The central role of fibroblasts in androgenic alopecia: A systematic umbrella review

3.3.1 Unique properties of DP cells

DP cells have unique biological characteristics that make them the “command center” of hair follicles. ³⁷ Firstly, they exhibit characteristics of mesenchymal stem cell, including self-renewal and pluripotency. ³⁸ This inherent potential is activated during the transition from dormancy to growth, enabling DP cells to drive epithelial stem cell proliferation and differentiation, thereby initiating a new growth cycle.^19,39

Secondly, DP cells act as a highly active secretion centers, producing large number of key signaling molecules such as VEGF, FGF7, FGF10, IGF-1, BMPs, Wnt ligands, and extracellular matrix components.^20,40–43 These molecules form a precise paracrine network that regulates the behavior of epithelial cell, ultimately determining the growth rate, shaft thickness, and cycle progression of hair. The subtle changes in this secretion pattern can shift follicle from growth to miniaturization.^17,19,39,44

Thirdly, DP cells exhibit unique spontaneous aggregation behavior in vitro. These three-dimensional spheres reflects their functional integrity and is crucial for maintaining their hair inducing ability.^23,45–49 In AGA, this aggregation ability has been severely compromised; DP cells become dispersed, leading to functional decline, secretion imbalance, and inability to maintain a robust growth phase, which is the core event of miniaturization. Therefore, aggregation characteristics are both functional markers and key indicators for evaluating the physiological and therapeutic status of DP cells. ⁵⁰

3.3.2. Functions of perifollicular fibroblasts

The DS cells that encapsulate follicle provides crucial structural and mechanical support.^36,51–53 In addition to this static function, DS is also a dynamic cell bank with multiple functions. It is an important source of signaling molecules that communicate with epithelial cells and the DP.^54,55

Its most critical function is to serve as a reservoir for DP cells. During the transition from telogen to anagen, specific DS cells are activated, proliferated, migrated, and aggregated at the nascent hair bulb to participate in forming a new, functional DP—a essential process for successful follicular regeneration.^56,57 Therefore, the activities and health statue of the DS are crucial for supplementing DP.

In AGA, the functional decline of the DS is significant. DS cells may be indirectly affected by dysregulated androgen signaling, thereby affecting their efficacy as cellular reservoirs. ⁵⁸ This damage may lead to insufficient supply of healthy progenitor cells for DP. exacerbating DP dysfunction and accelerating follicular miniaturization. Therefore, DS and DP form a collaborative functional unit, and the interruption of their interaction is a key driving force for the progress of AGA.

3.4.1. Expression of AR

The pathogenesis of AGA revolves around the abnormal response of hair follicles to androgens, exhibiting significant cellular specificity.^59,60 Numerous studies have confirmed that DP cells are the main direct target of androgen action. ⁶¹ The key evidence for this conclusion lies in the cellular distribution pattern of the AR: DP cells consistently exhibit high levels of AR expression, while the surrounding hair follicle epithelial cells (such as hair stromal cells and outer root sheath keratinocytes) show significantly lower level of AR expression.^62,63

This differential distribution of AR expression determines the pathway of androgen signaling. Circulating androgens, mainly testosterone, penetrate the capillary network around follicles and are absorbed by DP cells. ⁶⁴ In these cells, the highly expressed 5α-reductase type II enzyme catalyzes the conversion of testosterone to the more potent dihydrotestosterone (DHT). Subsequently, DHT binds with high affinity to the extensively expressed AR in the nucleus, forming a DHT-AR complex.^65,66 This complex undergoes conformational changes, dimerizes, and binds to specific androgen response elements (AREs) in nuclear DNA, thereby initiating or repressing the transcription of downstream target genes.^67,68

Therefore, the DP unit serve as a “signal transducer”. They receive DHT and convert it into a local cellular responses, specifically, an alteration of their secretory profile—which in turn regulates the behavior of the entire follicular unit. In contrast, epithelial cells exhibit the least direct response to androgens due to their low AR expression levels. Their behavioral changes are largely indirectly driven by changes in the secretion factors of DP cells. This highly specific pattern of AR expression establishes the molecular foundation for DP cells to act as trigger and signal amplifier in AGA pathophysiology. It also explains why follicular miniaturization is an orderly process driven primarily by dysfunction of the mesenchymal “command center”.

3.4.2. Response of DP cells following androgen activation

After DHT binds to AR highly expressed in the nucleus of DP cells, the DHT-AR complex produced acts as a key transcriptional regulator, triggering a series of profound cellular responses and ultimately disrupting the steady-state balance of the hair follicle microenvironment. ⁶⁶ This process begins with a global change in gene expression profiles within the cell nucleus. The DHT-AR complex translocate into the nucleus and specifically binds to the androgen responsive AREs located in the promoter region of target gene. Its function is similar to a “molecular key”, directly initiating or inhibiting the transcription of a series of key genes, thereby reshaping the biological function of DP cells.

The core consequence of this transcriptional reprogramming is the disruption of the balance between signaling pathways that determine the fate of hair follicle. Under steady-state conditions, the growth promoting (e.g., Wnt/β-catenin) and anti-growth (e.g., TGF-β, BMP) pathways are in dynamic balance, maintaining a normal follicular cycle.^20,69 However, sustained androgen activation can severely disrupt this balance. The DHT-AR signaling pathway upregulates multiple anti-growth pathways: it effectively activates the TGF-β1 and BMP pathways, which can drive the follicle into the catagen phase prematurely. ²⁰ At the same time, it inhibits or antagonizes key growth promoting pathways, most notably by inhibiting the activity of the Wnt/β-catenin pathway—the primary driver for initiating and sustaining the anagen phase.^70,71

The ultimate and most direct manifestation of these changes in gene expression and signaling pathways is the pathological changes in the secretion profile of DP cells. Dysfunctional DP cells transition from a “pro-growth center” into a “growth inhibiting signal sources”. The net effect of its secreted factors shifts from promoting to inhibiting growth: on one hand, the expression of key factors that support papilla vascularization and hair matrix cell proliferation—such as VEGF and IGF-1—is reduced; on the other hand, the secretion of hair growth-inhibiting factors, such as TGF-β1 and DKK-1 (a potent Wnt signaling inhibitor), is significantly increased. This altered secretory profile acts via paracrine signaling on surrounding epithelial cells, directly resulting in a shortened anagen phase, impaired hair matrix cell proliferation, and ultimately driving the follicle toward irreversible miniaturization. Therefore, the response of DP cells following androgen activation fundamentally represents a pathological transformation of their functional identity, serving as the molecular initiation point for the process of follicular miniaturization.

3.5.1. Imbalance in signal transduction and disruption of intercellular communication

The homeostasis of hair follicle depends on a fine dynamic balance between pro-growth and anti-growth signaling pathways. In AGA, dysfunctional DP cells disrupt this balance, tilting the follicular growth program toward suppression and thereby initiating the miniaturization process. ¹⁴ The imbalance in signal transduction represents the core molecular mechanism underlying follicular miniaturization.

The fundamental reversal of the signaling pathway is the molecular core of this process. Dysfunctional DP cells undergo pathological changes in their secretion profile, transitioning from a “growth promoting center” to a “growth inhibiting signaling source”. This manifests as a synergistic “riple blow”: firstly, the Wnt/β-catenin pathway, which is crucial for initiating and maintaining growth, is significantly inhibited by the secretion of antagonists such as DKK-1. ⁷² Secondly, growth inhibitory signaling pathways such as TGF-β1 and BMP are continuously activated and amplified.^20,73 Among them, TGF-β1 can not only directly induce apoptosis of hair germ cells and drive hair follicles to enter the degenerative phase prematurely, but also act as a key “stop signal” to forcibly shorten the growth phase. The imbalance between these pathways fundamentally reverses the microenvironmental signals of hair follicles.

The imbalance of this signal directly leads to the collapse of the intercellular communication network. On the one hand, the instruction transmission between DP cells and epithelial cells is ineffective: due to the weakening of pro proliferative signals (such as FGF7) and the enhancement of pro apoptotic signals (such as TGF-β1), the proliferation of dermal cells is impaired, and stem cells in the bulge region remain quiescent due to the inability to receive correct activation instructions.^21,74,75 The communication failure between the “command center” and the “execution unit” directly disrupted the regenerative ability of hair follicles. On the other hand, the connection between hair follicles and external support systems is severed: DP cells secrete factors such as VEGF to maintain the ability of the surrounding capillary network, leading to insufficient blood supply to the hair follicles; Its signal communication with peripheral nerve endings is also impaired. This puts hair follicles in an unfavorable microenvironment of “malnutrition” and “signal islands”, further exacerbating growth disorders.

Therefore, the dysfunction of DP cells promotes the irreversible miniaturization of hair follicles through the imbalance of internal signaling pathways and the breakdown of external communication support systems.

3.5.2. Destruction of the stem cell niche

The regenerative ability of the hair follicle comes from their powerful stem cell system. Hair follicle stem cells (HFSCs) are located in the bulge region and serve as a reservoir for periodic hair follicle regeneration. ⁷⁶ However, a key finding is that HFSCs themselves are insensitive to androgens because their surface expressed AR levels are extremely low. This indicates that androgens cannot directly instruct stem cell activation. On the contrary, the behavior of HFSCs is primarily governed by their microenvironment—specifically, the signals originating from DP cells. Consequently, in AGA, the dysfunction of DP cells directly leads to the disruption of the stem cell niche, thereby severing the fundamental driver of hair follicle regeneration.

In a healthy hair follicle, as a new anagen phase initiates, functionally competent DP cells send a series of potent activation signals to the bulge region. The Wnt/β-catenin pathway acts as the “starter switch” in this process. Concurrently, signals that maintain stem cell quiescence, such as BMP signaling, are correspondingly downregulated. ⁷⁷ This precisely timed combination of signals functions like an accurate “departure command”, prompting HFSCs to migrate downward, proliferate, and differentiate into new follicular components, ultimately forming a thick terminal hair.

In the pathological state of AGA, this activation mechanism fails completely. As DP cells are the primary target of androgen action, their functional disruption leads to a fundamental alteration in their secretory profile. On one hand, the secretion of key activating signals is reduced, while the expression of Wnt pathway inhibitors increases, resulting in a weakened or even absent “starter switch” signal. On the other hand, the signaling environment that suppresses stem cell activity may be reinforced. The ultimate consequence is that DP cells become incapable of delivering an effective and correct activation command to HFSCs. ⁷⁸ Without receiving the crucial “departure” signal, the HFSCs are forced into a prolonged state of quiescence and cannot be recruited to the new hair bulb to participate in hair shaft formation.

The direct consequence of this failed stem cell activation is the “congenital deficiency” of the newly formed hair follicle. Due to a reduced available progenitor cell pool and weakened downstream proliferative and differentiation drive, the follicular structure rebuilt with each subsequent cycle becomes progressively smaller and more shallow. Consequently, the hair shaft gradually thins, transitioning from terminal hair to vellus hair. This indicates that follicular miniaturization does not stem from the depletion of stem cells, but rather from the “silencing” of stem cells caused by DP cells dysfunction. Therefore, restoring DP cells function and rebuilding a healthy stem cell niche represent crucial strategic objectives for reversing follicular miniaturization and restoring the hair follicle’s regenerative capacity.

3.7.1. Indirect effects of existing treatments

The first-line medications currently widely used in clinical practice for AGA primarily exert their therapeutic effects by modulating or influencing the functional state of DP cells, although their mechanisms of action do not directly target fibroblasts. These therapies indirectly intervene in the abnormal activation of DP cells through different pathways, thereby slowing the progression of follicular miniaturization.

Finasteride and dutasteride, as specific inhibitors of 5α-reductase, operate by systemically reducing levels of DHT in the scalp and circulation. ³ By inhibiting the key enzyme responsible for converting testosterone into the highly active DHT, these drugs effectively interrupt the pathological signaling source that chronically stimulates DP cells. When the concentration of DHT in the DP cells microenvironment decreases significantly, the overactivated AR signaling pathway is “unburdened”. This leads to beneficial adjustments in the gene expression and secretory profiles of DP cells—for instance, potentially reducing the expression of pro-apoptotic factors like TGF-β1—thereby normalizing the hair growth cycle. Consequently, these medications essentially work by removing the abnormal stimulus, creating an “unburdened” or “resting” microenvironment for the dysfunctional DP cells and indirectly restoring some of their normal function. However, this therapy cannot reverse pre-existing DP cells functional decline or perifollicular fibrosis, and the therapeutic effects diminish upon discontinuation as the stimulatory source returns.

In contrast, minoxidil’s mechanism of action more directly targets the local microenvironment. ³ Although its precise molecular targets are not fully elucidated, substantial evidence suggests it acts as a potassium channel opener and vasodilator, directly or indirectly influencing DP cells. Studies indicate that minoxidil promotes VEGF expression in DP cells, significantly improving blood supply to the follicular bulb and thereby providing enhanced nutrition and oxygen to the follicle. Concurrently, it likely exerts effects through multiple pathways: prolonging epithelial cell survival, exerting mild anti-inflammatory effects, and directly stimulating DP cells proliferation. Thus, minoxidil can be regarded as a “functional enhancer” for DP cells or a microenvironment modulator. By creating more favorable growth conditions, it partially counteracts the negative signals induced by androgens, thereby helping maintain the hair follicle in a healthier state.

In summary, the strategy of current mainstream pharmacological treatments for AGA—whether systemically removing the pathogenic signal (finasteride/dutasteride) or locally improving the microenvironment (minoxidil)—ultimately converges on correcting the functional imbalance of DP cells. This clinically confirms the central role of DP cells in AGA pathogenesis and simultaneously highlights the limitations of current therapies: they are primarily indirect and palliative, rather than directly repairing or replacing functionally compromised DP cells. This very limitation defines a clear direction and creates an urgent need for next-generation therapeutic strategies that target the fibroblasts themselves.

3.7.2. Emerging research directions and therapies

Building on the profound understanding of the central role of fibroblasts—particularly DP cells—in AGA, the research focus is shifting from traditional hormonal interventions toward innovative strategies that directly target and rejuvenate these critical cells. These emerging therapeutic approaches aim to fundamentally rebuild a healthy follicular microenvironment, offering new promise for the treatment of AGA.

Cell therapy represents one of the most promising directions.^49,82 Its core concept involves “replacing” or “replenishing” functionally compromised DP cells. Researchers isolate healthy DP cells from a small number of donor hairs and expand them via 3D culture in vitro to restore their inherent high aggregative behavior and hair-inductive capability. These cultured, healthy DP cells are then transplanted into the balding scalp. It is expected that the transplanted healthy DP cells can establish a functional “signaling command center” in vivo. By secreting the correct network of factors, they can reactivate resident epithelial stem cells within the follicle, thereby inducing de novo hair follicle formation or reversing the miniaturization of existing follicles. Similarly, strategies leveraging DS cells—exploiting their inherent role as a reservoir for DP cells—are also under investigation for transplantation purposes.

Compared to whole-cell transplantation, exosome therapy represents a more refined and safer “cell-free” strategy. ⁸³ Exosomes are nanoscale vesicles secreted by cells, carrying bioactive substances from their parent cells such as proteins, messenger RNAs, and microRNAs. Exosomes derived from DP cells are believed to encapsulate the key signaling instructions that enable DP cells to induce hair regeneration. The extraction, purification, and topical application of these exosomes can mimic the function of healthy DP cells by delivering pro-growth signals (e.g., activating the Wnt pathway) to downstream target cells, while simultaneously circumventing potential issues associated with live cell transplantation, such as immune rejection and ethical concerns.

At the molecular level, precisely targeting key signaling pathways within DP cells is a major focus of drug development. For instance, developing small-molecule agonists to specifically activate the Wnt/β-catenin pathway in DP cells, or employing antagonists to suppress the overactive TGF-β pathway, aims to directly modulate the “signaling switches” responsible for follicular miniaturization and restore pathway homeostasis. This strategy demands that the therapeutic agents exhibit high targeting precision and specificity to minimize off-target effects on other tissues and cells.

More forward-looking tissue engineering strategies aim to “de novo construct” hair follicles in vitro. By co-culturing highly viable DP cells, epidermal stem cells, and other components in a three-dimensional system using various biocompatible scaffold materials, researchers have successfully generated organoids or miniature hair follicles in the laboratory capable of producing hair fibers. Although this technology remains in its early stages and faces significant challenges—such as achieving synchronized hair cycling and controlling growth orientation—it provides the ultimate blueprint for achieving true “hair follicle regeneration” and transplantation.

Finally, targeting the pathological endpoint of perifollicular fibrosis in advanced AGA, anti-fibrotic therapy represents an important adjuvant strategy. Exploring the use of approved or novel anti-fibrotic agents—such as monoclonal antibodies or small-molecule drugs targeting TGF-β signaling—aims to degrade the excessive extracellular matrix and alleviate the physical constriction of hair follicles, thereby creating a more permissive microenvironment for follicular regeneration. This strategy could potentially be combined with other regenerative therapies to establish conditions for restoring vitality to severely fibrotic areas of alopecia.

3.7.3. Challenges of drug delivery systems

The development of novel therapies targeting hair follicle fibroblasts highly relies on efficient drug delivery systems for their efficacy. The core challenge currently faced is how to effectively penetrate the skin barrier with therapeutic drugs (such as small molecules, growth factors, nucleic acids, or cell products), accurately target and enrich the DP cells area deep in the hair follicle, while maintaining a sufficient duration of action locally to reshape the hair follicle microenvironment. The penetration efficiency, targeting specificity, controllable release ability, and feasibility of production of delivery systems are key bottlenecks that determine the successful translation of many cutting-edge therapies.