waynakyo
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I think this is a must-read for anyone who wants to make claims and debate HF regeneration. I am jumping into it now.
Functional hair follicle regeneration: an updated review (Nature)
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waynakyo
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I wish I started with the conclusion, as the article builds up hope and you get the sense that we are almost there:
Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies. In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress. For example, the creation of transplantable HFs that closely mimic the structures and functions of native tissue may be accomplished by combining organoid technology with a drug delivery system. Depending on the controllable release of the relevant factors in hair cycling, such as WNT or BMP, hair cycling activation and maintenance of HF organs may be achieved. We also need to continue to optimize the in vitro culture systems of potential cells and look for more efficient reprogramming techniques, such as chemical reprogramming induced by small molecules or genetic reprogramming of genes delivered by biomaterials. Finally, we want to reiterate that, based on existing work, it is worth considering whether the achievement of the activation and maintenance of hair cycling in regenerated HFs could be the heart of the next phase.
There is a lot more to unpack, needs several rounds of reading. Those who are interested in deep microdeenling and wound regeneration there is a lot of material (including apparently available drugs) to think about. What is shocking is that this whole HF regeneration research started in 1980s. Jahoda's work feature strongly. Tsuji's as well:
"Although hair transplantation has been widely applied, transplanted hair is not maintained in the long term." I have yet to see studies on this one.
No mention of Terkish's work but page 4 iPSCs discusses that avenue which it finds promising. However, the problems these cell sources have in common are that their potential to regenerate HF fails to be maintained during long-term culture in vitro.
Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies. In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress. For example, the creation of transplantable HFs that closely mimic the structures and functions of native tissue may be accomplished by combining organoid technology with a drug delivery system. Depending on the controllable release of the relevant factors in hair cycling, such as WNT or BMP, hair cycling activation and maintenance of HF organs may be achieved. We also need to continue to optimize the in vitro culture systems of potential cells and look for more efficient reprogramming techniques, such as chemical reprogramming induced by small molecules or genetic reprogramming of genes delivered by biomaterials. Finally, we want to reiterate that, based on existing work, it is worth considering whether the achievement of the activation and maintenance of hair cycling in regenerated HFs could be the heart of the next phase.
There is a lot more to unpack, needs several rounds of reading. Those who are interested in deep microdeenling and wound regeneration there is a lot of material (including apparently available drugs) to think about. What is shocking is that this whole HF regeneration research started in 1980s. Jahoda's work feature strongly. Tsuji's as well:
"Although hair transplantation has been widely applied, transplanted hair is not maintained in the long term." I have yet to see studies on this one.
No mention of Terkish's work but page 4 iPSCs discusses that avenue which it finds promising. However, the problems these cell sources have in common are that their potential to regenerate HF fails to be maintained during long-term culture in vitro.
waynakyo
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Most excitingly, the treatment of deep second-degree scalding injuries with human erythropoietin (EPO) to, whether by the local subcutaneous injection of nanosized rhEPO (recombinant human EPO)/ infusion pumping or the topical application of rhEPO gel, achieved excellent skin repair with conical and HF structures, which was related to the combined expression of EPO receptor and β-subuni
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thank you for sharing, interesting to read
"Current strategies to regenerate HF in vivo are aimed at simulating EMI, mostly adopting the principle of combining epithelial (Epi-SC and keratinocyte) and mesenchymal (DP cell [DPC] and skin derived precursors [SKPs]) components"
AND
"Another way to rapidly expand SKPs via lineage reprogramming is to expose pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKPs. Acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency"
I am wondering if microneedling is a type of stress?
Also, it seem that micoenviroment have a role
"During the hair growth cycle, HFSCs periodically switch between the active and inactive stages to maintain stem cell populations and generate new HFs, while this potential is impaired in aged HFSCs. However, in transplantation assays in vivo, aged HFSCs could still regenerate HFs when supported with the young dermis, while young HFSCs failed to regenerate HFs when combined with the aged dermis, which shows that the ageing skin microenvironment dictates stem cell behaviour and illustrates the dominant role of the niche microenvironment"
BTW a lot of questions remain to be solved:
How long can the regenerated HFs last? Can the regenerated HFs go through full hair cycling?
"Current strategies to regenerate HF in vivo are aimed at simulating EMI, mostly adopting the principle of combining epithelial (Epi-SC and keratinocyte) and mesenchymal (DP cell [DPC] and skin derived precursors [SKPs]) components"
AND
"Another way to rapidly expand SKPs via lineage reprogramming is to expose pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKPs. Acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency"
I am wondering if microneedling is a type of stress?
Also, it seem that micoenviroment have a role
"During the hair growth cycle, HFSCs periodically switch between the active and inactive stages to maintain stem cell populations and generate new HFs, while this potential is impaired in aged HFSCs. However, in transplantation assays in vivo, aged HFSCs could still regenerate HFs when supported with the young dermis, while young HFSCs failed to regenerate HFs when combined with the aged dermis, which shows that the ageing skin microenvironment dictates stem cell behaviour and illustrates the dominant role of the niche microenvironment"
BTW a lot of questions remain to be solved:
How long can the regenerated HFs last? Can the regenerated HFs go through full hair cycling?
waynakyo
Experienced Member
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- 466
Interesting questions, I will get back to you on some later, but regarding how long the regenerated HF last, my reading of this is:
HF have been generated through some of the methods of DP/Epidermis/organoids but the effect did NOT last. Indeed, we have seen so many follicles on the back of mice, but they did not last long. Which is why Tsuki's latest paper is important, because that was his focus: cycling, and the environment needed for that.
HOWEVER: This is NOT a problem with wound-induced hairs.
In WIHN, a fully functional follicle can regenerate in the centre of a full-thickness wound with a large enough size, and the cellular origin of this process is similar to an embryonic process. The neogenic follicles have similar functions to embryonic HFs, which also have a growth cycle.
In other words: The elusive wound-healing method such as Follica has more support for potential long term growth as opposed to the other methods so far (instead of using DC cells/injecting them/and so on).
Having said that, Follica has not succeded yet at all. But that could be from lack of trying/luck. It may very well be, that those amazing success stories from wounding + minoxidil that they have generated de-novo hair follicles. We can never be sure without an analysis, but their results are impressive enough to suggest that this might be the case. What do you think? Is that the overall impression?
After reading bunch of papers in the last few weeks, I really think that WIHIN holds the key for an earlier treatment, as the other methods will take a long time to be figured out.
HF have been generated through some of the methods of DP/Epidermis/organoids but the effect did NOT last. Indeed, we have seen so many follicles on the back of mice, but they did not last long. Which is why Tsuki's latest paper is important, because that was his focus: cycling, and the environment needed for that.
HOWEVER: This is NOT a problem with wound-induced hairs.
In WIHN, a fully functional follicle can regenerate in the centre of a full-thickness wound with a large enough size, and the cellular origin of this process is similar to an embryonic process. The neogenic follicles have similar functions to embryonic HFs, which also have a growth cycle.
In other words: The elusive wound-healing method such as Follica has more support for potential long term growth as opposed to the other methods so far (instead of using DC cells/injecting them/and so on).
Having said that, Follica has not succeded yet at all. But that could be from lack of trying/luck. It may very well be, that those amazing success stories from wounding + minoxidil that they have generated de-novo hair follicles. We can never be sure without an analysis, but their results are impressive enough to suggest that this might be the case. What do you think? Is that the overall impression?
After reading bunch of papers in the last few weeks, I really think that WIHIN holds the key for an earlier treatment, as the other methods will take a long time to be figured out.