Hair is one of the most important symbols of youth and vitality. People throughout history have sought methods to maintain and restore ones hair. Hair loss, especially in the young, can be psychologically devastating (1). For sufferers of male- and female-pattern baldness there is the potential for surgery to move healthy hair bearing follicles to bald scalp. Surgery however is not always possible in cases where the cause of hair loss is autoimmune as is the case in alopecia areata and scarring alopecia.
New research into the hair growth cycle and its associated phases has revealed the striking link between dermal adipose tissue (fat tissue) and the hair follicle (2–5). Fat tissue, it seems, is a multi-functional tissue that performs essential tasks outside of the scope of simple energy storage.
Fat tissue has also demonstrated its potential as a source of stem cell with the capability of being harnessed for therapeutic treatments. Here we present some of the exciting science of hair regeneration using adipose derived stem cells.
The Hair Cycle
Hair growth in humans is the result of the asynchronous growth of the follicles of the scalp (6). Each follicle undergoes four distinct phases: anagen, where the hair follicle grows; catagen, where the hair follicle ceases producing hair; early telogen, where the follicle is in a resting phase; and late telogen, where the follicle has shed its hair and is awaiting a signal to commence growth of a new hair. Humans are unlike other mammals in that they do not shed all of their hair at once. The anagen phase of hair growth can last between 3 to 10 years resulting in an average maximum length of hair of 100 cm. At any given time roughly 80% of follicles are in anagen and the remaining 20% are shedding, or resting. The combination of short growing hairs, full length (trimmed to desired length), and resting follicles results in the appearance of a full head of hair.
Investigations into the anatomy of the hair follicle in relation to the hair growth cycle have demonstrated that the follicle undergoes great changes in size. The follicle is at its largest during anagen and begins to recede during catagen. During telogen, the follicle is at its smallest. Along with these changes in size was the observation that the fat that lies under the skin, the dermal adipose tissue, would increase in size with the follicle such that the two tissues would physically touch. This observation was made in other mammal including mice and rabbits.
Fat tissue as a source of stem cells
Fat tissue is composed of more cell types than previously thought. Primarily the fat tissue is composed of adipocytes that contain the white fat that define the tissue. The other cells that reside in adipose tissue are circulating blood cells, fibroblasts, pericytes, endothelial cells, and pre-adipocytes. Pre-adipocytes are the most sought after cells because of their characteristic of being stem cells. For simplicity, pre-adipocytes are typically referred to as adipose derived stem cells. Adipose derived stem cells, it turns out, are one of the primary cell types responsible for driving the hair cycle.
When we think of stem cells, we think of the ability of specialized cells to change their function and become other types of tissue. While adipose derived stem cells have the ability to be coaxed into various cell types under lab specific conditions, during the hair cycle these cells don’t actually become hair follicle cells. They instead chemically communicate with the follicle in the creation of a feedback loop (discussed below). For a stem cell to make a good therapeutic treatment it must adhere to some basic characteristics. These include: obtainability through minimally invasive procedures, possess the ability to differentiate into multiple cell types reproducibly, be in high abundance, and be able to handle transplantation. Adipose derived stem cells are relatively abundant in fat tissue at roughly 3% which is significantly higher than other stem cell sources such as bone marrow who are only composed of roughly 0.01% stem cells (7,8). Adipose derived stem cells are easily transplanted and in high abundance making them an excellent candidate for therapeutics for these reasons (4,5).
Hair Follicle Anatomy
Hair follicles produce hair by going through distinct phases that involve the chemical feedback loop between adipose derived stem cells, mature adipocytes (fat cells) and the hair follicle. The anagen phase when the hair is growing sees the hair follicle grown to its largest size. At this point the adipose tissue also expands to engulf the root of the follicle. The cells of the hair follicle communicate with the adipose derived stem cells within the fat tissue. This indicates to the adipose derived stem cells to begin differentiation into fat cells. Differentiation is the act of a stem cell committing to a cell type. The hair follicle signals also tell the surrounding adipocytes to begin growing and increase their size.
During catagen, the hair follicle undergoes programmed cell death resulting in its overall shrinkage. At this time the hair follicle stops signaling for the fat tissue to grow and maintain its size resulting in the two tissues separating.
In early telogen, the hair follicle conversely, begins to be influenced by the fat cells. The fat cells send inhibitory signals to the hair follicle that encourage it to remain in a resting state, not producing hair. During this time the follicle has reached its smallest size but we still see a full length hair.
At the end of telogen, the hair is shed and the signaling environment begins to change. Induced by an unknown factor, the ASCs cells begin to send growth signals to the hair follicle inducing its grown and entry into the anagen phase. The signals of the fat cells are potentially blocked or out competed by the pro-growth signals of the adipose derived stem cells. Once the hair begins growth the follicle is back in the anagen phase.
The role of adipose in the form of adipose derived stem cells (stimulatory) and fat cells (inhibitory) then becomes clear. While the role of adipose derived stem cells is only half of the communication, it presents the question of whether it is possible to induce follicle entry into anagen (growth phase) by transplanting adipose derived stem cells into bald scalp.
Adipose derived stem cells used therapeutically
Fat cells and adipose derived stem cells compete for influence over the hair follicle. Transplantation of complete fat tissue into the scalp may not influence the microenvironment of the hair follicle because of this inherent competition. For effective use as a therapeutic the cell transplantation should contain an enriched population of adipose derived stem cells. Adipose tissue is harvested easily and routinely through liposuction procedures. To process the tissue and enrich the adipose derived stem cells population they must be separated from the fat cells. Centrifugation forces non-fat containing cells to the bottom of a sample tube thus making separation of the cells easy. Fat cells contain large quantities of white adipose making them unable to sink. These floating cells can then be discarded leaving only active cells. The cells can used in this state or undergo further processing. The optimal procedure for preparing and administering adipose derived stem cells has not been yet been determined.
Ongoing in clinical trials
The gold standard for developing a treatment is to perform clinical trials. Clinical trials are composed of a few crucial components that prove efficacy and safety of a given intervention. The two exciting trials discussed below are registered with the National Institute of Health (NIH, http://clinicaltrials.gov/) and are great examples with use of placebo (no active ingredient in the intervention) and participant blinding (preventing the patient or physician from knowing the true identity of the intervention). The world of stem cell research is expanding quickly and regulatory bodies like the FDA are responding in kind to create investigatory pipelines that expedite the approval of novel therapies (9).
The first trial (NCT02849470) is being undertaken by Healeon Medical in the treatment of male and female pattern baldness (10). The trial utilizes adipose derived stem cells that are further processed enriched, and administered to the scalp. The trial is currently enrolling patients 18 and older and is estimated to have 60 participants. The study began in 2016 and is slated to be completed in 2023.
The second trial (NCT03078686) is being undertaken by Dr. Ryan Welter of Regeneris Medical (11). This trial tests the hypothetical abilities of ASCs even further by utilizing them to treat scarring alopecia and alopecia areata. Both scarring alopecia and alopecia areata being autoimmune related with patients having reduced options for treatment. The trial is set to be completed in June 2019.
Non-FDA approved uses of stem cells
The FDA is extremely cautious when it comes to approval of new therapeutics. Current the only approved use of stem cell is in the transplantation of bone marrow (9,12). For any treatment to attain approval they must be backed up by a large body of clinical trials. The status of most stem cell applications are either for use with patients with terminal conditions, who have exhausted their options, or in experimental treatments whose efficacy and safety have not been determined. The hype around the potential uses of stem cell therapies have led to innumerable unscrupulous businesses administering and marketing untested and potentially dangerous treatments to naïve patients.
If a treatment sounds too good to be true then it probably is! Certainly make sure to question any treatment that does not report potential adverse reactions. If you find yourself unsure of an offered treatment, the FDA provides excellent resources for patients on a wide range of treatments and medical devices (https://www.fda.gov/).
We at Seager Hair Transplant Centre are excited about the future of adipose derived stem cell treatments. With the methods and safety still in the experimental stage, we are not ready to provide stem cell treatments at this time. The results of the clinical trials discussed above will greatly increase our understanding of stem cell use in hair regeneration.
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