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Cotsarelis/Garza Genetic analysis
Just thought I would bring forward some key points about Cotsarelis/Garza's research.
They are still the only team who have directly studied AGA in the hope of finding the underlying mechanisms of the disease. The take the logical approach of actually comparing bald vs non-bald scalp for genetic/enzymatic differences. They used quite new techniques(microarray and flow cytometry) so cutting edge that Cotsarelis himself(among many other people) does not know how to do them. Garza did these techniques during the study.
Recall:
2011 (http://www.ncbi.nlm.nih.gov/pubmed/21206086)- Stem cells maintained
- Lack progenitor cells (1/10 normal amount)
- Progenitor cells were tested in assays and found to be able to generate long hairs
So, strong evidence that lack of progenitor cells causes miniaturization. That fact that there is 1/10 the amount makes sense as there is still some hair there just very small.
Potential reversal of AGA by reactivation of these cells. Why? Because AA is always reversal even after many years and is also due to lack of progenitor cells. (http://www.niams.nih.gov/health_info/alopecia_areata/)
Cotsarelis/Garza:
"In reversible types of alopecia (e.g., alopecia areata), inflammation targets hair follicle progenitor cells but spares hair follicle stem cells. In these disorders, regrowth occurs with suppression of inflammation and subsequent regeneration of the hair follicle from uninjured stem cells. Our finding that AGA, in the clinical category of nonscarring alopecia, demonstrated preservation of hair follicle stem cells suggests potential reversibility of this condition. "
Then they scanned bald vs non-bald scalp they found many genes upregulated/downregulated here are some quotes from the patent: http://www.google.com/patents/US20110021599
Note: Yes lots of useless info can be found in patents, but this was taken from his experiment results at the bottom of the patent not the never-ending statements at the top. I.e they are scientific/proven
"Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples ........Thus, LRRC15 functions in cell migration necessary for hair growth."
"Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B)."
"GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth."
"The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular."
"GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E)."
"FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G)."
"The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth."
Not only are they noted, but also there location and some function stated.
Then of course there is PDG2: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/)- Inhibits explanted human hair follices by 62 +/- 5%
- Mice overexpressing PDG2 phenocopy(not just mimic, phenocopy has stronger definition) human AGA
- Relates to testerone
- PDG2 was able to inhibit hair growth for 50 days after last application
So, strong evidence that PDG2 causes miniaturization but not that removing it will reactivate stem cells. Some home experiments(alecbaldone and friends) have reported stoppage of hair loss and some small regrowth(very small).
So, reactivation of stem cells will probably require more than just GPR44 blockers. Cotsarelis has accounted for this he is not naive.
Thats were all the above genes come into play as well as the following(from the patent again)
"A population of alpha-6 integrinhigh CD200high cells was found to be present in the haired but not bald samples (FIG. 9). These findings demonstrate the existence of a stem cell population that can be transplanted to generate new HF and treat baldness. Further, these findings demonstrate that administration of CD200 and analogues thereof can be used to treat baldness."
"The gene expression profile of alpha-6 integrinhigh CD200high cells is determined, as described in Example 3. Genes enriched in the alpha-6 integrinhigh CD200high cells (e.g. relative to non-bulge basal keratinocytes) play a role in HF formation. Thus, administration of these genes, their protein products, or mimetics and analogues thereof, can be used to stimulate hair growth."
plus there is also PGE2/F2 etc.
If you are going to take anything from this post let it be this:
Cotsarelis is aware of almost every gene that is differently regulated in bald/haired scalp. PDG2 seems to be his key focus but he will almost certainly test other pro-growth genes when he starts clinical trials within 1/2 years. Overall we should all be very excited about his upcoming clinical trial
My opinion:
Pdg2 causes original deactivation of stem cells and hence hair growth inhibition and miniaturization. Blockage of GPR44 will stop further hairloss. Reactivation of stem("mother")cells should reverse miniaturization in a perfect world and cause serious regrowth if we are unlucky. How exactly we will reactivate the stem cells is still unproven but:
"possibilities include a cream or lotion that is rubbed onto the scalp, or a technique that involves removing the stem cells from the scalp, kick-starting them in the lab and transplanting them back."
http://www.dailymail.co.uk/sciencete...#ixzz2VcwYnkFY
Some FAQS:
Why hasnt we started already?
He could be waiting for one of the GPR44 blockers to finish its own clinical trials.
Why has nothing come of his research yet?
Histogen is based off his earlier work on wnts and it is almost here so he wasnt that wrong with his timeline.... ok so maybe he is bad with predictions but the science is undoubted. Time taken does not make his work redundant
What about fgf9?
Not sure I think it has more to do with whole new follicles(scarring hairloss), in AGA follicles are maintained so need for wounding etc. Follica also dont seem to be related to pdg2.
Are you a Cotsarelis fanboy?
Yes but it is justified
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Thanks for sharing this HairlossAt15, I really appreciate it!
Cotsarelis is one of the Follica guys, right?
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What would be your current recommendation for treatment at this moment? I'm currently on RU, but I'm hearing a lot of good with tm30089 and indo/cromo from HLH.
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Well done sir!
This is the line I focused on:
A population of alpha-6 integrinhigh CD200high cells was found to be present in the haired but not bald samples (FIG. 9). These findings demonstrate the existence of a stem cell population that can be transplanted to generate new HF and treat baldness."
It makes sense that inhibiting PGD2 will not reverse, but will only stop hair loss, but something needs to be done to activate stem cells to TA and progenitor cells. I believe this is what Dr Nigam is trying to do with his HM procedure, extract bulge cells and convert them to TA cells, and reinject them. Perhaps wounding will do this as well?
Dr Nigam, what's your take?
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KO,
CD200 POSITIVE CELLS,ALPHA6 INTEGRIN POSITIVE CELLS..
are present in donor, non aga scalp..in case of mpb.
THESE CELLS ARE PROLIFERATIVE,LARGER IN SIZE .
CD200 IS PRESENT IN THE BULGE AND ALPHA6 INTEGRIN AT
THE SUPRABASAL COMPARTMENT OF STEMCELL NICHE OF THE MID FOLLICLE BULGE.
KRT19+ CELLS are present in non balding scalp area,these are quiescent and smaller in size,and as you are aware,cd200,alpha6 integrin are either missing or present in low numbers in the balding scalp..
1)I started my HM protocol with injections of cd200+,alpha 6 integrin + and cd34+ multiplied cells..and got some success..(remember cd200+,alpha 6 integrin,cd34+ cells are active or progenitor cells already..in good quantity at the donor scalp)
2)Than ,I ADDED TO THIS,OTHER FOLLICULAR STEMCELLS i.e BOTH EPIDERMAL AND MESENCHYMAL DERMAL STEMCELLS..my results improved further..
3)3mo9nths back ,i started adding trichogenic freshly isolated dermal papilla cells..this lead to sudden jump in success rate
..and with subsequent addition of trichogenic 3d spheroidal dp culture..i am hoping to further improve results..
most important weapon , we have as on today is intervention by above mentioned progenitor cells and cultured trichogenic dp cells...
all these stuff like..fgf2,pgd2 blockers,,anti androgens,anti mast cells,growth factors ,ecm, fina,minox and many other compounds... which cotsarelis is working on..
will definitely be used as an adjunct ..probably with micro wounding... with stemcells and dpculture injections...to grow new follicle formation...
stand alone...none of these compounds can lead to new follicle formation,
as there is no single factor apart from progenitor stemcells and trichogenic dp cultured cells..which has the maximum potential to create new follicles..
all other compounds discussed in forums..may prevent hair loss,delay the follicle damage,may give little regrowth..
Causative vehicles to damage follicles are dht via receptors in dermal papilla through tgf beta1..microinflammation via pgd2 and others ...
apart from genetic predisposition..what is triggering these vehicles to accumulate and damage the follicles residing at the particular location of mpb scalp..!
is the absence or reduction in progenitor stemcells in the balding scalp due to ..damage by pgd2 or any other compound is not known..as there are no pdg2 receptors found at any stemcells of the follicle...
..as i am the only one..apart from aderans..who is injecting and hence observing..new follicles in good numbers on mpb scalp after cultured progenitor stemcells and trichogenic cell injection..
which is the only good and realistic news as on today..but yes we are half way..as some patients get unbelievable amazing result with these injections..and others do not get any result..
this is the puzzle..which needs to be worked. on..
looking optimistically..if some patients can get excellent results..sooner or later,with further improvement others will get too hopefully...
with these injections..when i am using fragments of follicle as in hairdoubling with bisected follicles and stemcells,dpcells injetion..we have already achieved 100% success as a cure..with THEORITICALLY unlimited donor hair option..
WITH STAND ALONE HM ..IS JUST A MATTER OF TIME ..FOR THE RESEARCHERS..TO FIND THE MISSING LINK..TO ACHIEVE HIGHER SUCCESS RATE...
Originally Posted by KO1
Well done sir!
This is the line I focused on:
It makes sense that inhibiting PGD2 will not reverse, but will only stop hair loss, but something needs to be done to activate stem cells to TA and progenitor cells. I believe this is what Dr Nigam is trying to do with his HM procedure, extract bulge cells and convert them to TA cells, and reinject them. Perhaps wounding will do this as well?
Dr Nigam, what's your take?
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Originally Posted by drnigams
all these stuff like..fgf2,pgd2 blockers,,anti androgens,anti mast cells,growth factors ,ecm, fina,minox and many other compounds...
... which Nigams could find on hair loss forums.
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More on pdg2 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/)
"we found a detectable Ptgds pattern by immunostaining (Fig. 3,
D and F). Lower outer root sheath cells—but not bulge cells—expressed
Ptgds. Furthermore, at day 19 after depilation, keratinocytes in catagen
follicles expressed Ptgds, without overlapping Krt15-positive keratino-
cytes (Fig. 3G). These results demonstrate that Ptgds is abundant in
nonpermanent keratinocytes of the hair follicle in mouse."
So ptgds (ptdgs --->pdg2)is not expressed around the bulge. This explains why stem cell remain untouched in bald scalp, if ptgds was found around the bulge then perhaps stem cells would be lost as well.
More evidence can be found in the WCHR 2013 abstracts(http://www.hair2013.org/news.asp?newsid=27)
"P130
Human scalp hair follicles possess the enzymes to synthesize prostaglandins and
prostamides from phospholipids and contain PGF2ain vivo"
Dr Nigam perhaps pdg2 targets progenitor cells? What are your thoughts.
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Originally Posted by EDB
What would be your current recommendation for treatment at this moment? I'm currently on RU, but I'm hearing a lot of good with tm30089 and indo/cromo from HLH.
I dont risk using untested compounds etc myself. You will have to ask someone else sorry.
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Are these treatments designed to protect the yair you still got?
And in what timeframe they will develop it? 5-10-20 years?
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Originally Posted by Tomb10
Are these treatments designed to protect the yair you still got?
And in what timeframe they will develop it? 5-10-20 years?
A cautiously optimistic timeline is within 5-10 years IMO, and by cautiously optimistic I mean at least only one or two of all these new treatments coming through - if they really have something and will make it to market, it won't be more than 5-10 years away. 5 years is also quite conservative for Histogen and Replicel IMO, as both companies are well into their development phases already, but who knows.
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