Immune Cells (Treg) Actually Affect Hair Loss

Where there are people, there will be hair loss. Every day, a small amount of hair falls from a person's head. Generally, they don't cause much trouble, and few people are even aware of their presence. However, due to factors such as age, hormones, stress, and diseases, some people's hair loss tends to be serious, resulting in a significant reduction in hair volume, or even "baldness". Although folks have jokes like "a smart head doesn't grow hair", after all, not everyone can face this phenomenon calmly.

Today, a research team from the University of California, San Francisco (UC San Francisco) brought an interesting study. Professor Michael Rosenblum from the School of Medicine has discovered that a class of immune cells called regulatory T cells (Tregs) can directly activate stem cells in the skin and promote healthy hair growth. If these T cells lose their function, hair follicles cannot regenerate, resulting in "baldness". The study was published online today in the biology heavyweight academic journal "Cell".

Interestingly, this discovery was purely accidental. Although Professor Rosenblum belongs to the Department of Dermatology of the School of Medicine, his main research direction is immunology, and he has a deep knowledge in the study of regulatory T cells. In the immune system, this special group of T cells often acts as a diplomat and can tell the immune system which friends are friends and which are enemies. So once these cells lose their normal function, the body can develop an allergic reaction to an otherwise harmless substance like peanut butter or cat hair. In even worse cases, the immune system turns its guns on the body's own tissues, causing autoimmune disease.

The latest research has found that regulatory T cells (red) play a key role in the growth of hair

Most regulatory T cells, like other immune cells, reside in the body's lymph nodes. But there are small numbers of regulatory T cells that colonize other parts of the body and assist in immune regulation locally. This is exactly the subject that Professor Rosenblum is interested in. Previously, he and other colleagues found that regulatory T cells in the skin help newborn mice develop tolerance to "healthy skin flora" and help skin wounds grow into adults. of healing.

To better understand the effect of regulatory T cells on mouse skin, Professor Rosenblum and his team developed a method to temporarily remove these cells. In one study, they first shaved the surface hair of mice to remove these regulatory T cells from the skin, and then began to assess the health of the mice's skin.

Under the induction of the drug DT, the regulatory T cells in the mouse skin expressing Foxp3 DTR will be removed, and the hair growth ability will also be lost

The accident came quietly. "We quickly found that the hair that was shaved off the surface of these mice never grew back ," Professor Rosenblum recalls. "This was very interesting, so we decided to investigate this phenomenon further."

First, the researchers identified the location of regulatory T cells in the skin by fluorescently labeling them. They found that these T cells tended to be enriched around the hair follicle, and their numbers tripled during the regeneration phase of the hair follicle cycle! This seems to indicate that regulatory T cells play an important role in the regeneration of hair follicles.

Regulatory T cells are often enriched around hair follicles

Subsequent research confirmed this assumption. In a more elaborate experiment, the researchers removed the regulatory T cells during hair follicle regeneration in one group of mice, and removed the regulatory T cells after hair follicle regeneration had already started in another group of mice. T cells. The experimental results showed that the hair of the mice in the former group could not grow smoothly, while the mice in the latter group regrown their hair. Thus, the critical role of these T cells in hair follicle regeneration was confirmed.

So, how do these regulatory T cells affect hair follicle regeneration? The researchers isolated these regulatory T cells from the skin and analyzed their gene expression levels. The study found that expression of a gene encoding the Jag1 protein was significantly increased in these T cells near hair follicles compared with regulatory T cells in skin-draining lymph nodes (SDLNs) . Jag1 is a classic Notch signaling pathway protein involved in cell-to-cell communication. Perhaps it is the Jag1 protein secreted by these T cells that tells the skin stem cells when is the right time to regenerate hair follicles.

Compared with regulatory T cells in other parts, the expression of Jag1 protein in the regulatory T cells near the hair follicles surged

Consistent with this hypothesis, when the researchers removed regulatory T cells near hair follicles, skin stem cells showed a significant drop in Notch signaling. And when the researchers coated the surface of the microspheres with a layer of Jag1 protein and placed them in the skin of mice, the mice's hair follicles were still able to regenerate even without regulatory T cells. This confirmed the function of Jag1 protein in hair follicle regeneration.

"It's as if skin stem cells co-evolved with regulatory T cells. Regulatory T cells not only protect these stem cells from inflammation, but also participate in the regenerative engineering of hair follicles. For these stem cells to start regeneration, they are completely dependent on Regulatory T cells tell them when to start ," Professor Rosenblum was surprised by this discovery: "We used to think that immune cells only have the effect of fighting infection, while stem cells automatically repair damage. But now we find that stem cells and immune cells It has to work together to facilitate the regenerative cycle. ”

The new mechanism of hair growth revealed by this study

The researchers believe the findings help to understand why autoimmune diseases like alopecia areata disrupt hair follicle regeneration, leading to hair loss. Globally, alopecia areata afflicts even more people than type 1 diabetes, yet scientists have remained poorly understood about the disease. Now, by comparing the previous data, Professor Rosenblum's team found that the genes related to alopecia areata are more or less related to regulatory T cells. This is expected to bring new treatments for hair loss in the future and benefit the majority of hair loss people.

Dawn! Stem cells are effective in preventing hair loss and promoting hair regeneration

Hair loss is a common and disturbing problem caused by a complex array of causes including genetics, hormones, trauma, and iatrogenic events. About 160 million people in China alone suffer from hair loss. Currently, there are several treatment options for hair loss patients, such as oral or topical medication, or surgery. However, these treatment modalities have limitations, and drug therapy can only temporarily relieve symptoms, and the hair will start to fall out again after the patient stops taking the drug. For example, oral finasteride has sexual side effects and can be teratogenic. After stopping the drug, hair loss will accelerate. Autologous single hair follicle and follicular unit transplantation is a reliable surgical treatment method, but the number of hair follicle donors is limited, and the survival rate of hair follicle transplantation is low and the cost is high, and it will bring great pain to the patient. Therefore, hair loss urgently needs some new therapeutic means. A large number of studies have found that stem cells have a significant effect on hair regeneration and prevention of hair loss, which brings light and hope to hair loss patients.

Alopecia is an inflammatory cytokine-mediated disease . The pathogenesis of hair loss is closely related to Th-1 and NKG2D-mediated signal transduction. Studies have shown that the hair follicle is a site with immune immunity. When the immune immunity of the hair follicle collapses, CD4 and CD8 T cells and some natural killer cells gather around the hair bulb's autoantigens and cause hair loss. Mesenchymal stem cells have immunomodulatory and anti-inflammatory effects. Ji and his colleagues injected stem cells intravenously into depilated rats and found that stem cells could inhibit the production of IFNG, CXCL9 and CXCL10 and the production of NKG2D+ T cells Penetration, can effectively prevent hair loss.

Stem cells can secrete a large number of growth factors, such as keratinocyte growth factor, vascular epithelial cell growth factor, platelet growth factor and hepatocyte growth factor. These growth factor proteins play an important role in the process of promoting hair regrowth. The latest Korean experimental research found that stem cell conditioned medium is effective in treating female hair loss. Shin microneedle-injected the stem cell-conditioned medium into the patient's skin. After 12 weeks, the patient's hair density and thickness increased significantly without any toxic side effects. Fukuoka and Suga subcutaneously injected stem cell-conditioned medium into 22 hair loss patients. These patients received 6 courses of treatment, each course of treatment lasted 3-5 weeks, and the results showed that both male and female patients had significantly increased hair.

The ability of stem cells to promote hair regrowth is greatly enhanced after pretreatment. Vitamin C, PDGF, hypoxia and UVB can all stimulate stem cells to enhance their proliferation and hair regeneration potential. Fukuoka cultured stem cells under hypoxic conditions, collected stem cell-conditioned media, and added cysteine, coenzyme Q10, and vitamins. The 12 female patients and 13 male patients who received the treatment experienced a significant increase in hair by subcutaneously injecting the pretreated stem cell conditioned medium 4-6 times every 3-5 weeks.

The above experimental research results show that stem cells and their conditioned medium can promote hair regeneration and prevent hair loss. Compared with hair follicle transplantation, stem cell therapy for hair loss has the advantages of convenience, safety, significant effect, simple treatment process, and high patient acceptance, which brings an alternative treatment method for hair loss patients.

Literature source

Byun, J et al (2016). Bone marrow-derived mesenchymal stem cells prevent alopecia areata development through the inhibition of NKG2D expression: a pilot study. Revised Oct 05, 2016. https://pubmed.ncbi.nlm.nih.gov/27892603/

Jin, S & Sung, J. Hair regeneration using adipose-derived stem cells. https://pubmed.ncbi.nlm.nih.gov/26536569/

Fukuoka, H et al, The Latest Advance in Hair Regeneration Therapy Using Proteins Secreted by Adipose-Derived Stem Cells. Retrieved from The American of Cosmetic Surgery. Vol. 29, No.4, 2012. https://journals.sagepub.com/doi/10.5992/AJCS-D-12-00015.1

Application of stem cells in hair loss

Hair loss has become an epidemic problem, and it has a trend of younger age. Young and middle-aged people have become the main force of the " hair loss army " . Common types of hair loss include: androgenetic alopecia ( AGA) , alopecia areata, trichotillomania, telogen effluvium, senile alopecia, etc. Among them, androgenetic alopecia (AGA) is a common disease of progressive hair loss occurring in and after puberty , which can occur in both men and women , but the incidence rate increases with age.

People with AGA experience shrinkage of the hair follicles and loss of hair volume in the affected scalp area. Cell transplantation is one of the strategies to achieve functional regeneration of hair follicles. Stem cell therapy has received a lot of attention as a potential novel therapy , and for AGA the focus is on the reactivation of hair follicle stem cells, thereby improving hair follicle growth and hair regrowth . There are two main types of sources of stem cells for transplantation : autologous and allogeneic. The stem cells in an autologous transplant come from the same person who received the transplant, so the patient is their own donor. Stem cells in an allogeneic transplant come from someone other than the patient, which can be a matched related or unrelated donor.

Research has shown that injecting a mixture of skin epithelial and mesenchymal stem cells can induce new hair follicles. Importantly, hair follicle stem cells (HFSCs) periodically switch between active and inactive phases, thereby maintaining a stable population of stem cells in the follicle; however, this ability diminishes with age.

Hair follicles contain a variety of cellular resources, such as melanocytes, epithelial cells, and stem cells of different developmental origins, which can continuously renew and regulate hair growth and skin homeostasis. There are two main types of stem cells in the hair follicle. The first is HFSC, which are located within the outer root sheath (ORS) in the region of the arrector pili muscle attachment and in the proximal region of the isthmus, both of which are referred to as the 'bulge'. The second is dermal papilla cells (DPCs), which are responsible for controlling hair induction and growth and are involved in the formation of new hair follicles.

Unlike cicatricial alopecia, AGA belongs to non-scarring alopecia, HFSCs are not damaged, and progenitor cells are damaged. This fact makes androgenetic alopecia potentially reversible. DPC replication potential was reduced in skin affected by androgenetic alopecia, and loss of shape, size, and characteristic markers was also found.

In recent years, some outpatient clinics in western countries have carried out simple stem cell culture and transplantation. Meanwhile, stem cell therapy has gained popularity among doctors and patients suffering from androgenetic alopecia due to their regenerative potential and media hype.

With the development of these technologies, numerous studies have been published on the efficacy of stem cell therapy in AGA. The author conducted a systematic review of the research on the efficacy of stem cell therapy in the treatment of AGA. MEDLINE, Web of Science and Scopus databases were queried with keywords of (androgenetic alopecia or alopecia) and (stem cells or ADSC or ASC or FDSC or HFSC or MSC), searched on January 11, 2023. A total of fifteen articles met the inclusion criteria and were summarized in this review.

Stem cells vs placebo

Of the 15 studies, six compared stem cells to a placebo. Four of them compared HFSC and two compared ADSC.

A double-blind randomized controlled study was conducted by Lee et al. There were 30 women and men aged 20-61 with MPHL (male pattern hair loss) or FPHL (female pattern hair loss). The course of treatment consisted of repeated weekly applications of ADSC-conditioned medium or local injections of normal saline (placebo) for 12 consecutive weeks. At the end point, the hair density of the placebo group was 89.3±3.79/cm 2 , and that of the ADSC conditioned medium group was 102.1±4.09/cm 2 , the difference was statistically significant (p<0.05). No adverse events occurred during this study.

Another study conducted by Gentile et al. Twenty-one participants in 2019 demonstrated that patients in the HFSCs-treated group had an increase in mean hair density of more than 30 ± 5.0%, compared with less than 1% in patients in the placebo group after 12 weeks of treatment. There is no mention of any side effects occurring.

Furthermore, in 2020, Gentile et al. injected 3 HFSCs using autologous micrografts in a group of 27 participants, 45 days apart, and reported an improvement in mean hair count after 58 weeks. The average increase (compared to baseline) in the treated area was 18.0 hairs , while the control area showed an average decrease of 1.1 hairs. There is no mention of any side effects occurring.

Tsuboi et al investigated the effectiveness of autologous cell therapy using dermal sheath goblet cells (DSCs) . Subjects received three concentrations of DSC cell suspension ( 7.5×10 6 , 1.5×10 6 , and 3.0×10 5 cells) and placebo (each in a volume of 1 mL ) at 4 randomly assigned sites . Hair density and hair diameter were analyzed by images taken before injection and 3 , 6 , 9 , and 12 months after injection . Compared with placebo, total hair density and cumulative hair diameter at the injection site of low-dose DSC cells increased significantly at 6 and 9 months . Mild adverse reactions such as erythema, purpura, and small bleeding occurred at the injection site in 14 cases.

Efficacy of stem cell therapy alone

Of the 15 studies, four analyzed stem cell therapy alone. Two of them assessed HFSC and the remaining two assessed ADSC .

The efficacy of autologous cell micrografts containing HFSCs for AGA was confirmed in a cohort of 140 adults by Zari et al. The efficacy was evaluated by analyzing changes in hair measurement parameters 1-6 months after treatment, and the results showed that the average hair density increased by 4.5-7.12 hairs/cm2 without any side effects.

Ruiz et al. conducted a study in a cohort of 100 participants whose HFSCs were derived from autologous micrografts obtained by the Rigenera® microtransplantation technique. The results showed that after 2 months of treatment, a mean increase in total hair density of 30% ± 3.0% had been achieved compared to the baseline value in the treated area . In addition, scalp dermoscopic analysis also showed improvements in hair density after 4 and 6 months of treatment.

Kim et al. reported 9 patients with AGA in whom a single autologous SVF graft was performed on their upper scalp. Hair density on the ADSCs-treated side was significantly increased at 3 and 6 months after transplantation compared with the untreated side (p = 0.01 and p = 0.009, respectively). There is no mention of any side effects occurring.

El-Khwalawany et al analyzed the efficacy of SVF in 30 AGA patients. Patients received one SVF injection and a 6-month follow-up. The number of hairs increased from 130.87±14/cm2 to 151.93±22.36/ cm2 . Patients were asked about pain they experienced during and after surgery, and 21 patients reported mild pain and 9 patients reported moderate pain. None reported severe pain. Apart from this, no other side effects were reported.

In their retrospective observational case series, David Perez-Mesa et al analyzed the results of SVF augmentation of adipose tissue in six men and women aged 18-55 years with MPHL and FPHL. In this pilot case series, an average scalp increase of 31 hairs/cm 2 was documented in patients receiving liposuction .

Shin et al. also performed a retrospective observational study on the outcomes of 27 FPHL patients treated with ADSC medium. Weekly application of ADSC-conditioned medium with a microneedle roller showed efficacy in the treatment of FPHL after 12 weeks of treatment. Hair density increased from 105.4 to 122.7 hairs/cm 2 (p<0.001). Hair thickness increased from 57.5 lm to 64.0 lm (p<0.001). No serious side effects were observed in any patient.

Stem Cells Compared to Other Therapies

Of the 15 studies, three compared the use of stem cells with another treatment.

Elmaadavi et al investigated the safety and efficacy of autologous bone marrow-derived mononuclear cells (BMMC) including stem cells and hair follicle stem cells (FSCs) in 40 patients with alopecia areata (AA) and AGA. Among 20 AGA patients, 10 received BMMCs and 10 received intradermal injection of HFSCs.

Evaluation by immunostaining and digital dermoscopy showed that all groups experienced increases in hair thickness and hair density after six months of treatment with a single injection, with no significant difference in either type of hair loss between the two methods (p=0.426). The mean percent improvement in AGA patients was 52±28 in subjects receiving autologous BMMC and 42±27 in subjects receiving autologous FSC, which was not statistically different.

Narita et al. evaluated the effectiveness of ADSC medium in 21 male and 19 female patients. Patients received monthly intradermal injections of ADSC culture fluid for 6 months, followed by follow-up evaluations at 2 and 6 months. In this study, hair density increased significantly in all groups. There is no mention of any side effects occurring.

In a study published in 2015, the effectiveness of ADSC culture medium was compared in male patients with AGA who took finasteride with those who did not, and in female patients who did not take finasteride. Patients received 6 injections of ADSC culture solution every 3-5 weeks. Hair count significantly increased in both male (n=11) and female (n=11) patients after treatment. The mean increase in the number of hairs was 29±4.1 in male patients and 15.6±4.2 in female patients. No significant differences were observed between males and females.

In male patients, the most common complication during the procedure was pain during and after the injection of ADSC medium.

In conclusion

A total of 15 studies involving 653 patients in this review showed the effect of different sources of stem cells on hair density. The main conclusion reached was that stem cell therapy had a positive effect on hair density, regardless of the source.

An important limitation of the evidence is that the studies proposed different treatment options, including different types of stem cells and different courses of treatment, follow-up time, etc. Patients at various stages of the disease, including those at very advanced stages, were included in the study. In addition, many factors can affect the quality of stem cells, and not all studies report information on how stem cells were collected and prepared.

Based on the results of this review, the use of stem cell injections appears to be a promising treatment option in both women and men with AGA. Future research should focus on improving clinical study designs, conducting more research on stem cells, and establishing best practice protocols in terms of injection site, cell type, duration, and frequency. Before starting to consider stem cells as a treatment option, it would be helpful to conduct a study comparing the effectiveness of different types of stem cells for treating AGA.