Two recent studies highlight novel ways to combat pattern hair loss in men and women using small molecules such as JAK inhibitors that reawaken dormant hair follicles, as well as stem cell therapies aimed at growing new follicles.
In the first study, researchers led by Angela Christiano, Ph.D., the Richard & Mildred Rhodebeck Professor of Dermatology at Columbia University Vagelos College of Physicians and Surgeons, discovered previously unknown cells that keep mouse hair follicles in a resting state and show that inhibiting the activity of these cells can reawaken dormant follicles.
In a second study, Christiano’s team created a way to grow human hair in a dish, which could open up hair restoration surgery to more people, including women, and improve the way pharmaceutical companies search for new hair-growth drugs.
Study Discovers Cells That Put Hair Follicles to Sleep
In male and female pattern baldness, many hair follicles still exist but are dormant.
The search for new drugs that reawaken follicles and induce hair growth has been limited by the field’s focus on finding drugs that work along the same pathways as finasteride and minoxidil, the only two drugs currently available for men with male pattern baldness.
Christiano and her colleagues previously discovered a new pathway, called JAK-STAT, that is active inside the stem cells of resting hair follicles and keeps them in a dormant state.
They previously demonstrated that JAK inhibitors applied to mouse skin are a potent way to reawaken resting hair follicles in mice.
In their latest study, the researchers wanted to get a detailed picture of the natural processes that keep follicles dormant, so they looked for factors that controlled the JAK pathway activity in the hair follicle.
New Cells Called Trichophages
The search revealed a previously unknown immune-related cell type that produces a substance known as Oncostatin M that keeps the follicles in a state of dormancy.
“Rare subsets of immune cells were previously difficult to identify in whole skin, but this work was facilitated by our ability to sequence individual cells and pinpoint the ones making Oncostatin M,” says Etienne Wang, Ph.D., first author of the study.
These cells are most similar to macrophages, which are scavenger cells of the immune system, and the team found them in close association with resting hair follicles.
The researchers named these cells trichophages, after the Greek word tricho for hair.
Targeting the trichophages can also turn on the hair cycle.
By using small molecule inhibitors and antibodies to block Csf1R, a receptor on the trichophages, the researchers could block the flow of Oncostatin M and restart the hair cycle.
Reawakening Dormant Hair Follicles with New Drugs
“Our previous studies implicated JAK-STAT signaling as one potential new therapeutic pathway for hair loss disorders by targeting hair follicle stem cells with JAK inhibitors,” Christiano says. (A biotech company recently reported results of a small phase 2 trial of a topical JAK-STAT inhibitor based on these studies.)
“Here, we show that blocking the source of the JAK activating signal outside the hair follicle is another way to target this mechanism.”
Most drug development has focused on treatments for male pattern hair loss, and the majority of clinical trials are conducted exclusively in men.
“These new pathways may lead to new treatments for both men and women suffering from hair loss, since they appear to be acting independently of male hormone pathways,” Christiano says.
“Especially if treatments are used topically, that could avoid the related side effects seen with finasteride and minoxidil.”
Growing New Hair Follicles in a Dish
In a second study, aimed at using stem cells for hair growth, the Columbia researchers have created a way to grow human hair in a dish, which could open up hair restoration surgery to more people, including women, and improve the way pharmaceutical companies search for new hair growth drugs.
It is the first time that human hair follicles have been entirely generated in a dish, without the need for implantation into skin.
For years it’s been possible to grow mouse or rat hairs in the lab by culturing cells taken from the base of existing follicles.
“Cells from rats and mice grow beautiful hairs,” Christiano says. “But for reasons we don’t totally understand, human cells are resistant.”
To break the resistance of human hair cells, Christiano has been trying to create conditions that mimic the 3-D environment human hair cells normally inhabit.
The lab first tried creating little spheres of cells inside hanging drops of liquid.
But when the spheres were implanted in mice, the results were unpredictable: The cells from some people created new hair while others didn’t.
But when the spheres were implanted in mice, the results were unpredictable: The cells from some people created new hair while others didn’t.
3-D Printing Creates Patterned Hair Follicles
In the new study, Christiano’s team exploited the unique capability of 3-D printers to create a more natural microenvironment for hair follicle growth.
The researchers used 3-D printing to create plastic molds with long, thin extensions only half a millimeter wide.
“Previous fabrication techniques have been unable to create such thin projections, so this work was greatly facilitated by innovations in 3-D printing technology,” says Erbil Abaci, Ph.D., first author of this study.
After human skin was engineered to grow around the mold, hair follicle cells from human volunteers were placed into the deep wells and topped by cells that produce keratin.
The cells were fed a cocktail of growth factors spiked with ingredients, including JAK inhibitors, that the lab has found stimulates hair growth.
After three weeks, human hair follicles appeared and started creating hair.
Hair Farms Could Expand Availability of Hair Restoration
Though the method needs to be optimized, engineered human hair follicles created in this way could generate an unlimited source of new hair follicles for patients undergoing robotic hair restoration surgery.
Hair restoration surgery requires the transfer of approximately 2,000 hair follicles from the back of the head to the front and top. It is usually reserved for male patients whose hair loss has stabilized and who have enough hair to donate.
“What we’ve shown is that we can basically create a hair farm: a grid of hairs that are patterned correctly and engineered so they can be transplanted back into that same patient’s scalp,” Christiano says.
“That expands the availability of hair restoration to all patients—including the 30 million women in the United States who experience hair thinning and young men whose hairlines are still receding. Hair restoration surgery would no longer be limited by the number of donor hairs.”
The engineered follicles also could be used by the pharmaceutical industry to screen for new hair growth drugs. Currently, high throughput screening for new hair drugs has been hampered by the inability to grow human hair follicles in a lab dish.
No drugs have been found by screening; the only two approved for the treatment of pattern hair loss – finasteride and minoxidil – were initially investigated as treatments for other conditions.
The team hopes that cultured hair farms will open up the ability to perform high throughput drug screens to identify new pathways that influence hair growth.
The first study, titled “A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth,” was published in Cell Stem Cell.
The second study, titled “Tissue engineering of human hair follicles using a biomimetic developmental approach,” was published in Nature Communications.
Although this most welcome new therapeutic option is only symptomatic, with hair loss typically reoccurring within months of the discontinuation of therapy, even alopecia areata patients with long-standing, therapy-resistant disease can experience impressive hair regrowth,1, 3, 4 which can exert a profoundly positive effect on the quality of life of affected patients.
However, a double-blind, placebo-controlled study that meets accepted evidence-based medicine standards remains to be published.
More importantly, the understandable euphoria surrounding JAK inhibitors in the alopecia areata field must not blind one to potential risks.
We feel that increasing general awareness of potential adverse effects of any new drug is important and responsible, including in the case of JAK inhibitors, in which the promising positive effects reported in alopecia areata might over-encourage their use even in patients in whom it would be ill-advised.
Therefore, we call for a more cautionary approach to systemic therapy with JAK inhibitors, at a time when their long-term adverse effects remain insufficiently established.
Although related concerns might appear theoretical, a fully informed and responsible treatment decision demands a sober risk–cost–benefit calculation, given that alopecia areata, despite the psychoemotional havoc it can cause,2 is not a life-threatening disease and that JAK inhibitors are prohibitively expensive.
The therapeutic efficacy of JAK inhibitors is based on their broad, relatively non-specific anti-inflammatory activities as a result of their ability to block several signalling pathways used by type I and type II cytokines5 and the related significantly reduced number and activity of T cells, dendritic cells, and NK cells and suppression of macrophage activation.6
This broad activity explains the wide range of potential adverse effects reported for various JAK inhibitors (table; appendix), including severe bacterial, fungal, mycobacterial, and viral infections (eg, recurrent herpes zoster) and even the development of malignancy, probably due to impaired tumour immunosurveillance.7, 8, 9
TableDocumented clinical adverse effects of systemic Janus kinase inhibitors
|Dose||Relatively minor adverse effects||Major adverse effects|
|Tofacitinib||10 mg or 20 mg twice daily||Headache, nausea, urinary tract infections, respiratory tract infections, viral gastroenteritis, paronychia, anaemia, thrombocytopenia, raised liver transaminase concentrations, raised HDL, LDL, and creatinine concentrations, neutropenia||Fungal infection||Varicella zoster||Non-melanoma skin cancer, tuberculosis, Pneumocystis jiroveciipneumonia, vertigo|
|Ruxolitinib||20 mg twice daily||Urinary tract infections, thrombocytopenia, raised HDL, LDL, and creatinine concentrations, neutropenia||Viral gastroenteritis, fungal infections, raised liver transaminase concentrations||Varicella zoster||Tuberculosis, P jiroveciipneumonia, sepsis and septic shock, non-melanoma skin cancer|
|Baricitinib||4–8 mg once daily||Urinary tract infections anaemia, raised HDL, LDL, and creatinine concentrations, neutropenia||Viral gastroenteritis, respiratory tract infections||..||Tuberculosis, P jiroveciipneumonia, varicella zoster, non-melanoma skin cancer|
Systematic review and meta-analysis of serious infections with tofacitinib in 66 randomised controlled trials and 22 long-term extension studies revealed a risk ratio versus placebo of 2·21 for treatment with 5 mg twice a day and 2·025 for 10 mg.10Interleukin-10 (IL-10) provides an important example of a pathway whose targeting by JAK inhibitors might be undesired, because its inhibition can be associated with increased risk of autoimmune diseases, including multiple sclerosis and diabetes mellitus,11, 12and IL-10 deficiency is seen in very early-onset inflammatory bowel disease.13
Theoretically, alopecia areata patients treated with JAK inhibitors might even be more prone to develop hair follicle autoimmunity, since IL-10 is one of the recognised so-called immune privilege guardians of the human hair follicle.14, 15
Thus, one wonders whether inhibiting IL-10 signalling might actually counteract the therapeutically crucial restoration of hair follicle immune privilege in alopecia areata.14
Additional concerns relate to the inhibition of prolactin or erythropoietin receptor signalling (appendix).
One might also wish to keep in mind the severe clinical consequences of congenital defects in JAK signalling (appendix).
Nevertheless, some JAK inhibitors are reportedly well tolerated short-term.16 Also, the level and type of immunosuppression varies substantially with the range of targeted JAKs and with the dose and schedule used, with narrow and partial JAK inhibition potentially producing effects similar to some biologics frequently used in psoriasis therapy, whereas other biologics might produce more profound levels of immunosuppression.
Also, the US Food and Drug Administration has accepted clinical studies with JAK inhibitors for alopecia areata by the so-called investigational new drug process, which implies a favourable risk–benefit ratio assessment.We appreciate that JAK inhibitor treatment can change the life of affected alopecia areata patients, just as the introduction of biologics has done for patients with psoriasis.
But, exactly as in the latter case, we remain challenged to carefully balance clinical advantages against possible disadvantages and risks of any new therapy; the use of JAK inhibitors for treating alopecia areata is not exempted from this rule.Clearly, trials of the long-term efficacy and safety of JAK inhibitors with the most favourable toxicological profile that still effectively block the key signalling pathway in alopecia areata pathobiology (ie, interferon-γ signalling)2, 14 are warranted specifically in alopecia areata patients and preferably with monotherapy (ie, exclusion of other immunosuppressants, such as glucocorticosteroids).
Until these data are available so that the risk–benefit ratio can be assessed more robustly, it might be the most prudent and responsible alopecia areata management strategy to restrict systemic JAK inhibitor therapy stringently, and to accelerate the clinical exploration of topically applicable JAK inhibitors.
More information: Etienne C.E. Wang et al. A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth, Cell Stem Cell (2019). DOI: 10.1016/j.stem.2019.01.011
Hasan Erbil Abaci et al. Tissue engineering of human hair follicles using a biomimetic developmental approach, Nature Communications (2018). DOI: 10.1038/s41467-018-07579-y
Journal information: Nature Communications , Cell Stem Cell
Provided by Columbia University Irving Medical Center