Secretome as a novel regenerative strategy for atopic dermatitis: a comprehensive review

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by disrupted epidermal barrier function, immune dysregulation, and persistent inflammation. Affecting both children and adults, AD significantly impairs quality of life due to its visible symptoms and associated psychosocial and economic burdens. Traditional treatments such as application of topical corticosteroids, calcineurin inhibitors, moisturizers and antibiotics, while managing symptoms, often fall short of providing long-term solutions and can lead to adverse effects over time. This review explores innovative approaches to AD management, focusing on the therapeutic potential of the secretome. The secretome, a collection of bioactive molecules secreted by cells, has shown promise in promoting tissue regeneration and modulating immune responses. This study investigates how secretome therapy can restore the integrity of keratinocytes, the primary cells responsible for maintaining the skin barrier, which is severely compromised in AD. Using in vitro AD models, the secretome’s potential to reduce inflammation and enhance skin barrier function is evaluated. By targeting the underlying mechanisms of AD, secretome-based therapies could offer a novel approach to treatment, providing both regenerative and anti-inflammatory benefits. The findings from this study may pave the way for more effective, non-invasive treatments that address the root causes of AD, potentially reducing the disease’s impact and improving patient outcomes.

Introduction on AD

Atopic dermatitis (AD), commonly known as eczema, is a chronic skin condition characterized by inflammation, redness, dryness, and irritation. It affects up to 20% of children and 10% of adults worldwide, making it one of the most prevalent skin diseases. According to the WHO Global Burden of Diseases initiative, AD impacts over 230 million individuals globally, contributing significantly to the non-fatal disease burden, particularly in industrialized nations where its incidence is rising. Based on Fig. 1, AD often begins in childhood, with symptoms like scaly, dry, and itchy skin, frequently accompanied by red spots and inflamed areas. In infants, it typically affects the face, scalp, and extensor surfaces but later shifts to flexural areas like the elbows and knees. Persistent dryness, itching, and scratching exacerbate the condition, leading to lichenification and further skin barrier damage. Although most individuals outgrow AD, up to 30% continue to experience severe symptoms into adulthood, facing significant physical, social, and psychological challenges [11].

Fig. 1.

Symptoms of AD across different age groups, showing common presentations in infants (A, B), children (C, D), and adults (E, F)

The pathogenesis of AD is multifactorial, involving genetic predisposition, immune dysregulation, epidermal barrier dysfunction, and environmental factors. Compromised skin barrier function, primarily due to defects in keratinocyte function, increases susceptibility to allergens and irritants. Keratinocytes play a crucial role in maintaining skin integrity and regulating inflammation, but their dysfunction in AD results in impaired skin repair and exacerbated inflammation [5].Overview of immune responses involved in AD, including roles of key immune cells, cytokines, and immunoglobulins Immune cells like T lymphocytes and eosinophils release cytokines such as IL-4, IL-13, and TNF-α, driving persistent inflammation and further compromising the skin barrier [31].

The economic and psychosocial impacts of AD are substantial, including direct medical costs for treatments and indirect costs related to lost productivity and reduced quality of life [1]. Patients with AD also face stigmatization, anxiety, and depression, which compound the overall burden of the disease [9]. Despite a wide range of available treatments, including corticosteroids, calcineurin inhibitors, and biologics, current therapeutic approaches largely provide symptomatic relief rather than addressing the underlying epidermal barrier defects and immune imbalance. Long-term use of many standard therapies is limited by side effects, reduced effectiveness over time, and high cost particularly for biologic agents. This persistent gap highlights a critical unmet need for targeted, regenerative therapies capable of restoring barrier integrity while simultaneously modulating pathological inflammation. Despite a wide range of available treatments, including corticosteroids, calcineurin inhibitors, and biologics, current therapeutic approaches largely provide symptomatic relief rather than addressing the underlying epidermal barrier defects and immune imbalance. Long-term use of many standard therapies is limited by side effects, reduced effectiveness over time, and high cost particularly for biologic agents. This persistent gap highlights a critical unmet need for targeted, regenerative therapies capable of restoring barrier integrity while simultaneously modulating pathological inflammation.

Recent advancements in regenerative medicine and secretome-based therapies offer new hope for managing AD. Secretomes, derived from mesenchymal stem cells, may address underlying disease mechanisms by promoting skin barrier repair and modulating inflammation [51]. These novel approaches could provide safer, more effective, and personalized treatment options, alleviating both the physical and psychosocial burdens of AD. Unlike conventional treatments, secretomes contain a rich repertoire of bioactive molecules including cytokines, growth factors, and extracellular vesicles that collectively promote keratinocyte repair, enhance barrier restoration, and exert potent anti-inflammatory effects. This multifaceted mechanism positions secretome therapy as a uniquely comprehensive approach capable of addressing both root causes of AD barrier dysfunction and immune dysregulation while offering the potential for safer, more effective, and personalized treatment strategies. This review explores the potential of secretome therapies to revolutionize AD management by targeting the root causes of the disease and bridging the limitations of current treatments to improve long-term patient outcomes (Table 1).

Table 1.

Overview of immune responses involved in AD, including roles of key immune cells, cytokines, and immunoglobulins

Immune respone	Cytokines involved	Role in AD	Symptoms	Stage of disease	References
Th2 response	IL-4, IL-5, IL-13, IL- 31	Drives allergic inflammation and eosinophil activation	•Red, inflamed skin •Pruritus (itching)	Acute phase	[25, 67, 31]
Th1 response	IFN-γ, IL-12	Promotes chronic inflammation and skin thickening	•Skin lichenification •Dry, scaly, thickened skin	Chronic phase	[25, 67, 17]
Skin barrier defects	Loss of filaggrin (FLG)	Weakened skin barrier	•Prone to infections	Both acute and chronic phases	[17]
IgE production	IgE (ImmunoglobulinE)	Enhances allergic responses	•Increased serum IgE	Acute phase	[81]
Microbiome imbalance	Overgrowthof Staphylococcus aureus	Triggers and worsens inflammation	•Skin infections	Chronic phase	[36]

Pathophysiology of AD

Immune dysregulation in AD

The pathogenesis of AD involves an immune imbalance among Th1, Th2, and Treg cells, leading to hypersensitivity reactions mediated by IgE [84]. The role of Th17 and Th22 cells have gained attention for contributing to chronic inflammation and disruptingskin homeostasis [74]. Immune dysregulation in AD is driven by interactions between antigen- presenting cells (APCs), IgE, T-cell activation, mast cells, keratinocytes, and eosinophils,causing both immediate and cellular immune responses [19]. In mouse models, an increase in Treg cells with a Th2 cytokine profile has been linked to disease worsening [84]. Immune dysfunction in AD involves both innate and adaptive systems. Key immune cells like dendritic cells, keratinocytes, and eosinophils drive inflammation, while elevated IgE levels and mast cell activation trigger hypersensitivity reactions. A deficiency in antimicrobial peptides (AMPs), often due to mutations in pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), increases susceptibility to infections [10].

Mutations in NOD1 and NOD2, which help recognize viral and parasitic infections, further contribute to immune dysregulation in AD [78]. On the adaptive side, AD is marked by an excessive Th2 immune response, with elevated levels of cytokines like IL-4, IL-13, and IL-31 [60]. These cytokines not only drive inflammation but also reduce the production of key skin barrier proteins like filaggrin (FLG), weakening the skin's defenses. The higher Th2 response in AD promotes IgE production, contributing to allergic hypersensitivity. Skin barrier abnormalities and immune dysfunction play a critical role in this process [84]. Based on Fig. 2, the higher Th2 response also promotes IgE production, leading to allergic hypersensitivity. Furthermore, mutations in interferon (IFN) and thymic stromal lymphopoietin (TSLP) pathways are linked to severe forms of AD, such as eczema herpeticum (EH), by impairing the skin’s antiviral defenses and exacerbating immune dysfunction [10]. This dysregulated immune environment is not unique to AD, as similar T-cell–driven disturbances are observed in other immune-mediated dermatoses and even during certain immunotherapies. Immune-mediated dermatoses such as atopic dermatitis share overlapping inflammatory pathways with psoriasis. Recent evidence shows that immunotherapies, including nivolumab, can induce or exacerbate psoriasis, with 69.1% of cases presenting as new-onset disease and a median onset time of 28 days [87]. Moreover, Pembrolizumab-induced psoriasis illustrates how immune checkpoint inhibitors can disrupt cutaneous immune homeostasis, leading to exaggerated inflammatory responses [71]. This reinforces a broader concept relevant to atopic dermatitis that shifts in systemic immune regulation, particularly T-cell–driven pathways, can precipitate or aggravate chronic inflammatory skin disorders, emphasizing the need for therapies that restore immunological balance in AD. The adverse events and limitations of currentatopic dermatitis treatments, summarized in Table 2, underscore the need for safer therapeutic approaches that minimize systemic immune disruption.

Fig. 2.

Overview of the Th2 immune response in AD, illustrating cytokine involvement in IgE production, eosinophil activation, and itching

Table 2.

Summarization of current treatments for AD and their challenges

Treatment category	Current treatment	Mechanisms	Challenges	References
Topical corticosteroids	•Hydrocortisone •Betamethasone	•Reduce inflammation by suppressing the immune response	•Side effects (skin thinning) •Cause skin atrophy, striae and infection •Tachyphylaxis	[33, 69]
Calcineurin inhibitors	•Tacrolimus •Pimecrolimus	•Reduce T-cell activation and pro- inflammatory cytokine production	•Side effects include burning, stinging, or itching •Potential increased risk of skin cancer and lymphoma	[73, 3]
Systemic immunosuppressant	•Cyclosporin •Methotrexate •Azathioprine	•Suppress the immune system to reduce inflammation by targeting immune dysregulation	•Hypertension •Liver toxicity •Bone marrow suppression •Gastrointestinal issues	[26]
Emollients and moisturizers	•Petrolatum •Glycerin	•Restore skin barrier •Improve hydration •Reduce transepidermal water loss	•Adherence issues due to frequent application requirement •Requires proper selection based on skin type and patient preferences	[7]
Biologics	•Dupilumab	•Target specific immune components contributing to AD	•High-cost limit access •Limited availability in some regions	[42]

Skin barrier dysfunction in AD: genetic and environmental factors

The skin, the body’s largest organ, comprises three layers: the epidermis, dermis, and hypodermis. It acts as a protective barrier against microorganisms, pathogens, and mechanical damage. In AD, the stratum corneum (SC) is compromised due to reduced essential lipids like ceramides, leading to impaired moisture retention and weakened defense. AD is a multifactorial condition influenced by genetic and environmental factors, with over 70 associated genes categorized into five groups, including those affecting epidermal barrier function, immune responses, interleukin production, and vitamin D metabolism [56]. AD is driven by a type 2 immune response, with excessive Th2 and Th22 cytokines reducing filaggrin (FLG) levels, a key protein for skin barrier integrity, hydration, and keratinization [37]. The reduction in FLG exacerbates skin barrier dysfunction, increasing susceptibility to allergens and pathogens [77]. Additionally, mutations in proteases, protease inhibitors, such as serine peptidase inhibitor Kazal-type 5 (SPINK5), and corneodesmosin disrupt normal desquamation, leading to defects in the skin barrier. These alterations impair the natural process of skin shedding and renewal, compromising the integrity of the skin barrier and making it more susceptible to environmental irritants and pathogens [86]. Mutations or deficiencies in filaggrin, a structural protein, contribute to increased transepidermal water loss (TEWL), resulting in dry skin and further weakening the barrier. Furthermore, tight junction proteins such as claudin-1, which help maintain cell integrity, are reduced in AD, allowing allergens and microbes to penetrate more easily [84]. This compromised barrier facilitates inflammation and exacerbates the symptoms of AD. Environmental influences, including urbanization, pollution, early-life exposure to allergens, and changes in skin microbiota, can trigger or worsen AD, particularly when combined with genetic predispositions [10]. This comprehensive breakdown of each aspect allows for a more detailed understanding of AD's pathophysiology. As illustrated in the Fig. 3, AD will result in the penetration of allergens and irritants initiating inflammation and water loss due to weakened skin barrier.

Fig. 3.

The penetration of allergens and irritants, weakened skin barrier, and water loss

Standard treatments for AD and their challenges

Topical corticosteroids

Topical corticosteroids are the most commonly used anti-inflammatory treatments for AD [15]. They help control acute flare-ups by reducing inflammation, itching, and redness. However, the use of topical corticosteroids for managing AD or eczema involves several significant challenges. Many patients and caregivers fear potential side effects, such as skin thinning or systemic absorption, leading to underuse or avoidance of corticosteroids, which can result in inadequate disease control. Prolonged or improper use of topical corticosteroids can lead to local side effects like skin atrophy, striae (stretch marks), telangiectasia (visible blood vessels), and increased susceptibility to skin infections [23]. In rare cases, systemic side effects may occur, especially with higher-potency corticosteroids. Over time, the skin can become less responsive to corticosteroids, a phenomenon known as tachyphylaxis, which can reduce them effectiveness with continuous use [6]. Moreover, abruptly discontinuing corticosteroids after symptom improvement can trigger rebound flare-ups, causing the condition to worsen [54].

Recent studies show increasing rates of “corticophobia,” especially among parents, contributing to poor adherence and uncontrolled disease [34]. Emerging evidence also suggests that prolonged corticosteroid exposure may downregulate key epidermal barrier proteins such as filaggrin and loricrin, potentially worsening barrier impairment rather than restoring it [43]. For chronic conditions like AD, long-term use of topical corticosteroids is often discouraged due to worries about cumulative side effects, prompting clinicians to explore alternative treatments or combination therapies. In some cases, the skin may even develop resistance to corticosteroids, requiring higher doses or alternative therapies, which complicates management.

Calcineurin inhibitors

Calcineurin inhibitors (CNIs) are immunomodulatory medications commonly used in the treatment of AD, particularly when traditional therapies like topical corticosteroids are ineffective or inappropriate. These drugs, including tacrolimus and pimecrolimus, work by inhibiting calcineurin, an enzyme essential for T-cell activation and the production of pro- inflammatory cytokines [33]. These medications work by inhibiting T-cell activation, reducing inflammation without the side effects of steroids. CNIs are indicated for patients with moderate to severe AD, especially in sensitive areas like the face and skin folds [20]. They are often used as a steroid-sparing treatment to minimize the risks associated with prolonged corticosteroid use, such as skin thinning and atrophy [30]. However, they can cause burning or stinging sensations upon application, and their long-term safety is under scrutiny due to concerns about a potential increased risk of skin cancer and lymphoma.

Recent post-marketing surveillance has not confirmed a definite cancer risk, but the lack of long-term pediatric data keeps safety concerns active [40]. A significant issue is the occurrence of application site reactions, as many patients experience local irritation, such as burning, stinging, or itching, especially when starting treatment [18]. These discomforts can lead to poor adherence to therapy. Additionally, while CNIs are generally deemed safe for long term use, there is limited long-term safety data compared to traditional treatments like topical corticosteroids, causing hesitation in prescribing them for extended periods [57]. Another concern is the increased risk of skin infections, including viral, bacterial, and fungal infections, due to the local immunosuppressive effect of CNIs. This necessitates careful monitoring for signs of infection during treatment. Cost is also a barrier, as CNIs tend to be more expensive than topical corticosteroids, potentially leading to treatment delays or non-adherence for some patients [33]. Patient education is crucial because many may be less familiar with CNIs than with corticosteroids, leading to misunderstandings about their effectiveness and safety. Furthermore, CNIs may not be appropriate for certain populations, such as young children, due to concerns about systemic absorption and potential long-term effects, limiting treatment options for these groups. Some patients may also experience a rebound worsening of AD when transitioning from topical corticosteroids to CNIs. Finally, optimizing the use of CNIs in combination with other treatments, such as corticosteroids, can be challenging and requires careful management to ensure effective and balanced therapy. Overcoming these challenges involve thorough patient education, careful treatment selection, and close monitoring to ensure successful management of AD with calcineurin inhibitors.

Systemic immunosuppressants

Systemic immunosuppressants are frequently used to manage moderate to severe AD, particularly when topical treatments are ineffective. These medications work by suppressing the immune system, targeting the immune dysregulation that drives the condition [5]. Commonly used systemic immunosuppressants include cyclosporine, methotrexate, azathioprine mycophenolate mofetil, and systemic corticosteroids. Cyclosporine is effective in rapidly reducing inflammation, but its long-term use is limited by side effects such as hypertension [38]. Azathioprine, which suppresses T and B lymphocytes, is useful for long-term control of severe AD, but requires genetic testing for TPMT activity to manage the risk of bone marrow suppression [70]. Mycophenolate mofetil is an alternative for patients who cannot tolerate other systemic treatments, though it carries risks of gastrointestinal side effects and liver toxicity [58]. Systemic corticosteroids provide rapid relief during acute flare-ups, but prolonged use is avoided due to serious side effects such as adrenal suppression, osteoporosis, and increased infection risk. The guidelines increasingly discourage the long-term use of systemic immunosuppressants due to cumulative organ toxicity and the availability of safer, targeted biologics. Comparative real-world studies also show higher discontinuation rates for cyclosporine, methotrexate, and azathioprine due to renal, hepatic, and hematologic side effects [45].

The main challenges with systemic immunosuppressants involve their side effects and toxicity, including organ damage and heightened susceptibility to infections [66]. As a result, long-term use is typically discouraged, and these medications are often reserved for short-term flare management or used intermittently. Careful monitoring is essential to detect early signs of toxicity, requiring regular blood tests to assess liver and kidney function, blood pressure, and infection risks. Ultimately, the goal is to transition patients to safer, long-term therapies once symptoms are controlled, minimizing the risks associated with these potent drugs.

Emollients and moisturizers

There are various types of emollients and moisturizers, including occlusives like petrolatumhumectants such as glycerin and urea, and barrier repair creams containing ceramides, cholesterol, and free fatty acids. Emollients and moisturizers are essential in managing AD as they help restore the skin barrier, reduce dryness, and prevent flare-ups [8]. AD is marked by impaired skin barrier function and increased transepidermal water loss, so regular use of these products improves skin hydration and overall health. Emollients work by filling gaps between skin cells with lipids, smoothing the skin, and restoring natural oils, while moisturizers increase water content in the outer skin layer through humectants and occlusive agents that prevent water loss [28].

These products are beneficial in AD as they restore the skin barrier, reduce inflammation and itching, enhance the efficacy of other treatments like topical corticosteroids and calcineurin inhibitors, and prevent flare-ups by maintaining hydration and protecting against irritants. Despite these benefits, challenges such as adherence issues, skin reactions to certain ingredients, and cost can impact their use. To maximize effectiveness, emollients should be applied at least twice daily, especially after bathing, with a liberal amount covering the entire body. Selecting the right product based on the patient’s skin type and preferences is crucial for long-term management of AD. Studies also confirm that moisturizers alone are insufficient for moderate-to-severe AD, reinforcing the need for adjunctive therapies [21]. However, finding the right emollient can be challenging, as some patients may experience irritation or allergic reactions to certain ingredients. Emollients alone may also be insufficient in controlling moderate to severe AD.

Biologics

Biologics have emerged as a promising treatment for moderate to severe atopic AD, particularly for patients who do not respond well to traditional therapies like topical corticosteroids and immunosuppressants. These medications specifically target components of the immune system that contributes to AD inflammation, such as cytokines. For example, dupilumab, a widely used biologic, inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13), key drivers of the Th2 immune response in AD [27]. By blocking these pathways, biologics effectively reduce inflammation, itching, and skin lesions. One of the major advantages of biologics is their targeted action, providing more effective control of symptoms with fewer side effects than conventional treatments. They also help restore the skin barrier by reducing inflammation, which prevents infections and flare-ups [64]. Additionally, biologics offer long-term symptom relief, improving patients' quality of life and reducing the need for corticosteroids, thereby minimizing risks like skin thinning. However, challenges exist in their use, including high costs that can limit access, especially where insurance coverage is inadequate. Moreover, most biologics are administered via injection, which can be uncomfortable or inconvenient for some patients [2]. Despite these challenges, biologics represent a significant advancement in AD treatment, offering targeted and lasting relief for those with severe cases.

Antibody treatment for atopic dermatitis

Several monoclonal antibody therapies have emerged as effective treatments for AD, targeting key cytokines involved in the disease’s pathogenesis. Dupilumab, a fully human monoclonal antibody, blocks the shared IL-4 receptor alpha subunit (IL-4Rα), thereby inhibiting both IL-4 and IL-13 signalling [50]. It is widely used for moderate-to-severe AD in both adults and children, offering significant improvement in skin barrier function, inflammation, and pruritus. Tralokinumab specifically targets IL-13 and has been approved for adult patients with moderate-to-severe AD [72]. It neutralizes IL-13 activity, helping to reduce inflammation and enhance skin barrier repair. Similarly, lebrikizumab, another anti-IL-13 antibody that binds a distinct epitope from tralokinumab, has demonstrated promising results in late-phase clinical trials [4]. In addition to these, nemolizumab targets the IL-31 receptor A (IL-31RA), addressing one of the hallmark symptoms of AD which is chronic itch. By blocking IL-31 signaling, nemolizumab has shown significant efficacy in reducing pruritus and improving patients’ quality of life [68]. Together, these antibody therapies represent a major advancement in the targeted treatment of AD by modulating specific pathways responsible for skin barrier dysfunction, inflammation, and itch.

Alternative therapeutic approaches for AD

In vitro approaches

Alternative therapies for atopic dermatitis (AD) target its complex pathophysiology, including immune dysregulation, skin barrier dysfunction, and chronic inflammation. These approaches include stem cell therapy, which utilizes the immunomodulatory and regenerative properties of stem cells and their secretomes to promote skin healing and reduce inflammation [51]. Probiotics and prebiotics are being studied for their ability to restore skin microbiota balance, enhance barrier function, and lower inflammation [44]. Herbal remedies, such as Centella asiatica and Glycyrrhiza glabra, show promise due to their anti-inflammatory and wound-healing properties, while traditional practices like acupuncture are explored for itch relief and immune modulation [79]. These strategies aim to provide long-term relief and minimize side effects compared to conventional treatments like corticosteroids and immunosuppressants. Recent advancements in regenerative medicine and tissue engineering also offer new tools for understanding AD and testing innovative therapies.

In vitro approaches involve studying atopic dermatitis (AD) at the cellular and molecular level using cell cultures outside living organisms. These models are crucial for understanding disease mechanisms, testing therapeutic agents, and analyzing treatment effects on keratinocytes, fibroblasts, and immune cells. Three-dimensional (3D) skin models, composed of keratinocytes and fibroblasts, effectively simulate the AD epidermal barrier, enabling studies on skin barrier function and inflammatory responses. They also help investigate cellular interactions, identify drug candidates, and assess treatments like stem cell secretomes, botanical extracts, or synthetic molecules [46].

Recent research highlights the role of cytokines, such as IL-31 and IL-33, and the potential of stem cell-derived secretomes in reducing inflammation and promoting wound healing [83]. In vitro models are vital for studying immune dysfunction in atopic dermatitis (AD). T-cell studies from AD patients help evaluate the effects of immunomodulatory drugs on Th2- associated cytokines like IL-4 [48]. Co-culture models of keratinocytes and immune cells reveal critical skin-immune interactions [13]. Research using botanical extracts like Polygonum cuspidatum and probiotics such as Lactobacillus reuteri has shown anti- inflammatory and skin-protective effects [61]. WJ-MSC secretome demonstrates potential to reduce inflammation and promote healing in keratinocytes and immune cells. Other studies on Centella asiatica extract and the skin microbiome, including strains like Staphylococcus epidermidis, highlight their roles in modulating inflammation and enhancing skin barrier function [80]. Staphylococcus aureus colonization significantly contributes to AD exacerbations, but rising resistance including Vancomycin-Resistant Staphylococcus aureus (VRSA) has complicated traditional treatment strategies. Emerging evidence indicates that Ziziphus nummularia extract demonstrates notable anti-VRSA activity, likely due to its diverse antimicrobial phytocompounds such as tannins, flavonoids, saponins, phenols, and terpenoids [59].

In vivo models

In vivo models involve studying AD within living organisms, primarily through the use of animal models like mice. These models allow researchers to study the complex interactions between skin, the immune system, and external factors in a whole organism. Mouse models of AD, such as those genetically modified to exhibit features of human AD (e.g., filaggrin-deficient mice), are widely used to investigate the pathophysiology of the disease, test new treatments, and explore their effects on skin inflammation, immune responses, and the skin barrier [65]. In vivo models provide critical insight into the systemic effects of treatments, helping to predict the therapeutic potential and safety of interventions before human clinical trials. They also allow for the testing of combination therapies, such as biologics and small molecule inhibitors, to observe long-term outcomes in a dynamic environment.

In vivo studies followed these in vitro findings, including the testing of LGG's efficacy a mouse model of AD, which showed reduced skin inflammation and improved skin condition. The WJ-MSC secretome was also evaluated in vivo, revealing significant improvements in skin lesions and barrier function in a mouse model of AD. Moreover, the efficacy of Centella asiatica extract was tested in a mouse model, resulting in significant reductions in inflammation and improvements in skin symptoms [75]. Finally, findings from skin microbiome studies were applied in a mouse model, demonstrating that specific bacterial strains could effectively reduce AD symptoms and enhance skin barrier integrity [41]. This comprehensive approach highlights how the combination of in vitro and in vivo studies provides a deeper understanding of AD and facilitates the development of novel therapeutic strategies.

In recent studies, MSC secretome therapy has been evaluated in vivo, showing promising results in reducing inflammation and promoting skin regeneration in AD mouse models. Additionally, herbal extracts such as Curcuma longa (turmeric) have been tested in AD mice, where significant reductions in inflammatory cytokine levels were observed, as well as improvements in skin symptoms [52]. Phototherapy, including UVB and UVA1 light treatments, has also been tested in vivo to reduce inflammation and skin thickening in AD models [53]. Both in vitro and in vivo models are essential for advancing the understanding of AD and developing alternative therapies that target the root causes of the disease while minimizing side effects.

The role of secretomes in regenerative medicine

The role of secretomes in regenerative medicine has garnered increasing attention due to their potential to promote healing and tissue regeneration through the complex interplay of bioactive molecules they contain. Secretomes refer to the collection of soluble factors secreted by cells, including growth factors, cytokines, chemokines, extracellular vesicles, and various proteins that contribute to cell communication and tissue homeostasis. In the context of regenerative medicine, secretomes derived from various cell types, such as mesenchymal stem cells (MSCs), have been shown to possess remarkable therapeutic properties. In addition. For instance, the secretome of MSCs contains numerous factors that can modulate inflammation, stimulate cellular proliferation, and enhance tissue repair mechanisms, making them attractive candidates for treating a wide range of conditions, including injuries, degenerative diseases, and inflammatory disorders [24]. Beyond their anti-inflammatory and tissue-regenerative properties, secretomes are increasingly being studied for their role in immune modulation. The immunomodulatory potential of MSC-derived secretomes, in particular, is of great interest in treating autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis [55]. These secretomes help regulate the immune response by inhibiting pro-inflammatory cytokines and enhancing regulatory T-cell activity, which can help restore immune homeostasis in patients with dysregulated immune systems.

As shown in the Fig. 4, the secretome, derived from mesenchymal stem cells (MSCs), plays a crucial role in regenerative medicine by creating a healing environment. It promotes angiogenesis, reduces cell death (anti-apoptotic), and supports the migration of the body's own stem cells to injury sites. Secretomes also regulate immune responses, reducing inflammation and preventing tissue damage. Preclinical and clinical studies have demonstrated their effectiveness in treating conditions like osteoarthritis, cardiac infarction, and chronic wounds [51]. For instance, secretomes from adipose-derived stem cells enhance wound healing by boosting fibroblast migration and keratinocyte proliferation, speeding up tissue regeneration.

Fig. 4.

Overview of the WJ-MSC secretome and its regenerative functions, including cytokine and growth factor delivery, anti-apoptotic effects, angiogenesis, and wound healing capabilities

Compared to whole-cell therapies, secretomes are safer and less invasive. They carry no risk of tumor formation or immune rejection, making them ideal for allogeneic use [29]. Researchers are also integrating secretomes with biomaterials to develop advanced scaffolds that deliver bioactive molecules to damaged tissues, further enhancing their regenerative effects. However, challenges like standardizing their isolation, characterization, and storage remain unclear. Efforts are ongoing to optimize their use by identifying key regenerative factors, paving the way for targeted therapies to improve clinical outcomes. Overall, secretome-based treatments hold significant promise in advancing natural healing and tissue repair strategies.

Secretomes as a treatment for AD

The link between tissues, organs, systems, and even the body as a whole is a different branch of regenerative medicine that allows us to integrate several cellular methods into a single therapy plan. Extracting secretome from WJ-MCS is one of the examples of it to reduce inflammation, promote tissue development pathways [63]. The utilization of secretomes as a treatment for AD represents a novel and promising approach in dermatological therapeutics. Secretomes, which are composed of a diverse array of bioactive molecules secreted by various cell types, including growth factors, cytokines, chemokines, and extracellular vesicles, have garnered interest due to their ability to modulate inflammatory processes and promote skin repair. The versatility of secretomes arises from their complex composition, which can vary based on the cell type and the physiological conditions under which they are derived. This diversity allows for tailored therapeutic applications depending on the specific needs of AD patients.

In the context of AD, a chronic inflammatory skin condition characterized by disrupted skin barrier function and heightened immune responses, secretomes can play a critical role in restoring homeostasis and alleviating symptoms. The interplay between immune cells, keratinocytes, and the extracellular matrix in the skin is crucial for maintaining barrier integrity and function. Secretomes can influence this interaction, promoting a more favourable microenvironment for healing.

Recent studies have highlighted the potential of secretomes derived from mesenchymal stem cells (MSCs) and other progenitor cells in managing AD. MSC secretomes are particularly rich in anti-inflammatory cytokines and growth factors that can mitigate the inflammatory response typically associated with AD. For example, factors such as transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF) present in MSC secretomes can enhance tissue regeneration and reduce inflammation [16]. These bioactive components have been shown to reduce the production of pro-inflammatory cytokines, such as interleukin-4 (IL-4) and interleukin-13 (IL-13), which are known to drive the Th2-dominant immune response in AD. By inhibiting these pathways, secretomes can help restore the balance of immune responses in the skin, potentially leading to improved clinical outcomes for patients suffering from AD.

In addition to their anti-inflammatory effects, secretomes can enhance skin barrier function by promoting keratinocyte proliferation and differentiation. Enhanced keratinocyte function is critical for the repair of the epidermal barrier, which is often compromised in AD patients. By promoting the differentiation of keratinocytes into their mature forms, secretomes support the formation of a robust barrier. This is particularly important in AD, where the impaired skin barrier allows for increased transepidermal water loss and susceptibility to allergens and irritants. Studies have demonstrated that secretomes can stimulate the expression of key proteins involved in maintaining skin integrity, such as filaggrin and loricrin, thus aiding in the restoration of the epidermal barrier. Referencing the Fig. 5, secretomes may also promote the synthesis of ECM, cytokines and growth factors essential for barrier function, helping to re-establish moisture levels in the skin.

Fig. 5.

The mechanism of keratinocyte dysfunction in AD mediated by pro-inflammatory cytokines and the therapeutic effects of WJ-MSC secretome in restoring skin barrier integrity

Moreover, secretome-based therapies offer several advantages over traditional treatments for AD, such as topical corticosteroids and calcineurin inhibitors. These conventional therapies, while effective, are often associated with side effects, including skin thinning and the risk of infections. In contrast, secretomes can reduce the dependency on these treatments, addressing the root causes of inflammation and barrier dysfunction without the same level of adverse effects. Secretomes utilize the body's natural healing processes and provide a more focused treatment approach with a good safety profile [32]. Furthermore, the use of secretomes can be integrated with existing treatment modalities, enhancing their effectiveness and potentially reducing the need for higher doses of pharmacological agents.

Ongoing research is focused on optimizing secretome formulations and determining the most effective delivery methods to ensure consistent and beneficial outcomes for patients with AD. Innovative delivery systems, such as microencapsulation or topical hydrogels, are being explored to enhance the stability and absorption of secretomes in the skin [76]. Recent exosome-based approaches also demonstrate therapeutic potential; for example, M2 macrophage–derived exosomes significantly enhanced angiogenesis and tissue regeneration via the HIF1AN/HIF-1α/VEGFA pathway in skin flap models [49], highlighting the broader regenerative relevance of cell-derived secretomes. As our understanding of secretomes continues to evolve, they may become a cornerstone in the future of AD management, offering a novel and effective strategy for restoring skin health and improving the quality of life for affected individuals. Long-term studies are necessary to assess the durability of secretome effects in managing chronic conditions like AD, paving the way for evidence-based treatment protocols.

Challenges and future directions in secretome-based therapies for AD

Secretome-based therapies for AD hold great promise; however, several challenges must be addressed to optimize their clinical application and effectiveness. One significant challenge is the variability in the composition and bioactivity of secretomes, which can differ based on the source of the cells such as mesenchymal stem cells from adipose tissue, bone marrow, or Wharton’s jelly and the methods used for their isolation and processing. For instance, differences in culture conditions, such as the presence of growth factors or cytokines, can significantly alter the composition of the secretome, impacting its therapeutic efficacy [47]. This variability can lead to inconsistent therapeutic outcomes, making standardization crucial for developing reliable treatments. Moreover, the lack of established protocols for the characterization of secretomes can hinder the identification of the specific bioactive components responsible for their therapeutic effects, complicating the development of targeted therapies [32]. Standardized assays and analytical techniques, such as mass spectrometry and enzyme-linked immunosorbent assays (ELISA), are needed to accurately assess the composition and functional properties of secretomes.

Another challenge lies in the delivery methods for secretome-based therapies. Effective delivery systems must ensure the stability of secretomes while allowing for controlled release at the target site. Innovations in delivery systems, such as microneedle patches or transdermal delivery systems, could provide efficient ways to administer secretomes directly to the skin, enhancing patient compliance and therapeutic effects. Research into advanced delivery systems, such as hydrogels, nanoparticles, or biomaterials, is ongoing to enhance the stability and localization of secretomes in the skin, which could improve their therapeutic efficacy. Additionally, the optimization of dosages and treatment regimens is necessary to determine the most effective application strategies, as both underdosing and overdosing can impact treatment outcomes. Dose–response studies are crucial for identifying the optimal concentrations of secretomes that yield the best clinical results while minimizing side effects.

Regulatory hurdles also pose challenges for the clinical translation of secretome therapies. As these treatments often involve biological products, they must meet rigorous safety and efficacy standards before gaining approval for clinical use. This requires extensive preclinical and clinical studies to demonstrate their safety profiles, mechanisms of action, and long-term effects, which can be resource-intensive and time-consuming. Engaging with regulatory agencies early in the development process can help streamline the approval pathway by clarifying the necessary safety and efficacy requirements.

Looking ahead, future research should focus on addressing these challenges through the development of standardized protocols for secretome isolation and characterization, as well as optimizing delivery systems and treatment regimens. Advancements in biomanufacturing techniques could facilitate the large-scale production of secretomes with consistent quality and composition, making them more accessible for clinical use. Additionally, larger clinical trials are needed to validate the efficacy and safety of secretome-based therapies for AD in diverse patient populations. Investigating the potential of combination therapies that integrate secretomes with existing treatments, such as topical corticosteroids or biologics, could enhance overall therapeutic outcomes. Although the therapeutic role of MSC-derived secretomes in atopic dermatitis is primarily attributed to their anti-inflammatory and pro-regenerative signalling molecules, their clinical translation may be further enhanced through advanced biomaterial platforms. For example, Janus hydrogels designed with asymmetric structures, high water retention, and wound-repair properties illustrate how novel delivery matrices could improve secretome stability, penetration, and sustained release on barrier-defective AD skin [82]. Furthermore, personalized medicine approaches that consider individual patient characteristics, such as genetic predispositions and disease severity, could optimize treatment strategies and improve patient outcomes. As understanding of the underlying mechanisms of AD and the role of secretomes continues to grow, it is likely that secretome-based therapies will evolve into a significant and effective option in the management of AD, offering new hope for patients struggling with this chronic condition. Compared to conventional treatments, the secretome, which consists of bioactive molecules like growth factors, cytokines, and exosomes, has the potential to modulate immune responses and promote skin healing in a more targeted and natural way. The purpose of this review is to evaluate thebody of research on the pathogenesis of AD, conventional therapeutics, and the recently developed field of secretome therapies, highlighting secretomes as a potential cutting-edge in AD treatment.

Experimental approaches for secretome studies in atopic dermatitis research

Several studies have investigated the therapeutic potential of secretomes in the context of AD using various cell sources and experimental designs. In this study, Wharton’s Jelly-derived mesenchymal stem cells (WJ-MSCs) and dermal fibroblasts are cultured under defined conditions, including normoxic and hypoxic environments, to enhance the secretion of bioactive factors. Secretomes are typically collected from conditioned media after specific culture durations and processed via centrifugation or filtration to remove cellular debris. Characterization methods reported in the literature include proteomic profiling, flow cytometry for cell surface markers, and immunocytochemistry to validate the presence of key cytokines and growth factors. Some studies further quantify specific bioactive molecules, such as IL-10, TGF-β, or VEGF, using ELISA or multiplex assays. These experimental approaches allow researchers to link secretome composition to functional effects on keratinocytes, immune modulation, and skin barrier repair in in vitro and in vivo AD models, thereby providing mechanistic insights and guiding potential translational applications. Table 3 shows summarization experimental designs, cell sources, secretome isolation protocols, and characterization methods commonly reported in studies on atopic dermatitis, psoriasis, and wound healing.

Table 3.

Summarization of experimental design, cell sources, secretome isolation protocols, and characterization methods

Study/Indication	Cell source (MSC or other)	Secretome isolation protocol	Characterization	Outcome of the study	References
Wound healing 3D culture secretome vs 2D (epidermal regeneration)	Adipose-derived MSCs (ASCs) in a tissue-mimetic 3D hydrogel system vs conventional 2D culture	Culture in 3D hydrogel (to better mimic tissue environment), collect secretome (CM / presumably enriched EVs) from 3D system	Functional assays: keratinocyte sheet formation (epidermal regeneration), cell migration/proliferation, likely EV/secretome comparison between 2D vs 3D secretomes	Stronger pro-regenerative effects than 2D, Improving keratinocyte sheet formation and wound repair	[35], [39], [62]
Wound healing MSC extract	MSCs (unspecified or general from an oral anatomy context)	Instead of collecting CM, cells are lysed to obtain an “MSC-extract”	In vitro: proliferation/migration of dermal fibroblasts, epithelial cells, endothelial cells. In vivo: mouse skin defect model, dermis thickness, cell proliferation, collagen deposition	Improved wound closure Enhanced fibroblast/epithelial proliferation	[14]
Wound healing infected wounds (MRSA)	Bone marrow-derived MSCs (from horses translational wound model)	Conditioned medium (CM) collected from MSCs; applied daily to full-thickness skin wounds (acute or MRSA-infected) in vivo	Wound closure rate via photography; histological analysis: granulation tissue formation, vascularization, hair follicle regeneration; immunofluorescence for immune cell infiltration (neutrophils, macrophages)	CM reduced bacterial burden, accelerated healing, and improved tissue regeneration in MRSA-infected wounds	[62]
Psoriasis-like skin inflammation (in vivo)	Bone marrow MSCs (BM-MSC) or adipose-derived MSCs (Ad-MSC)	Secretome was considered but actual therapy was via cell infusion after induction of psoriasis-like lesions	Psoriasis Area and Severity Index (PASI)-like scoring, gene & protein expression of inflammatory and regulatory cytokines, keratinocyte differentiation markers, immunomodulatory and pro-angiogenic markers via qRT-PCR & multiplex assays	Enhanced anti-inflammatory profiles and significantly reduced psoriasis-like skin inflammation	[12]
Psoriasis-like skin inflammation topical secretome application	Human amniotic epithelial cells (AEC) secretome (AEC-SC) and human umbilical cord MSC secretome (UMSC-SC)	Secretome collected from cell cultures; applied topically on the skin in an imiquimod (IMQ)-induced psoriasis-like mouse model	Assessment of skin lesion severity (visual), histology / skin inflammation, plus identification of key mediators	Reduced erythema, scaling, epidermal hyperplasia, and normalized inflammatory cytokines	[85, 22]
Comparison of secretomes from skin-derived MSC (dermal) vs adipose-MSC for wound healing	DSCs from skin; ASCs from subcutaneous adipose tissue (human)	Tissue digestion: dermis with trypsin–EDTA; adipose tissue with collagenase I; filtering, centrifugation, RBC lysis; culture to expand MSCs	Proteomics analysis: mass spectrometry to identify proteins in secretomes; bioinformatic analysis	Dermal secretome contained more ECM-regulating proteins; ASC secretome had stronger angiogenesis-related proteins	[88]

Mechanisms and comparative effects of secretomes in induced in vitro atopic dermatitis models

Several studies have investigated the effects of secretomes derived from Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) and dermal fibroblasts on keratinocytes and other skin cells using in vitro models that mimic atopic dermatitis (AD) conditions. These induced AD models typically involve stimulating keratinocytes with Th2 cytokines such as IL-4 and IL-13 to mimic the inflammatory and barrier-deficient environment seen in AD. WJ-MSC secretomes have been shown to upregulate key barrier proteins, including filaggrin, loricrin, and involucrin, while downregulating pro-inflammatory cytokines like IL-4, IL-13, and IL-31, thereby promoting epidermal repair and reducing inflammation. In contrast, fibroblast-derived secretomes demonstrate more variable effects, with some studies showing modest anti-inflammatory activity but limited enhancement of barrier proteins. Differences in cell source, culture conditions, and secretome collection methods likely contribute to these discrepancies. Critically, while these findings highlight the therapeutic potential of secretomes in restoring AD-related defects, further studies using standardized in vitro AD models and comparative analyses are needed to optimize their clinical relevance.

Conclusion

The chronic and complex nature of atopic AD continues to provide major obstacles to patient quality of life as well as the broader healthcare system. Although corticosteroids, immunosuppressants, and biologics are examples of traditional treatments that provide symptom alleviation, they frequently have drawbacks such as side effects and insufficient long-term efficacy. This review emphasizes how our knowledge of the fundamental mechanisms causing AD is developing and how promising secretome-based medicines are as treatments for the illness. Secretomes, produced from mesenchymal stem cells are a rich mixture of bioactive chemicals that have demonstrated potential in regulating immune responses, supporting skin barrier repair, and lowering inflammation. The increasing body of research examining the function of the secretome suggests that secretome-based medicines may provide a more focused and potent form of treatment, especially for patients suffering from moderate to severe AD and finding it difficult to comply with established treatment options.

Abbreviations

AD

Atopic Dermatitis

IL

Interleukin

FLG

Filaggrin

WJ-MSC

Wharton-Jelly Mesenchymal Stem Cell

ECM

Extracellular Matrix

TGF-β

Transforming growth factor-beta

HGF

Hepatocyte growth factor

Th

T-helper

AMPs

Antimicrobial peptides

PRRs

Pattern recognition receptors

NOD

Nucleotide-binding oligomerization domain

UV

Ultraviolet

IgE

Immunoglobulin E

Author contribution

Conceptualization, P.S.,M.N.S.,N.I.M.F., M.M.; validation, N.I.M.F., M.B.F., M.M.; writing—original draft preparation, P.S., N.I.M.F., M.M.; drawings of figures, P.S.,; writing—review and editing, P.S., N.I.M.F., M.B.F., and M.M.; visualization and supervision, M.N.S.,N.I.M.F., M.B.F., M.M.; project administration, M.M.; funding acquisition, M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded through the UKM research grant, FF-2025-374 & GUP-2023-065.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Informed consent

Not applicable.

Competing interest

The authors declare no competing interests.