hair cloning, progression of baldness and short term rejuvenation therapy

[scientist_0005]

I want to ask the more knowledgeable and biochem savy people on this forum something that has popped into my mind recently and has been a reason for why I made this account. I provided evidence in form of research publications for all my assumptions

so if i got this right, the most accepted theory of progressive baldness with age is not that DHT levels rise as you get older(duh!), the opposite is the case, plus the free androgens get decimated as well by increase of SHGB, also it should not be the case, that your DP cells increase their expression of androgen receptors as you age(no evidence to support epigenetic changes of such sort) but rather accumulated damage over time.

so basically, with time, the number of your DP cells get lower with every hair cycle, thus they can induce less inductive signal during the initiation of the hair cycle to command resting epithelial stem cells in the bulge to migrate down, proliferate differentiate into hair matrix cells thus form a new hair shaft and at the same time, they have less capabilities of sending off growth and proliferative signals during the hair cycle to the hair matrix cells. androgens deplete the dermal papilla over time in people that are genetically prone to it and have excessive expression of the androgen receptor.

Hair follicle dermal papilla cells at a glance - PMC

www.ncbi.nlm.nih.gov

this has been well established in various studies that link size of the DP to induction of hair cycles, thickness of hair etc.

Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline - PubMed

Although the hair shaft is derived from the progeny of keratinocyte stem cells in the follicular epithelium, the growth and differentiation of follicular keratinocytes is guided by a specialized mesenchymal population, the dermal papilla (DP), that is embedded in the hair bulb. Here we show that...

pubmed.ncbi.nlm.nih.gov

Gone today, hair tomorrow? Changes in dermal papilla cell number drive hair thinning and loss. - the Node

Over the course of a lifetime, each hair follicle makes a series of new hairs, temporarily ceasing hair production before beginning again anew.

thenode.biologists.com

these cells are very important and the prime target for androgenic action. in fact, it has been shown that epithelial derived cells, cells part of the hair matrix such as keratynocites do not express the androgen receptor, they are not a target, their proliferation is only modulated indirectly by alteration of growth signals from the DP cells(like wnt, tgf b, BMP etc.)

this is where it was samumeds time to shine, by restoring the altered wnt pathway caused by androgens interferring with DP transcriptome. but they failed, bc this pathway is quite complex as are most things in the human cell

Androgens modulate keratinocyte differentiation indirectly through enhancing growth factor production from dermal fibroblasts - PubMed

These observations suggested that androgens enhance growth factors production from dermal fibroblasts, and growth factors from fibroblasts alter keratinocyte differentiation in acne lesion.

pubmed.ncbi.nlm.nih.gov

Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells - PMC

Context/Objective: Androgen induces androgenetic alopecia (Androgenetic Alopecia), which has a regressive effect on hair growth from the frontal region of the scalp. Conversely, Wnt proteins are known to positively affect mammalian hair growth. We hypothesized that ...

www.ncbi.nlm.nih.gov

Androgens downregulate BMP2 impairing the inductive role of dermal papilla cells on hair follicle stem cells differentiation - PubMed

Hair follicle cyclical regeneration is regulated by epithelial-mesenchymal interactions. During androgenetic alopecia (Androgenetic Alopecia), hair follicle stem cells (HFSC) differentiation is impaired by deregulation of dermal papilla cells (DPC) secreted factors. We analyzed androgen influence on BMPs...

pubmed.ncbi.nlm.nih.gov

now, as far as hair cloning goes, the DP cells in the occipital scalp of course are genetically identical, however they have a different expression profile. in fact, some studies have been conducted where they found lower expression of AR and 5AR in those areas of the scalp explaining the Norwood pattern formation. there has been methylation of the AR promoters for example. it could also be higher expression in the more affect areas, it could be higher expression of 5AR as well.

(PDF) Evidence of increased DNA methylation of the androgen receptor gene in occipital hair follicles from men with androgenetic alopecia

PDF | On Mar 1, 2011, J.E. Cobb and others published Evidence of increased DNA methylation of the androgen receptor gene in occipital hair follicles from men with androgenetic alopecia | Find, read and cite all the research you need on ResearchGate

www.researchgate.net

so, when a company like tissues or Stemson take those DP cells and implant them, i think the technique really matters. when they go the conventional approach, take the DP cells, put them in a 3D medium(because research has suggested cells need the contact to others in a sphere or they lose their inductive abilities), the epigenetic profile should largely remain the same? because the fundamental point is that epigenetics is inherited during mitosis. so these cells should as well have a lower expression of the androgen receptor?

but with Stemson, they use IPCs, they take some somatic cells, it really does not matter which ones they use and they vector some genes into it that give it the capabilities of acting like stem cells. but their epigenetic profile is completely different, this is called the "epigenetics memory". so, if Stemson takes somatic cells, and these cells do not share the epigenome of the occipital scalp, then what happens? does the hair just miniaturize? how can they make sure they cloned hairs are as resistant to androgens as the ones from the donor zone when nothing of them is coming from that zone, its all just a creation of

https://stemsontx.com/wp-content/uploads/2019/06/Alexey-iPSC-Publication.pdf

Epigenetic memory in induced pluripotent stem cells - Nature

Pluripotent stem cells can be generated in the laboratory through somatic cell nuclear transfer (generating nuclear transfer embryonic stem cells, ntESCs) or transcription-factor-based reprogramming (producing induced pluripotent stem cells, iPSCs). These methods reset the methylation signature...

www.nature.com

"Different iPSC lines may have variable propensity to differentiate towards DP-like cells. Indeed, we had only modest success in generating DP-like cells with 1 out of 3 hiPSC lines used. The hiPSC-DP cells were not able to induce hair follicle formation when transplanted using patch method and had low frequency of incorporation into the DP of newly formed hair follicles. We speculate that this might be a result of the epigenetic memory phenomenon, known to influence IPSC differentiation"

they had more success generating DP cells by going the embryonic stem cell route than with the expensive high risk IPC they plan to use later on



which brings me to my second question: if hair loss is an effect of accumulated damage over time, what would actually happen if you take a non minaturized hair which is prone to baldness and implant it in a middle aged man, after puberty where the dht was highest, after all those years it took for others to minaturize? would it not be relatively save for quite some time? and if so, why would this not work: you run a short course of estrogen, 6-7 months, you convert the minaturized hairs back into terminal hairs with a long Anagen phase and a full dermal papilla. your old hair took many many years to go from this state to fully bald, why would it be faster this time? why can we not assume that people who gained ground on finasteride take as much time to lose that ground as it took them the first time to go bald from full head of hair?

do you think there could be a modification in the expression of the related genes while you are on the therapy that makes you lose ground faster than you did naturally? is there any evidence?

i apologize for such a long post but i think this would be an important realization to have. it could be the reason methods like stemson while being able to produce good hair could not really last very long.

 

[pegasus2]

The size of the hair follicle is in fact controlled by the size of the dp, but it's not accumulated damage. Hamilton showed that if you give young eunuchs testosterone they will go bald slowly, but if you give old eunuchs testosterone they bald quickly. As you get older you are less resistant to stress. The threshold for epigenetic changes that cause Androgenetic Alopecia are lowered. Don't worry about Stemson though, the cells they are using should be immune to the effects of androgens just like on the back of your head. I'm more familiar with Tsuji's work than Stemson's, but Terskikh knows all this, he is not stupid. He's not going to use cells that aren't DHT resistant

 

[scientist_0005]

it seems to me though that if the dermal papilla decreases in size every hair cycle, accumulative damage seems to be done as well. no question that the overall environment for older men is different, suddenly stuff like stem cell niche depletion is an actual thing. but what about the following example:

what if i as a young man take a graft of hair from my vertex region and freeze it. lets say i do this before i turn 20. then, at 25, my entire vertex region is bald and i implant this fully terminal thick hair into the vertex region. what is going to happen? is it going to minaturize faster than the 5 years it took the others that where not plugged or the same time? if it is the same time, one might wonder the following:

what if you gained ground on finsteride or an estrogen mtf regime that you ran for half a year. your minaturized hairs have turned terminal again, the dermal papillas have been repopulated with cells capeable of directing a proper hair cycle. then you get off treatment. it is generally believed that the gains will be lost fast. i wonder why this would happen any faster than the natural minaturisation took place. surely stem cell depletion or lack of regeneration is not at play here. so what could it be, a constant upregulation of AR as you get older? that does not seem to be it. this further leads to the question what exactly determines "when" a certain hair gets minaturized. the one idea is simply, some cells have a different epigenetic makeup than others. this could be compared like different gene expressions along a gradient like in embryology with homobox genes i suppose? is it just that cells in the vertex and temple region have the highest expression of AR and 5AR and those in the middle of the scalp less, those in the back none?

another concept that would go against accumiltive damage theory is that in some men, baldness can halt progression for a few years, then continue. however, AR signaling certainly does not just halt. so there needs to be other pathways that get switched on and off during different times of maturation.

it seems to me this is a lot more complex than i and many other people realize at first glance.

i do believe however that indeed people like Dr Terskikh are a lot smarter and more knowledgeable and would not run into dumb issues like the ones i mentioned. on the other hand, many companies like histogen worked with self proclamed experts on dermatology and stem cells biology and their product is a joke

 

[pegasus2]

It's not janey

 

[froggy7]

The size of the hair follicle is in fact controlled by the size of the dp, but it's not accumulated damage. Hamilton showed that if you give young eunuchs testosterone they will go bald slowly, but if you give old eunuchs testosterone they bald quickly. As you get older you are less resistant to stress. The threshold for epigenetic changes that cause Androgenetic Alopecia are lowered. Don't worry about Stemson though, the cells they are using should be immune to the effects of androgens just like on the back of your head. I'm more familiar with Tsuji's work than Stemson's, but Terskikh knows all this, he is not stupid. He's not going to use cells that aren't DHT resistant

maybe some source where stemson makes dht resistant hair?

 

[scientist_0005]

maybe some source where stemson makes dht resistant hair?

i don't think this is stated anywhere in literature but i assume they would be aware of this fact and it is actually very easy to figure that one out once you have manufactured the cells, for example with an in vitro experiment. much cheaper to do that before testing on actual living objects. now how they do it i cannot grasp. with tsuji and other approaches that do not derive the DP cells from less differentiated cells it is more obvious, when you clone DP cells which is apparently very hard to do if you do not want to lose hair inductivity, the epigenome should be inherited as well at least this is what happens in the living organism. so under the right circumstances you would have DP cells that are quite close in their behavior to the ones on the back of your scalp. so much like in a transplant when you out them in elsewhere they should be somewhat resistant. but DP cells derived from embryonic stem cells or IPC? i do not know. i think more research needs to be done on what is actually the major difference between cells from donor hair vs dht suspectible ones. science has still not really answered the cause for this strange pattern although it is quite obvious that dermal papilla heterogeneity may be the culprit. which is why dht grows beard hair and kills scalp hair even though the genetic makeup of the cells involved and even their types are exactly the same..

 

[froggy7]

i don't think this is stated anywhere in literature but i assume they would be aware of this fact and it is actually very easy to figure that one out once you have manufactured the cells, for example with an in vitro experiment. much cheaper to do that before testing on actual living objects. now how they do it i cannot grasp. with tsuji and other approaches that do not derive the DP cells from less differentiated cells it is more obvious, when you clone DP cells which is apparently very hard to do if you do not want to lose hair inductivity, the epigenome should be inherited as well at least this is what happens in the living organism. so under the right circumstances you would have DP cells that are quite close in their behavior to the ones on the back of your scalp. so much like in a transplant when you out them in elsewhere they should be somewhat resistant. but DP cells derived from embryonic stem cells or IPC? i do not know. i think more research needs to be done on what is actually the major difference between cells from donor hair vs dht suspectible ones. science has still not really answered the cause for this strange pattern although it is quite obvious that dermal papilla heterogeneity may be the culprit. which is why dht grows beard hair and kills scalp hair even though the genetic makeup of the cells involved and even their types are exactly the same..

there is no publication that they managed to grow dht resistant hair

 

[scientist_0005]

there is no publication that they managed to grow dht resistant hair

I don't think they are this far yet. they are at the stage of producing cells that produce any hair at all, cycle properly etc. although, in one interview Terkish said they have figured out ALL of the theoretical biochemistry and now it is just an engineering exercises, referring to the scaffold design. so if that is true, surely they must be aware of the resistancy. also I suppose that might be what all the computational approaches are for, running large data one genes and expressions to figure out the nature of the cells they produced and make predictions

 

[froggy7]

I don't think they are this far yet. they are at the stage of producing cells that produce any hair at all, cycle properly etc. although, in one interview Terkish said they have figured out ALL of the theoretical biochemistry and now it is just an engineering exercises, referring to the scaffold design. so if that is true, surely they must be aware of the resistancy. also I suppose that might be what all the computational approaches are for, running large data one genes and expressions to figure out the nature of the cells they produced and make predictions

everything sounds and looks good on paper, and life will verify everything as always

 

[scientist_0005]

everything sounds and looks good on paper, and life will verify everything as always

they commented on exactly this issue in an interview on follicle thought

 

[scientist_0005]

stemson said "t gives us a source of material that helps us look deeper into ‘what is DHT resistance?’ and ‘how does that compare to hairs that are not DHT resistant?"

this is basically an attempt to get to the root of what causes male pattern hair loss. i mean, if you figure that one out, thats the hardest challenge is it not? i think their attempt is much harder than tsujis just take donor area DP cells and culture them, combine them with epithelial stem cells and put them in a scaffold. this is a bottom up engineering attempt and for that they need to clear the hurdle of 1) proving that their IPC derived DP cells do not have cellular memory that might make them dangerous and 2) actually recreate the expression pattern of resistant cells or at least as much as they behave the same. it is also very costly to produce such an amount of IPC cells. I do not understand why they selected to go with this approach over a tsuji approach but they probably have much better understanding of the matter than we do. still, the fact that they have not even really though about the cosmetic aspect, they actual dht resistance questions makes me believe terkeshi was way to optimistic by suggesting "it is merely an engineering exercise now", it seems, that a lot of fundamental aspects have not even started to get any attention?

 

[froggy7]

stemson said "t gives us a source of material that helps us look deeper into ‘what is DHT resistance?’ and ‘how does that compare to hairs that are not DHT resistant?"

this is basically an attempt to get to the root of what causes male pattern hair loss. i mean, if you figure that one out, thats the hardest challenge is it not? i think their attempt is much harder than tsujis just take donor area DP cells and culture them, combine them with epithelial stem cells and put them in a scaffold. this is a bottom up engineering attempt and for that they need to clear the hurdle of 1) proving that their IPC derived DP cells do not have cellular memory that might make them dangerous and 2) actually recreate the expression pattern of resistant cells or at least as much as they behave the same. it is also very costly to produce such an amount of IPC cells. I do not understand why they selected to go with this approach over a tsuji approach but they probably have much better understanding of the matter than we do. still, the fact that they have not even really though about the cosmetic aspect, they actual dht resistance questions makes me believe terkeshi was way to optimistic by suggesting "it is merely an engineering exercise now", it seems, that a lot of fundamental aspects have not even started to get any attention?

nothing new, i think it will be costly, extremely

 

[scientist_0005]

nothing new, i think it will be costly, extremely

I do not think it will be extremely costly for the end customer, the process of manufacturing the cells itself is very costly as of now because they have to trigger a genetic program in the cells in order for them to differentiate into the exact right cell type which is not even known yet. but the fact that their nr 1 priority is to get the manufacturing process on point suggests they are trying to bring that price point way down and make it more reliable. but at the cost of how long it will take to initial trials and qhwn they can even start to think about cosmetic aspects of it.

this is also something tsuji and others have probably not even researched themselves and thus another reason why the entire tsuji 2020 trial claim was so utterly unrealistic from the start. i think stemson can get this right and learn a sh*t ton about MBP in the process beyond what their end product is but it will take another decade probably. id say though, better done right and be clear about that from the start to investors than to create non fulfillable expectations and lose funding down the line

 

[froggy7]

I do not think it will be extremely costly for the end customer, the process of manufacturing the cells itself is very costly as of now because they have to trigger a genetic program in the cells in order for them to differentiate into the exact right cell type which is not even known yet. but the fact that their nr 1 priority is to get the manufacturing process on point suggests they are trying to bring that price point way down and make it more reliable. but at the cost of how long it will take to initial trials and qhwn they can even start to think about cosmetic aspects of it.

this is also something tsuji and others have probably not even researched themselves and thus another reason why the entire tsuji 2020 trial claim was so utterly unrealistic from the start. i think stemson can get this right and learn a sh*t ton about MBP in the process beyond what their end product is but it will take another decade probably. id say though, better done right and be clear about that from the start to investors than to create non fulfillable expectations and lose funding down the line

another 20 years for hair?? come on

 

[scientist_0005]

another 20 years for hair?? come on

who is suggesting it would be 20 years? I dont think it will. I think stemson will either fail or succeed within 10 years. i think there is no other option. but in 10 years, i would be very surprised if our knowledge of hair biology does not far exceed what we do now. not because the interest in this ridiculous condition drives it forward but because stem cell research will need to be driven forward because regenerative medicine will have to make big step to eventually provide donor tissue for more vital organs(some of which are actually easier to produce than hair i would think but others much much harder). if we cant make hair by 2035, how are we supposed to make a kidney at any point before 2050?

one thing to learn though is that pop science articles are such utter bullshit, when ever you read a projection about what science can do, make it +50 years and you might get there