blockers are able to prevent inflammation. And as a result fibrosis. The main dermal adipose tissue pathology leading to Androgenetic Alopecia. That's how researchers evaluate negative effect of PGD2 and its receptors: "There is growing evidence that CRTH2 plays important roles in allergic INFLAMMATION OF the respiratory tract and THE SKIN".

PGD2 blockers, seems, are not able to revert existing fibrosis, just prevent it. So fibrosis reversion stuff should be used for aggressive or advanced balding. Preferably adiponectin-based ones, which are not market-ready yet - ADP355, ALY688, etc.

Meantime DWAT fibrosis prevention remedies are better tested and available. Would be nice if we try and share such experience. There are many, except Seti:
- Bematoprost
- Latanaprost
- OC000459
- AZD1981/Timapiprant
- Ramatroban/3405
- TM30089
- MK-8318
- ...and Niacin, too!

 

[LouisSarkozy]

how are latanoprost and bima pgd2 blockers? thought they were only pgf2a analogue. is cetirizine a crth2 blockers according to you as it said to inhibit pgd2 in studies could it be used as a poor man seti? thanks

 

[balda]

how are latanoprost and bima pgd2 blockers? thought they were only pgf2a analogue. is cetirizine a crth2 blockers according to you as it said to inhibit pgd2 in studies could it be used as a poor man seti? thanks

imo, they Bimatoprost and others produce the same effect, just a little different way - rebalancing prostaglandins or blocking prostaglandin receptors. Bimatoprost original tested as a cure for glaucoma, with is a fibrotic issue, for a research: "...for FIBROTIC ocular diseases including glaucoma".

Would be nice if there would be more scalp tissue researches and comparative researches for these stuff. To bring to mass market at least one of them, and for affordable price. Also i strongly believe it should be topical. As to produce the same effect on skin tissue via oral dosing, it should be really strong and potentially toxic. Imho, oral remedies could be good for liver or lung fibrosis, not for skin.

Cetirizine: thanks, will check it. From the first sight, looks legit and can be a potential remedy: "Cetirizine may have a protective effect against bleomycine induced pulmonary fibrosis...". Everything anti-fibrotic can be helpful, it just need to be tested specifically for dermal adipose tissue fibrosis. Preferably topically. To define right dosage, vehicle and so on.

What makes me optimistic about adiponectin-based treatments, than prostaglandin-based one, is that "adiponectines" are proved to REVERT fibrosis in dermal adipose tissue. Maybe prostaglandin-based remedies can revert too, but i afraid to prevent mostly (calming down inflammation).


PS. attached Bimatoprost for eyelashes experiment results. Good regrowth.

 

[Armando Jose]

Whiskers (vibrissae) and Eyeslashes are very different to scalp hair,

 

[balda]

Whiskers (vibrissae) and Eyeslashes are very different to scalp hair,

absolutely. but if the issue is solved thanks to anti-fibrotic properties of the remedy, it makes sense to test it for Androgenetic Alopecia too. i make all that assumptions based on the dwat hypothesis.

 

[balda]

"
Appearance of local fibrotic structures around and beneath hair follicles during their involution is a known hallmark of androgenetic alopecia (Androgenetic Alopecia). We hypothesise that this fibrosis can be connected with recently uncovered adipocyte‐myofibroblast transition (AMT) involving the dermal adipocytes.

Although there is no direct evidence that AMT can be induced by androgens, we would like to propose here that this step should be an integral part of the process. Indeed, the DEFICIENCY OF androgen receptors (AR) INDUCES a widespread EXPANSION of dWAT in ArTfm males, making this layer even thicker than in what is observed in females (S4). On the other hand, transgenic mice OVEREXPRESSING human AR in the skin demonstrate delayed hair regeneration and MIMIC Androgenetic Alopecia.
"

 

[LouisSarkozy]

imo, they Bimatoprost and others produce the same effect, just a little different way - rebalancing prostaglandins or blocking prostaglandin receptors. Bimatoprost original tested as a cure for glaucoma, with is a fibrotic issue, for a research: "...for FIBROTIC ocular diseases including glaucoma".

Would be nice if there would be more scalp tissue researches and comparative researches for these stuff. To bring to mass market at least one of them, and for affordable price. Also i strongly believe it should be topical. As to produce the same effect on skin tissue via oral dosing, it should be really strong and potentially toxic. Imho, oral remedies could be good for liver or lung fibrosis, not for skin.

Cetirizine: thanks, will check it. From the first sight, looks legit and can be a potential remedy: "Cetirizine may have a protective effect against bleomycine induced pulmonary fibrosis...". Everything anti-fibrotic can be helpful, it just need to be tested specifically for dermal adipose tissue fibrosis. Preferably topically. To define right dosage, vehicle and so on.

What makes me optimistic about adiponectin-based treatments, than prostaglandin-based one, is that "adiponectines" are proved to REVERT fibrosis in dermal adipose tissue. Maybe prostaglandin-based remedies can revert too, but i afraid to prevent mostly (calming down inflammation).


PS. attached Bimatoprost for eyelashes experiment results. Good regrowth.

thanks for your answer . do you think ceti could be used as an alternative to seti? thanks

 

[Will Be an Egg in 5 years]

"follicle regeneration" and follicles structure is affected during each natural hair follicle cycle.

In your opinion, have DWAT relation to sebaceous gland?

I think he mistook the folicle with the hole the hair strand makes in the scalp.

 

[balda]

thanks for your answer . do you think ceti could be used as an alternative to seti? thanks

No idea. According to the model, they act similarly. To say which one is stronger and how to administer it, we need to have researches with stats. I hope, forums like this one help to bring researches' attention to these points.

 

[balda]

I guess this guy is pretty close to the effective treatment regimen: @eldarlmario from BTT.

He doesn't operate such terms as dermal adipose tissue. But, in fact, he combines the remedies that cure it. That stuff following the similar key features as proposed according to dwat hypothesis:
- adipogenic (see "activating" factor)
- anti-fibrotic (see "resultant" factor)
- anti-androgenic (see "inhibiting" factor)

See the details here:

https://www.hairlosstalk.com/interact/threads/tying-in-lympth-calc-fibrosis-pdg-pge2-warning-complex.112286/#post-1627990

I have mentioned or plan to some of these remedies in my original posts on reddit.
We definitely need to play with such kind of stuff, finding optimal regimen.

 

[balda]

Why Minoxidil works and why it works "temporarily" only, according to dwat hypothesis.

From a research: "Minoxidil promotes the proliferation of DP cells and hair growth through stimulation of growth factor release from adipose-derived stem cells... Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs."

 

[balda]

Proper treatment should like like one the photo below. When hair sprouts across all the balding area near the same time and with the same quality. If you don't experience similar results, near to all of us don't, your protocol is far from what could be called a cure.

For example, Big3, is far from the cure for balding, because it contains only a few of these properties:
- adipogenic: nope, but mimicking (minoxidil)
- anti-androgenic/anti-inflammation: yes, but not so good (finasteride)
- anti-fibrotic: not at all

 

[LouisSarkozy]

Proper treatment should like like one the photo below. When hair sprouts across all the balding area near the same time and with the same quality. If you don't experience similar results, near to all of us don't, your protocol is far from what could be called a cure.

For example, Big3, is far from the cure for balding, because it contains only a few of these properties:
- adipogenic: nope, but mimicking (minoxidil)
- anti-androgenic/anti-inflammation: yes, but not so good (finasteride)
- anti-fibrotic: not at all

excuse i tried to read the other post but i'm too retarded to get the whole ideal protocol in detail could you highlight which product should be used?

And are you sure minoxidil isn't reducing scalp fibrosis throug collagen reduction?

 

[balda]

excuse i tried to read the other post but i'm too retarded to get the whole ideal protocol in detail could you highlight which product should be used?

And are you sure minoxidil isn't reducing scalp fibrosis throug collagen reduction?

Frankly, i don't know for now. Trying to collect and arrange remedies that have any sense from the dwat hypothesis point of view.
For example, thanks for pointing to Cetirizine. It looks pretty promising, if properly administered (vehicle, dosage and so on).

Not fully sure about collagen's importance for hair cycling. We need to revert/prevent myofibroblasts (dermal fibrosis) formation. To transform fibrotic cells back to adipose tissue. I guess collagen is not a fibrotic cell, as it's not a cell.

 

[waynakyo]

Anyone has links to real bald people, who have been bald for years, who actually regrew hairs following ANY therapy including transition/estrogen supp? I have seen the wound healing one, but that is a different story, where the skin might form de novo follicles.

My understanding is that fibrosis play an important role in why follicles eventually suffocate and "die". And fibrosis is the culprit of many diseases, and so far there is no proven way to reverse it.

 

[balda]

Anyone has links to real bald people, who have been bald for years, who actually regrew hairs following ANY therapy including transition/estrogen supp? I have seen the wound healing one, but that is a different story, where the skin might form de novo follicles.

My understanding is that fibrosis play an important role in why follicles eventually suffocate and "die". And fibrosis is the culprit of many diseases, and so far there is no proven way to reverse it.

Kind of that. According to what i've read:
- follicles DON'T die. it's kind of pointless mantra. if there are legit evidences/researches, please share. follicles just blocked and, probably, miniaturized
- fibrosis is reversible. some anti-fibrotic drugs are sold for many years. see my original post "The Big Fat Layer II" on reddit. ADP355/PEP70/ALY688 and tons of other stuff able to revert dermal fibrosis.

 

[Armando Jose]

A recent paper

Dermal adipose tissue secretes HGF to promote human hair growth and pigmentation

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte-HF communication remains unexplored. Therefore, we in…

www.sciencedirect.com

Dermal adipose tissue secretes HGF to promote human hair growth and pigmentation​

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte-HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of organ-cultured human anagen scalp HFs. Quantitative (immuno-)histomorphometry, microCT and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen-catagen transition, whilst fluorescence lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge/sub-bulge region. Ex vivo, dWAT significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted hepatocyte growth factor (HGF) during human HF-dWAT co-culture, for which the c-Met receptor is expressed in the hair matrix and dermal papilla. These effects were abrogated by an HGF-neutralising antibody, and reproduced using recombinant HGF. Laser capture microdissection-based microarray analysis of the hair matrix showed that dWAT-derived HGF up-regulated KRT27, KRT73, KRT75, KRT84, KRT86 and TCHH. Mechanistically, HGF stimulated Wnt/β-catenin activity in the HM by inhibiting SFRP1 in the dermal papilla, up-regulating matrix AXIN2, LEF1, WNT6 and WNT10B expression. Our study demonstrates that dWAT regulates human hair growth and pigmentation via HGF secretion, and thus identifies important, molecular and cellular targets for therapeutic intervention in disorders of human hair growth and pigmentation.

 

[balda]

That's why i think of minoxidil as bumping solution, having no long term cumulative effect. Even though it acts via adipose tissue too:
"Minoxidil promotes the proliferation of DP cells and hair growth through stimulation of growth factor release from ADIPOSE-derived stem cells.
Minoxidil DID NOT ALTER ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs"

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells - PubMed

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if...

pubmed.ncbi.nlm.nih.gov

PS.
A citation from the research, thanks to @Armando Jose, shared above: "HGF secretion by dWAT is sufficient and necessary for stimulating scalp HF growth and pigmentation."

 

[balda]

Linkage between dermal adipose tissue status, WNTb catenin, PGD2 prostaglandins, Androgenic receptors.

"As different prostaglandins have opposing biological effects, PGD2 MAY MEDIATE testosterone INHIBITION OF WNT signaling IN Androgenetic Alopecia. Future studies are needed to test this hypothesis. ! It is interesting to speculate that AR roles in other physiological processes may be tied to its role as a β-catenin/Wnt inhibitor."

"We conclude that activation of Wnt/β-catenin signaling in adult epidermis STIMULATES ADIPOGENESIS in association WITH INDUCTION OF anagen and ectopic HF FORMATION."

"They also show that overexpression of localized WNT CONVERTS dermal ADIPOSE CELLS INTO a distinct FIBROBLAST subtype, which leads to fibrosis and disrupted hair follicle cycling."

"The authors of several articles (Hamburg and Atit, 2012, Mastrogiannaki et al., 2016, Wei et al., 2011), speculate that inhibition of Wnt signaling could be a new therapeutic target for the treatment of skin fibrotic diseases."


Has anyone investigated or even tried any WNTb modulating drugs? GSK3B inhibitors? DKK1 inhibitors? SM04554?