As has been mentioned numerous times by myself and many others over the past several years, Japan’s government is heavily promoting regenerative medicine in the rapidly aging country. One of the main ways it is doing so is via speeding up the usually lengthy and expensive clinical trial process (which is common in most developed countries).
Smart Hair Transplants
In the case of SHT, the process is autologous in nature. So clinical trials are possibly not required, or will be fairly short in duration if required.
Smart hair transplants theoretically provide unlimited donor hair. By isolating cells from the dermal papilla and then culturing and multiplying them, this procedure supposedly forms neopapillae. According to TissUse:
“Neopapillae are the precursors of hair follicles which have been shown to grow hair follicles under controlled conditions in vitro. Each of these neopapilla has the potential to form a brand new hair follicle.”
FYI — Dr. Ataç’s Phd thesis was titled: “Development of a vascularized human hair follicle equivalent” and her mentors for that project included Dr. Gerd Lindner and Dr. Roland Lauster.
Here’s my recount of the discussion I had with Dr Linder & Dr Atac about their work.
Firstly, it is with great excitement to mention that their work into regeneration of a hair follicle did not stop in 2010 after their ground breaking paper was published but rather continued at a remarkable pace with significant breakthroughs being made and some patents filed. Their presentation at the congress gave a great insight into how far along they actually are. It is also important to mention that their lab is subdivided into several teams, each working on regenerating a particular organ of the body such as the liver, kidney and of course the hair follicle.
Their aim is to have at least 10 organ models that are of human origin in order to provide a much better prediction of how a drug would perform in a clinical trial compared to animal studies. A FDA study showed that more than 92% of substances tested in animals show false negative results, and have to be excluded from use in/on humans because of toxic effects. They gave a few examples of where investigational drugs showed to be safe in animal studies but proved to be fatal in human subjects. Tegenero trial being an example.
The hair follicle team (Dr Lindner, Lauster & Atac) have FOUR goals:
1) To create a microchip system where many organs thrive.
2) To create a human hair follicle model that allows rapid screening of compounds that may have an impact on hair regeneration or removal! This may be performed on a single follicle or on a follicle embedded in an engineered full thickness skin equivalent
3) To engineer neopapillae (ECM coated dermal papilla cell spheroids) that will be transplantable into human subjects for patients suffering from Androgenetic Alopecia.
4) and ultimately, to have personalised chips of all genetic backgrounds to give a full picture of pharmacokinetics & pharmacodynamics of an investigational drug.
As for what they have achieved so far:
1) In 2010: Their original paper was published which we are well aware of.
2) In 2011: They bioengineered “human micro-hair follicles” in vitro. These micro-follicles displayed key characteristics of human vellus-like hair follicles. Mesenchymal, ectodermal and neuro-ectodermal originated primary cells from dissected human hair follicles were isolated and expanded. Dermal papilla fibroblasts were kept under low adherent culture conditions (along the same line as the EVAL scaffolds of the Taiwanese that we came across) resulting in the formation of dermal papilla-like aggregates. They then forced keratinocytes and melanocytes to attach to these dermal papilla spheres to allow further follicular development. The result was a self-organizing micro-organoid made up of separate segments enclosed by extracellular matrix membranes, sheath formations and a hair shaft–like fiber. Central ECM proteins and defined mesenchymal and epithelial markers were expressed. Furthermore, inner root sheath formation was found to be present and the melanocyte markers “p-Mel17”, “c-kit” and “TRP-1” were expressed in the supra-papillary region of the microfollicle. These results showed that the de novo formation of human microfollicles in vitro is possible and contains all the basic hair follicle like characteristics.
At this point they realised that after the addition of keratinocytes and melanocytes, the self-organizing micro-organoids followed a stringent pattern of follicular-like formation by generating polarized segments, sheath formations and the production of a hair shaft-like fiber. But the bio-engineered hairs were vellus-like and didn’t turn terminal. This is most probably due to lack of nutrient and oxygen supply during cell culture but may also be caused by an altered gene expression, a problem that Dr Jahoda’s team faced a few years later with their 3D hanging drop spheroid cultures.
Since then, they transferred their culturing method to a perfused bioreactor system and finally came to the conclusion that the best way to improve the microfollicle development is by also co-culturing endothelial cells with the hair follicle which turn into micro-blood vessels and are normally feeding the hair follicles the necessary oxygen, hormones and nutrients. In fact, our hair follicles are very well vascularised, and one can see where they are coming from.
3) So in 2013, they went at it again. They again used an ultra-low adherent attachment conditions. The low-adherent surface which is polycarbonate-based mimics mesenchymal condensation during embryonic development. Under these conditions, DP cells self-aggregate and are then coated with keratinocytes, melanocytes and endothelial cells. After 48 hours the newly formed micro-follicles are placed in a multi-organ chip platform to grow. They also used a new 3D matrix environment to enhance gene expression. These micro-follicles were cultured for 14 days, which showed further improvements in hair follicle-like expressions as you’ll see in the presentation.
So, I guess although they haven’t managed to completely replicate a fully functional (terminal) hair follicle, these follicles look very promising indeed. Some may even call it the endgame (of chess), where there are very few pieces left to play. Exciting times indeed and what a wonderful team of individuals working on such a revolutionary project. The Lauster team as we know them is made up of some great minds: Dr Gerd Lindner and Beren Atac to name a few. I wish them all the very best and I’m sure they’ll have very exciting news to share with the world in a few years.