Speaker: Ralf Paus

The hair follicle microenvironment significantly influences hair growth and is shaped by various biological factors often overlooked in clinical practice. This microenvironment encompasses a complex interplay among the skin immune system, blood and lymphatic vessels, skin nerves, adipocytes, multiple stem cell populations surrounding the hair follicle, senescent cells, sebaceous glands, apocrine glands, and gradients created by the hair follicles themselves. Each of these elements contributes to the hair follicle's health and function and engages in intricate cross-talk that can profoundly impact hair growth. Senescent cells, typically associated with negative outcomes, can have surprising roles within the hair follicle microenvironment. A landmark study published in Nature by Max Plikus and colleagues revealed that nevocytes in hairy nevi secrete osteopontin, a factor that activates resting epithelial stem cells in hair follicles, promoting follicle enlargement. This unexpected finding illustrates the potential positive influence of senescent cells on hair follicle stem cells.

The cycling of hair follicles results in significant changes to the surrounding skin environment, which also influences the hair follicle's cycling process. The primary therapeutic challenge in managing hair growth is not merely to reactivate resting telogen follicles but rather to maintain anagen follicles and prevent their transition to catagen. Understanding the hair follicle microenvironment focuses on methods to extend the duration of the anagen phase. The microenvironment's changes can be observed more dramatically in animal models, where many hair follicles undergo synchronized cycling. In humans, the mosaic pattern of hair cycling allows for more subtle changes, yet the effects on angiogenesis during the transition from telogen to anagen are profound. The skin's physiological structure undergoes remodeling as hair follicles cycle, underscoring the idea that hair follicles play a dominant role in skin physiology.

Another perspective on the hair follicle involves its geometric organization, resembling Cuban cigars embedded in the skin in a straight line. This configuration contributes to the formation of gradients within the skin, linking the epidermis to the subcutis while simultaneously influencing the hair follicles. These gradients are mediated by various signaling molecules, including growth factors, cytokines, and chemokines, which are the targets of contemporary biological therapies and pharmacological treatments. Numerous other signaling molecules also affect hair follicles, such as lipids, cyclic adenosine monophosphate (cAMP), reactive oxygen species (ROS) secreted from mitochondria, neuropeptides, neurotransmitters, neurotrophins, hormones, metabolites, and exosomes. The list of influencing factors is extensive and indicates that hair follicles are responsive to alterations in their extra-follicular environment. The epithelial layer of hair follicles acts as a central architect, orchestrating the skin's growth and immunoregulatory signaling milieu.

Hair follicles, particularly those in the scalp, are complex structures that produce various non-classical agents, including neurohormones, neuropeptides, and neurotransmitters, many of which are regulated in a circadian manner. Among these agents are endocannabinoids, indicating that hair follicles create self-sustaining gradients of mediators that influence their biological functions. Hair follicles express cannabinoid receptor 1 (CB1), which plays a dual role: it inhibits proliferation in the hair matrix while simultaneously promoting the survival of stem cells, which require continuous stimulation from endocannabinoids. The neurohormones synthesized by hair follicles include melatonin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and growth hormone (GH). Notably, TRH is essential not only for thyroid function but also for hair follicle health, particularly in the scalp. Alpha-melanocyte-stimulating hormone (α-MSH) regulates hair follicle pigmentation and immune responses, while GH, surprisingly, inhibits growth in female scalp hair follicles.

Additionally, hair follicles are among the most densely innervated organs in the body, with scalp hair follicles exhibiting an exceptional density of innervation. The nerves surrounding the hair follicle are equipped with neuromediators and serve not only to sense mechanical changes in the hair shaft but also facilitate communication through the release of neuropeptides, neurotransmitters, and neurotrophins. This creates a continuous exchange of signals between the nerve endings and the epithelial and melanocyte stem cells in the bulge region of the follicle. Moreover, emerging evidence suggests that the hair follicle microbiome, often overshadowed by discussions of the skin surface microbiome, plays a crucial role in follicular health. The microbiome thrives in the hair follicle's moist, immune-privileged environment and communicates with perifollicular skin by secreting bacterial metabolites. These interactions influence keratinocyte activity, promoting the secretion of antimicrobial peptides that regulate microbial populations and attract immune cells. Interestingly, specific bacteria, such as Staphylococcus epidermidis, are critical for maintaining follicular health, as the selective elimination of these bacteria using bacteriophages alters the gene expression patterns in hair follicles, leading to a more growth-promoting signaling environment. 

The hair follicle microbiome plays a crucial role in educating the immune system during early life, as demonstrated in mouse studies. While direct evidence in humans is challenging to establish, there is a strong rationale to believe that similar mechanisms operate in human hair follicles. The immune system associated with hair follicles significantly influences what the body learns to attack and what it tolerates. Immunocytes not only engage in attack against the hair follicle under pathological conditions but also regulate its function in normal circumstances. Although much of the current understanding is derived from mouse models, recent studies suggest that specific immune cell populations, including mast cells, macrophages, γδ T cells, regulatory T cells, CD8 T cells, neutrophils, and Langerhans cells, vary in number throughout the hair follicle cycle. Notably, initial evidence indicates that macrophages and mast cells may also play regulatory roles in human hair follicles. One intriguing observation pertains to male pattern hair loss, as highlighted by dermatologist Albert Kligman. He noted an accumulation of inflammatory cells around hair follicles in androgenetic alopecia during the transitional intermediate stage from terminal to vellus hair. Understanding the impact of commonly used hair loss treatments on these inflammatory cells and their physiological roles remains an area ripe for exploration.

Additionally, the concept of the pilosebaceous unit, traditionally defined as comprising the hair follicle and sebaceous gland, warrants re-evaluation. Recent findings indicate that the eccrine gland coil is a vital component of this unit, situated beneath the hair follicle's bulge. They are embedded into a cone of dermal white adipose tissue. This morphological complexity suggests functional interdependence, evidenced by the presence of various signaling molecules. For instance, hair follicles express transient receptor potential (TRP) channels, specifically TRPM5, which can detect pheromones, while the apocrine glands are believed to produce these pheromones. The eccrine gland coil secretes prolactin, known to influence hair growth, while the erector pili muscle releases neurotrophins, cytokines, and growth factors that interact with hair follicle stem cells in the bulge region.

The hair follicle (HF) is an integral part of a complex functional unit known as the adnexal skin unit, which includes the hair follicle, dermal white adipose tissue (dWAT) adipocytes, skin nerves, Schwann cells, HF microbiome, lipidome, endocrine components, and perifollicular vasculature. Together, these elements form the complex Moreover, adipocytes surrounding the hair follicle secrete hepatocyte growth factor (HGF), a potent growth factor that promotes hair follicle proliferation, prolongs the anagen phase, suppresses apoptosis, induces angiogenesis, and stimulates pigmentation. Notably, this secretion of HGF is driven by adipocyte progenitors located in the dermal white adipose tissue surrounding the follicle. The adnexal skin unit is integral to optimizing hair growth, necessitating a comprehensive approach that targets not just the hair follicle but the entire microenvironment, including the dWAT. This unit is characterized by its rich vascularization, which plays a crucial role in supplying oxygen and nutrients to the hair follicle. Notably, the hair follicle features a complex and dynamically remodeling blood vessel system throughout the hair cycle, supplemented by lymphatic vessels. Research by Michael Detmer has illustrated that selective manipulation of lymphatic vessels can significantly affect hair follicle cycling, underscoring their importance in maintaining hair health.

The hair follicle induces angiogenesis through the secretion of Vascular Endothelial Growth Factor A (VEGF-A), a key factor in skin rejuvenation. Studies indicate that enhancing VEGF-A levels is essential for promoting skin regeneration. The significance of keeping hair follicles in the anagen phase, where they produce maximum VEGF-A, cannot be overstated. This observation suggests that supporting the health of hair follicles could have broader implications for skin rejuvenation. The vascularized nature of the hair follicle allows for effective nutrient and drug delivery, yet targeting the hair bulb with topical agents poses significant challenges. Instead, systemic drugs and nutraceuticals may be more effective, given the hair follicle's engineering to absorb nutrients in its highly vascularized area, akin to a command center for hair growth. This unique structure enables hair follicles to function like mini-kidneys, efficiently absorbing toxins from the bloodstream and depositing them in the dead hair shaft, which is ultimately shed. This ingenious mechanism prevents unwanted substances from accumulating in vital organs, providing a protective function. In light of these insights, the therapeutic challenge lies in creating a microenvironment that sustains hair follicles in the anagen phase and addresses all micro-environmental factors affecting hair growth. Clinicians must evaluate how many of these factors their current treatments target and identify opportunities to enhance hair growth manipulation.

In response to a query regarding the clinical implications of this knowledge, it is crucial to consider the etiology of hair and scalp diseases beyond the hair follicle itself. For instance, in cases of androgenetic alopecia, understanding the role of inflammatory cells that infiltrate miniaturized hair follicles could inform anti-inflammatory treatment strategies. Moreover, manipulating the hair follicle microbiome to enhance the secretion of beneficial bacterial metabolites, such as butyrate, could promote hair growth. Although butyrate has an unpleasant odor, it has demonstrated efficacy in stimulating hair growth in organ-cultured micro-dissected hair follicles, exemplifying how targeted interventions can leverage microbial metabolism to support hair health. These examples illustrate the potential for integrating microbiome research into clinical practice to enhance hair restoration strategies.

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam.Top of Form