Bald truths

A cure for baldness is some way off but understanding why hair follicles ‘switch off’ – and overcoming this – could form the basis of potential treatments. Lou Reade reports

While baldness is not a serious condition on the scale of cancer or heart disease, it is nevertheless the subject of serious research. In commercial terms, a pharma company with a proven treatment for baldness could hit the jackpot, while a closer understanding of how hair regenerates – or stops regenerating – could also offer insights into areas such as wound healing.

A few commercial treatments such as the drugs minoxidil and finasteride already exist but typically require daily application. US-based start-up dNovo claims to have developed ‘personalised hair stem cells’. However, the company has not posted any news to its website in more than a year – and did not return requests for more information.

News during 2022 of the discovery of a signalling molecule that may stimulate hair growth – and one day form the basis of a treatment for baldness – has therefore been hailed as an important milestone. The paper, published by researchers at the University of California, Irvine, US (Developmental Cell; doi: 10.1016/j.devcel.2022.06.005), explains the exact mechanism used by dermal papilla cells – which sit at the bottom of every hair follicle – to promote new growth. Dermal papilla cells are known to be crucial in controlling hair growth, but the genetic basis of the activating molecules has not been well understood.

‘At different times during the hair follicle life cycle, the same dermal papilla cells can send signals that either keep follicles dormant or trigger new hair growth,’ says Maksim Plikus, Professor of developmental and cell biology at UCI, and the study’s corresponding author.

The dermal papilla cells naturally produce a signalling molecule called SCUBE3 that acts as a messenger, and ‘tells’ neighbouring hair stem cells to start dividing – stimulating new hair growth. The discovery could be used to treat androgenetic alopecia, a common form of hair loss in both men and women, Plikus adds.

In androgenetic alopecia, dermal papilla cells malfunction, reducing the level of activating molecules.

The researchers developed a mouse model – with hyperactivated dermal papilla cells and excessive hair – which helped them to identify SCUBE3 as the molecule that can drive excessive hair growth. The team micro-injected SCUBE3 into mouse skin, in which human scalp follicles had been transplanted. This induced new growth in the dormant human follicles – and in the surrounding mouse follicles. This proof of principle shows that SCUBE3 – or derived molecules – are a promising avenue for a hair-loss treatment, said the researchers. ‘Our test in the human hair transplant model validates the preclinical potential of SCUBE3,’ says Plikus.

Two commercial treatments – finasteride and minoxidil – are approved by the US Food and Drug Administration (FDA) for androgenetic alopecia. Finasteride is only approved for use in men. Neither are universally effective – and must be taken daily to maintain their clinical effect, said the researchers.

‘There is a strong need for new, effective hair loss medicines,’ says Plikus. ‘Naturally occurring compounds, which are normally used by the dermal papilla cells, present ideal next-generation candidates for treatment.’

UCI has filed a provisional patent application for the use of SCUBE3 and related molecules to stimulate hair growth. Further research will be conducted in Plikus’ lab and at Amplica Holdings, a biotechnology company he co-founded in 2021.

There is a strong need for new, effective hair loss medicines. Naturally occurring compounds, which are normally used by the dermal papilla cells, present ideal next-generation candidates for treatment.
Maksim Plikus Professor of developmental & cell biology, University of California, Irvine, US

Skin generation

Researchers at the University of California Riverside (UCR), meanwhile, have found a single chemical that controls when hair follicle (HF) cells divide – and when they die. The chemical, a protein called transforming growth factor beta (TGF-β), could potentially be used as a treatment for baldness, they say.

‘TGF-β has two opposite roles,’ says Qixuan Wang, a mathematical biologist at UCR and corresponding author of the reported study (Biophys. J., doi: 10.1016/j.bpj.2022.05.035). ‘It helps activate some hair follicle cells to produce new life, and later helps orchestrate apoptosis – the process of cell death.’

The effect of TGF-β depends on how much is produced: a certain quantity activates cell division, while an excess causes apoptosis. The reason why hair follicles kill themselves – causing baldness – is not well understood. One theory is that it is an inherited trait from animals shedding fur, to survive hot summer temperatures or to camouflage. However, the fact that animals re-grow fur shows that the process is not irreversible.

‘Even when a hair follicle kills itself, it never kills its stem cell reservoir,’ says Wang. Most cells in the human body, such as a blood cell and a nerve cell, are not interchangeable; one cannot be converted into the other. However, stem cells can turn into other types of cells. This adaptability makes them useful for repairing damaged tissue or organs.

‘When surviving stem cells receive a signal to regenerate, they divide, make new cells and develop into a new follicle,’ says Wang.

A greater understanding of exactly how TGF-β activates cell division – and communicates with other genes – may allow follicle stem cells to be re-activated, says Wang. As well as potentially treating baldness, it might also lead to a better understanding of wound healing.

Organs such as the liver and stomach regenerate themselves in response to wounds. Wang’s team studied hair follicles because they are the only human organ that regenerate automatically and periodically – even without injury.

‘It gets us closer to understanding stem cell behaviour, so that we can control it and promote wound healing,’ says Wang.

To understand the mechanisms behind the fate of HF cells, the researchers developed a probabilistic model of how their genes are regulated. First, the model was derived from literature. Then, it was refined using single-cell RNA sequencing data. The researchers used the model to study the mechanisms behind HF cell fate decisions – and make predictions to guide future experiments.

Pattern prediction

Hair loss due to androgenic alopecia – more commonly known as male- or female-pattern baldness – is caused by damage to hair follicles, by androgens, inflammation or species such as oxygen free radicals. Superoxide dismutase (SOD) is an enzyme that typically keeps oxygen free radicals in check – but it can become overwhelmed if levels are too high. One potential way to overcome this is to use ‘nanozymes’ – artificial enzymes that can also scavenge oxygen free radicals. However, their scavenging ability is typically much weaker than that of SOD.

Now, researchers from Qingdao University of Science and Technology in China, led by Lina Wang and Zhiling Zhu, have used a form of AI known as machine learning to design a better nanozyme for treating hair loss (Nano Letters; doi: 10.1021/acs.nanolett.2c03119).

The researchers knew that SOD-like activity was mainly related to the transformation between two different valences of a transition metal, such as from Mn+ to M(n+1)+. Beginning with a transition metal thiophosphate structure – a well-known regulator of enzyme activity – the researchers identified 91 promising compounds. Various machine-learning models were then trained and evaluated – and predicted that manganese thiophosphite (MnPS3) would be an efficient SOD mimic.

MnPS3 nanosheets were synthesised using chemical vapour transport of manganese, red phosphorus and sulfur powders. In initial tests with human skin fibroblast cells, the nanosheets significantly reduced the levels of reactive oxygen species without causing harm. This was then validated experimentally, showing that MnPS3 exhibited strong free-radical scavenging ability and high SOD-like activity. Researchers found that the IC50 of MnPS3 – which indicates how much of a drug is needed to inhibit a biological response by a half – was about 12 times lower than for other typical SOD mimics.

The compound was used to create microneedle patches, which were used to treat mice affected by androgenic alopecia. Within 13 days, the animals regenerated thicker hair strands that more densely covered their previously bald back sides than mice treated with testosterone or minoxidil. The researchers say the study produced a nanozyme treatment for regenerating hair – and indicated the potential of computer-based methods for designing future nanozyme therapeutics.

Prior to this, in 2021, a separate team of researchers from Zhejiang University in China created a microneedle patch using cerium nanoparticles. They had previously identified that the compounds could help to remove excess reactive oxygen species but could not cross the outermost layer of skin. They began by coating cerium nanoparticles with a biodegradable polyethylene glycol-lipid compound. Then, they made the dissolvable microneedle patch by pouring a mixture of hyaluronic acid, which is naturally abundant in human skin, and cerium-containing nanoparticles into a mould. The team tested control patches and cerium-containing patches on male mice with bald spots. Both applications stimulated the formation of new blood vessels around the hair follicles. However, those treated with the nanoparticle patch showed faster signs of hair undergoing a transition in the root, such as earlier skin pigmentation. These mice also had fewer oxidative stress compounds in their skin. Finally, the researchers found that the cerium-containing patches led to faster mouse hair regrowth with similar coverage, density and diameter, compared with a leading topical treatment – and could be applied less frequently (ACS Nano; doi: 10.1021/acsnano.1c05272).

Organoid culture

To study the process by which cells become hair follicles – morphogenesis – researchers from Yokohama National University, Japan, have turned to organoid cultures. Organoids are small, simple versions of an organ that can be used to study tissue and organ development in a laboratory culture dish.

‘Organoids are a promising tool to elucidate the mechanisms in hair follicle morphogenesis in vitro,’ says Tatsuto Kageyama, Assistant Professor in the faculty of engineering at Yokohama National University, Japan. The team produced hair follicle organoids by controlling the structure generated from two types of embryonic cell using a low concentration of extracellular matrices (ECMs – the framework that provides structure for cells and tissue). The ECMs adjusted the spacing between the two types of cell, from a dumbbell-shape to core-shell configuration. This increased the contact area between the two cell regions – enhancing the mechanisms that contribute to hair follicle growth (Sci. Adv.; doi: 10.1126/sciadv.add4603).

The team developed an organoid culture system that generated hair follicles and hair shafts with almost 100% efficiency. The organoids, which used mouse cells, produced fully mature hair follicles with long hair shafts around 3mm in length after 23 days. The researchers could then monitor hair follicle morphogenesis and hair pigmentation in vitro – and understand the signalling pathways involved. By transplanting the hair follicle organoids, they achieved efficient hair follicle regeneration with repeating hair cycles.

The researchers say that the model could improve understanding of hair follicle induction – for evaluating hair pigmentation and hair growth drugs, and for regenerating hair follicles. The research could open up new avenues for developing treatments for hair loss disorders such as androgenic alopecia, they claim.

In future, the team plans to optimise its organoid culture system. ‘Our next step is to use cells from human origin – and apply for drug development and regenerative medicine,’ says Junji Fukuda, corresponding author of the paper.

For now, most research into curing baldness is speculative, and addresses some underlying causes, including tissue growth, cell damage and biochemical pathways. However, none seems remotely close to commercialisation. For this reason, caffeine shampoo, hair transplants and internet advice – such as ‘eat more gelatine’ – would seem to be the only options.