Cotsarelis/Garza Genetic analysis

[HairlossAt15]

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