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Adipose-derived stem cells in immune-related skin disease: a review of current research and underlying mechanisms

Stem Cell Research & Therapy volume 15, Article number: 37 (2024) Cite this article

Abstract

Adipose-derived stem cells (ASCs) are a critical adult stem cell subpopulation and are widely utilized in the fields of regenerative medicine and stem cell research due to their abundance, ease of harvest, and low immunogenicity. ASCs, which are homologous with skin by nature, can treat immune-related skin diseases by promoting skin regeneration and conferring immunosuppressive effects, with the latter being the most important therapeutic mechanism. ASCs regulate the immune response by direct cell–cell communication with immune cells, such as T cells, macrophages, and B cells. In addition to cell–cell interactions, ASCs modulate the immune response indirectly by secreting cytokines, interleukins, growth factors, and extracellular vesicles. The immunomodulatory effects of ASCs have been exploited to treat many immune-related skin diseases with good therapeutic outcomes. This article reviews the mechanisms underlying the immunomodulatory effects of ASCs, as well as progress in research on immune-related skin diseases.

Introduction

Immune-related skin diseases are a type of damage caused by disorders of the immune system, which are characterized by overactivated immune cells, high levels of pro-inflammatory factors, and a series of complex immune responses. Clinical symptoms of immune-related skin disease include fibrosis, redness, swelling, itching, and dandruff of the skin [1]. Topical and oral immunosuppressive drugs are the most widely used to treat immune-associated skin diseases, and new, more targeted approaches to treatment are being developed, but existing methods are still limited by the long course of treatment, limited efficacy, and significant expense [2]. ASCs are a type of mesenchymal stem cells (MSCs) derived from adipose tissue, also originate from the mesoderm, and are closely related to the skin. ASCs can thus be used to replenish and treat damaged skin tissue. Compared to other MSCs, ASCs have a potent immunosuppressive effect, which is a significant treatment advantage for immune-related skin diseases [3]. ASCs undergo cell–cell interactions with a variety of immune cells, including T cells, macrophages, B cells, dendritic cells (DCs), and natural killer cells (NK cells). Paracrine mechanisms of ASCs also indirectly regulate the immune system via secretion of cytokines, growth factors, anti-inflammatory mediators, active enzymes, and extracellular vesicles (EVs). ASC-secreted EVs and apoptotic ASCs have similar therapeutic benefits to viable ASCs, suggesting that the paracrine mechanisms of ASCs are central to their immunomodulatory effects [4]. The present review describes ASC immunomodulatory mechanisms that contribute to their therapeutic effects in treatment of immune-related skin diseases and summarizes the progress of preclinical research and clinical application of ASC treatment of autoimmune skin diseases. In addition, the challenges and adverse reactions faced by ASCs in clinical application are also mentioned.

ASC overview

ASCs are a type of MSC derived from adipose tissue. Compared with bone marrow mesenchymal stem cells (BM-MSCs), umbilical cord MSCs, and other MSCs, ASCs display unique advantages with respect to immunomodulation [5]. They can be harvested repeatedly, and in large quantities, from subcutaneous tissue by liposuction under anesthesia. Liposuction is also more comfortable than the painful bone marrow aspiration process and is more desirable because more stem cells can be harvested from the same amount of tissue; the process even has esthetic effects [6]. Additionally, studies gradually show that ASCs facilitate generation of keratinocytes and the secretome, resulting in improved skin regeneration [7]. Generally, ASCs have outstanding immunomodulatory and skin repair-promoting effects, which makes them an ideal candidate for stem cell therapy of immune-related skin diseases.

ASCs have many abilities favorable for the treatment of immune-related skin diseases, such as direct differentiation into skin cells and release of secretomes that promotes skin growth, together with their immunoregulatory effects. However, the latter plays a central role in the therapeutic effects. This is because the restoration of the disordered immune system is the cornerstone for treatment of immune-related skin diseases [8].

The immunomodulatory effects of ASCs are due to both cell–cell interactions and paracrine mechanisms, which affect different targets. Cell–cell interactions with ASCs are most common in T cells, macrophages, and B cells, which are also related to the pathophysiological characteristics of pathogenic immune cells in immune-related skin diseases. Paracrine effects of ASCs affect the fate and function of immune cells and the immune microenvironment via multiple bioactive factors in secretomes, and these paracrine effects are essential to the immunomodulatory role of ASCs [9].

Immunomodulatory effect of ASCs in immune-related skin diseases

Compared to other MSCs, ASCs have the strongest immunomodulatory properties, suggesting the therapeutic utility of ASCs in immune-related skin diseases [3]. Because ASCs and skin are both derived from the mesoderm and are anatomically closely related, ASCs alleviate immune-related skin diseases by both promoting regeneration of damaged skin and suppressing autoimmunity. However, the immunomodulatory effects of ASCs are the most studied (Fig. 1).

Fig. 1
figure 1

Direct and indirect (paracrine mechanisms) interactions of ASCs during immunomodulation. This schematic highlights the direct cell–cell interactions of ASCs, such as their effects on T lymphocytes, macrophages, B lymphocytes, DCs and NK cells, and the factors secreted by these cells. Additionally, the paracrine effects of cytokines, growth factors, anti-inflammatory mediators, active enzymes, and EVs play an important role in regulating the immune environment and immune cell function. Created with BioRender.com

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According to the type of target, the immunomodulatory effects of ASCs can be divided into direct cell–cell interactions and indirect paracrine mechanisms (Table 1) [10].

Table 1 Mechanisms of ASC immunomodulatory effects
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Direct cell–cell interactions

Direct cell–cell interactions between ASCs and immune cells are general. Studies confirm that ASCs regulate immune cells, including T cells, macrophages, B cells, and other immune cells, to promote immune tolerance. These direct cell–cell interactions occur in the context of immune-related skin diseases. ASCs inhibit the overactivated autoimmune responses that cause immune-related skin diseases. Their immunomodulatory effects include regulating immune cell phenotypic and secretory function, and promoting a shift from a pro-inflammatory state to a static or anti-inflammatory state.

T lymphocytes

T cell immune dysregulation involves predominantly TH1/TH17 polarization and the inability of Treg cells to repress the immune response, which is implicated in immune-related skin diseases [76]. Prior studies have demonstrated that ASCs downregulate pro-inflammatory factors by affecting the expression of T cell subset transcription factors and promoting differentiation of TH0 cells into TH1, TH2, TH17, and FoxP3+ Treg cells to regulate adaptive immunity. Additionally, ASCs decrease the number of activated T cells by arresting the cell cycle in the G0–G1 phase [49]. Compared to ASCs derived from healthy donors, ASCs derived from patients with immune-related diseases can also affect the function and phenotype of T cells, which makes the latter a reliable source for autologous applications [77].

The immunosuppressive effects of ASCs are regulated by maintaining the TH1/TH2 balance and regulating T cell secretory phenotype. ASCs inhibit effector TH1 cells in autoimmune diseases and restore the TH1/TH2 balance by promoting TH1 cytokines and inhibiting TH2 cytokines [15, 16]. ASCs and ASC-derived cells attenuate atopic dermatitis (AD) by suppressing inflammation associated with the TH1/TH2 response [78, 79]. Additionally, prior studies have demonstrated that ASCs suppress development of lupus dermatitis by suppressing TH1/TH2 ratio and maintaining their secretome balance [80].

ASCs also inhibit TH17 cell differentiation and secretion of IL-17 factors to prevent the pro-inflammatory effects of TH17 cells [20]. However, prior studies have also identified that ASCs promote differentiation of activated T cells into TH17 cells in some inflammatory environments, suggesting that development of future ASC-based immunotherapies should carefully consider these complex and detailed molecular interactions [18]. Psoriasis is a typical TH17-driven immune-related skin disease, and its clinical manifestations are alleviated by ASCs [81, 82]. Subcutaneous injection of ASCs also ameliorates AD by downregulating IL-17 secretion by TH17 cells [83].

ASCs also respond to the stimuli of pro-inflammatory factors and secrete specific factors to induce formation of Treg cells, which are recruited to the skin and resolve inflammation associated with multiple autoimmune skin diseases and promote tissue healing in these contexts [12, 84]. Surprisingly, ASC-EVs also induce formation of Treg cells. A prior study found that ASC-EVs induce peripheral blood mononuclear cell (PBMC) apoptosis and suppress PBMC and CD4+ T cell proliferation [14].

Transplantation of ASCs ameliorated autoimmune pathogenesis in a mouse systemic lupus erythematosus (SLE) model by modulating the balance between Treg cells and TH17 cells [85]. ASC-induced Treg cell amplification significantly alleviates the clinical and pathological changes of immune-related skin diseases and promotes immune tolerance to the skin barrier.

Macrophages

The immunomodulatory effect of ASCs on macrophages is promoted by promoting the transition from the pro-inflammatory phenotype (“classically activated” or “M1” macrophages) to the anti-inflammatory phenotype (“alternatively activated” or “M2” macrophages). As classic immune cells, pro-inflammatory macrophages promote differentiation of TH1 cells and release pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1, IL-6, and NOS [63]. ASCs relieve tissue inflammation by inhibiting infiltration of pro-inflammatory macrophages and secreting PGE2 to promote polarization to the anti-inflammatory phenotype [23]. The inhibition of ASCs on pro-inflammatory macrophages synergizes with the anti-proliferative properties of ASCs to suppress abnormal cell hyperplasia induced by chronic inflammation [86].

Anti-inflammatory macrophages secrete anti-inflammatory factors such as IL-10 and Arg-1. The two arginine metabolic pathways catalyzed by Arg-1 and NOS arrest each other, which has essential functions in regulating macrophage polarization [63]. ASCs secrete IL-10 to activate the STAT3/Arg-1 pathway, thus inducing differentiation into an anti-inflammatory phenotype [28]. A prior study of remote ASC transplantation demonstrated that tissue infiltration of anti-inflammatory macrophages is increased by intervention, suggesting that the secretory function of ASCs likely has essential regulatory roles in macrophages [26]. Apoptotic ASCs also promote Arg-1 activity and decrease nitric oxide levels in macrophages [25].

Pro-inflammatory macrophages promote the development of psoriasis by maintaining TH1 cytokine levels, which could be inhibited by ASCs [87]. In the bleomycin-induced systemic scleroderma (SSc) mouse model, ASCs alleviate skin fibrosis by suppressing infiltration of macrophages into the dermis [88, 89]. Moreover, AD induced by skin infection with Staphylococcus aureus in mice is alleviated via enhancing the phagocytic activity of macrophages by ASCs [90].

B lymphocytes

Multiple studies have identified that ASCs affect B cell proliferation and differentiation, with complex effects depending on the inflammatory environment: At high levels of inflammation, ASCs inhibit B cell proliferation, while at low levels of inflammation, ASCs support formation of Breg cells [91]. ASCs suppress over-proliferation of B cells in postinfectious inflammatory state, which is mediated by galectin-9 and B cell activating factor, to modulate the B cell immune response in vivo [30]. ASCs also inhibit production of pathogenic plasma cells and autoreactive antibodies in multiple immune-related skin diseases, such as SLE, SSc, and psoriasis. Furthermore, ASCs increase Breg cell formation, prompting secretion of TGF-β1 and IL-10 to inhibit inflammation in an in vitro model co-cultured with B cells [31]. Autoreactive plasma cells elicit production of pathogenic antibodies and deposition of immune complexes in SLE [92]. Intravenous injection of ASCs alleviates autoimmunity in this context by inducing Breg cell expansion and decreasing effector B cells in the SLE mouse model [93].

Other immune cells

ASCs also interact with immune cells such as NK cells and DCs to exert immunosuppressive effects. ASCs significantly decrease the number of CD49b+ NK cells, decrease production of interferon-γ (IFN-γ), and increase production of IL-4 and IL-10 [34]. An additional study demonstrated that ASCs secrete high levels of IDO, IL-10, and TGF-β1 to affect NK cell phenotype, further supporting the immunosuppressive effects of ASCs on NK cells [33].

Additionally, ASCs affect DC maturation by altering the phenotypic profile of classical markers and decreasing production of pro-inflammatory cytokines while increasing the concentration of immunosuppressive factors [36]. ASC-derived Exosomes (Exos) also have regulatory effects on DCs, not only decreasing DC surface marker expression but also inhibiting DC release of inflammatory factors, indicating that the ASC-derived secretome is potentially an important modulator of immune-related skin diseases regulated in part by DCs [35]. ASCs inhibit DC maturation and secretion of cytokines via multiple regulatory mechanisms. DCs are the primary source of pathogenic TNF-α and IL-23 in psoriasis, suggesting ASC implantation as a potential therapeutic modality for this condition [94].

Indirect cell–cell interactions (paracrine mechanisms)

ASCs secrete diverse bioactive factors such as cytokines, growth factors, anti-inflammatory mediators, and EVs to modulate the immune response in many autoimmune diseases (Table 1) [10]. These ASC-derived immunomodulatory factors can be secreted in vivo through direct transplantation of ASCs, or enriched in ASCs derivatives obtained by culture in laboratory for further use [95]. Some preclinical trials of ASCs in the treatment of immune-related skin diseases are summarized here. ASCs have been found to alleviate tissue inflammation in animal models mainly by regulating many secretome [22, 78,79,80,81,82,83, 85, 89, 90, 93, 96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117]. The preclinical studies of the immunomodulatory effect of ASCs in immune-related skin disease are summarized in Additional file 1: Table S1.

Cytokines

IL-10 and TGF-β are prominent anti-inflammatory factors contributing to the therapeutic effects of ASCs. IL-10 has crucial immunomodulatory roles in immune-related skin diseases, suppressing excessive inflammatory responses and promoting tissue regeneration [37]. IL-10 inhibits release of pro-inflammatory factors and suppresses pro-inflammatory effects of many immune cell types [38]. Prior studies have identified that ASCs secrete IL-10 to induce polarization of immune cells into anti-inflammatory phenotypes [28]. Further, systemic ASC infusion increases spleen-derived IL-10 expression and release, exerting systemic anti-inflammatory effects [39]. Further, ASC-EVs have anti-inflammatory and pro-angiogenic effects that alleviate tissue damage, which is potentially due to IL-10 harbored in EVs [40].

TGF-β regulates immune cell function, for example by inhibiting the expansion of CD8+ cytotoxic T cells, and also promoting development of both CD4+ TH17 cells and Treg cells, with the latter role potentially being more functionally significant [41]. Additionally, the TGF-β pathway plays a major role in Breg cell induction and the immunomodulatory properties of Breg cells [32]. DCs are also regulated by ASC-derived TGF-β1, inhibiting DC maturation and expression of surface markers [118].

ASCs increase IL-10 and TGF-β levels to inhibit pathological inflammation in a variety of immune-related skin diseases. For example, ASC extract alleviates pathological AD symptoms due to its content of IL-10 and TGF-β1 [107]. ASC-derived IL-10 increase the proportion of CD4 + FoxP3 + cells and ameliorates immunologic dysfunction in the SLE mouse model [103]. However, TGF-β, a fibrogenic factor, contributes to skin sclerosis of SSC and chronic sclerodermatous graft-versus-host disease (Scl-GvHD) as well. ASCs also inhibit excessive TGF-β levels and subsequent activation of downstream signaling pathways in fibrotic dermatoses to improve skin texture [98, 117].

Growth factors

HGF is a pleiotropic growth factor with antifibrotic and immunomodulatory effects that are due not only to its inhibitory effects on TH1 and TH17 cells but also promotion of Treg cells [42, 45]. ASCs secrete high levels of HGF to alleviate inflammation and promote tissue regeneration. A prior study identified that ASC-rich stromal vascular fraction (SVF) expressed high HGF levels to inhibit inflammation and fibrosis [44]. Further, ASC-derived HGF promotes tissue vascularization and repair [43]. These findings suggest that ASC-secreted HGF could be advantageous in treatment of tissue damage caused by inflammation. ASC-derived HGF exerts the anti-inflammatory and antifibrotic effects in improving skin sclerosis in SSc [119].

VEGF is widely studied and has immunomodulatory effects in addition to its well-known roles in promoting angiogenesis and increasing vascular permeability. VEGF secreted by ASCs can both downregulate expression of adhesion molecules in endothelial cells to hinder immune cell adhesion and support the expansion of Treg cells and anti-inflammatory macrophage infiltration by promoting angiogenesis [46, 120]. VEGF also directly modulates immune cells, for example by inhibiting effector T cell function, hindering differentiation and activation of DCs, and increasing recruitment of Treg cells [121]. In immune-related skin diseases, increased VEGF levels are primarily related to promotion of vascularization and repair of damaged tissue. Many preclinical studies have demonstrated that local angiogenesis of lesions was significantly improved by ASC-derived VEGF and that ulcers and skin fibrosis caused by SSc were also alleviated [96, 101].

Anti-inflammatory mediators

Other anti-inflammatory mediators affected by ASCs include PGE2 and TSG-6. The immunosuppressive properties of PGE2 are primarily manifested by inducing macrophages to secrete IL-10, inhibiting DC maturation and decreasing NK cell cytotoxicity [122]. The effect of ASC-secreted PGE2 inhibits T cell proliferation and induces formation of Treg cells [49, 52]. Moreover, ASC-derived PGE2 modulates differentiation of myeloid cells toward anti-inflammatory profiles [50]. Co-culture of ASCs with T cells derived from SSc and SLE patients revealed that ASCs suppressed expansion of CD4+ and CD8+ T cells by secreting PGE2 and kynurenines [22]. ASCs also significantly activates the COX-2/PGE2 cascade to inhibit growth of abnormal fibroblasts in keloids, which exerts an anti-fibrotic effect as well [52].

TSG-6, which is produced by TNF-stimulated ASCs, attenuates the immune response and promotes tissue regeneration in multiple immune-related skin diseases [54]. ASCs secrete TSG-6 to inhibit pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α [55]. Intraperitoneally injection of ASC enhances TSG-6 levels to induce macrophage polarization from pro-inflammatory phenotype to anti-inflammatory phenotype [56]. Further, TSG-6 plays an important role in ASC-EV induction of Treg cells [57]. TSG-6 secreted by ASCs has essential anti-inflammatory effects in many autoimmune diseases and inflammatory injuries, which are modulated by regulating macrophage phenotypes and alleviating endoplasmic reticulum stress [56, 123]. Future research will better define the effects of TSG-6 in immune-related skin diseases.

Active enzymes

ASCs are the most potent MSCs in immunomodulation, and their immunosuppressive effects are mediated in part by the IDO-kynurenine pathway, which regulates T cell suppression [49]. Consistently, IDO-silenced ASCs were unable to increase TH2 cells, and HGF expression was decreased, suggesting that their immunosuppressive effects were attenuated [61]. More in-depth studies of IDO have revealed that the two IDO subtypes, IDO1 and IDO2, have different functions. IDO1 mediates T cell suppression, while IDO2 affects B cells, functioning as a pro-inflammatory mediator of B cell responses [60].ASCs-derived IDO1 also induce macrophage polarization to the anti-inflammatory phenotype, which consequently alleviates inflammation and fibrosis [62].

Arginine metabolism is important for macrophage polarization, and its distinct metabolic pathways are catalyzed by NOS and Arg, which block each other [63]. The pro-inflammatory macrophages primarily secrete NOS, while anti-inflammatory macrophages secrete Arg. ASCs decrease the initial expression of inducible NOS and promote Arg-1 expression in infiltrating macrophages, consistent with a shift toward an anti-inflammatory phenotype [64]. Moreover, ASC-Exos transferred into macrophages induce the anti-inflammatory phenotype via transactivation of Arg-1 via STAT3 contained in vesicles [65].

T cells are central mediators of host rejection in the GvHD model, and inhibition of T cells is therefore the primary target for prolonging the survival of skin allografts. In a humanized skin allograft rejection model, ASCs suppress T cell-mediated alloreactivity by increasing IDO mRNA expression and IDO protein activity [114]. In a full-thickness skin grafts rats model treated with ASCs, NOS levels were markedly decreased, while Arg-1 and IL-10 levels were substantially increased, suggesting that the anti-inflammatory effect of ASCs could indirectly contribute to skin graft survival by regulating macrophage polarization [115].

ASC-EVs

EVs are subcellular structures consisting of a lipid bilayer membrane encasing cytoplasm, formed by invagination of the plasma membrane, which is roughly divided into two types according to their diameter and origin, including Exos with a diameter of 50–150 nm derived from endosomes and microvesicles with a diameter of 50–500 nm derived from the plasma membrane [124]. Multiple studies have demonstrated that ASC-EVs have the same therapeutic effect as ASCs in inducing immune tolerance [95].

A prior study suggested that the anti-inflammatory effect of ASC-EVs could be related to the suppression of NF-κB-dependent inflammatory/catabolic environments [125]. Intravenous administration of ASCs enable the transfer of ASC-EVs to anti-inflammatory macrophages subsequently enhanced Treg cell induction, which underlies ASC immunotherapy [72].

As subpopulations of ASC-EVs, ASC-Exos also contain Arg-1, which promotes anti-inflammatory macrophages polarization while inhibiting T cell proliferation [73]. Interestingly, ASC-Exos can effectively donate mitochondria components to macrophages, which improves macrophage mitochondrial integrity and oxidative phosphorylation, allowing resumption of macrophage metabolic and immune homeostasis and mitigating inflammatory pathology [75].

ASC-Exos were injected subcutaneously into the lesion sites of AD, which decreased expression of pro-inflammatory factors in the skin, increased ceramide synthesis, and alleviated clinical symptoms of AD [110]. Further studies have demonstrated that ASC-Exo improvement of inflammation and skin barrier function is regulated by suppressing the JAK/STAT pathway in skin lesions of AD [111]. In addition, compared to ASCs, ASC-EVs cocultured with SSc-like myofibroblasts significantly downregulate myofibroblast markers and inhibit TGF-β stimulation, further underscoring the therapeutic potential of ASC-EVs in SSc [99].

Compared with naive ASCs, ASC-EVs not only have the advantages of stable transportation and convenient storage but also contain simple and well-defined components, allowing a more precise curative effect. Further, ASC-EVs can be used as effective carriers for multiple drugs, allowing more precise drug delivery and absorption in skin lesions [126].

Progress in clinical application of ASCs for treatment of immune-related skin diseases

Immune-related skin diseases include a range of complex disorders that may affect all systems or have skin-only manifestations. According to immune status, they can be roughly divided into two categories: suppressed or hyper-reactive. Among these, immunodepression leads to dermatologic diseases such as Herpes zoster, Kaposi sarcoma, and fungal infection in elderly patients or patients with organ transplants, especially those who have HIV [127]. Skin disorders caused by hyper-reactive immune responses are the most common immune-related skin diseases, which include autoimmune, allergic, infectious, and tumorous skin disorders [128]. ASCs have excellent immunomodulatory effects and skin reparative effects, prompting much research into their application to immune-related skin diseases. The utility of ASCs and their cell-free derivatives as immunotherapies in immune hyper-reactive dermatosis is supported by multiple studies (Table 2) [95]. Investigators have used ASCs and ASC derivatives for treatment of SSc, psoriasis, SLE, AD, and others (Fig. 2). Both autologous and allogeneic ASCs have been used in multiple clinical trials. While autologous ASCs are considered to be safer due to their lower immunogenicity, allogeneic ASCs are more commonly used due to their increased availability and reproducibility.

Table 2 Clinical efficacy ASCs in immune-related skin diseases
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Fig. 2
figure 2

Application progress of ASCs on immune-related skin diseases. The image shows the process of harvest, isolation, and in vitro culture of ASCs from a donor, and the application of amplified ASCs and collected ASCs derivatives in the treatment of patients with immune-associated skin diseases. Created with BioRender.com

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As early as 2013, Scuderi et al. conducted a clinical trial using autologous ASC transplantation for SSc patients, and all six patients enrolled in the study benefited from arrest of local disease progression. In addition, they also demonstrated that neither function nor phenotype differed between ASCs derived from patient donors and healthy donors, establishing the basis for subsequent use of autologous ASCs in patients with immune-associated skin diseases [129].

Khannaden et al. reported the largest randomized clinical trial thus far. Eighty-eight patients with SSc-induced hand disability were randomly assigned to the autologous ASC group or placebo group, and changes in hand function were assessed. Compared to the control group, the ASC group had improved hand function, but the difference was not statistically significant (mean ± SD improvement in Cochin Hand Function Scale score at 48 weeks 11.0 ± 12.5 vs 8.9 ± 10.5; P = 0.299). Among patients enrolled in the study, hand function was most improved in patients with diffuse cutaneous SSc (dcSSc) (52% dual-response rate compared to 16% in the placebo group; nominal P = 0.016). The authors suggested that further clinical trials of this intervention in the context of dcSSc are warranted [130].

Other studies have explored the therapeutic potential of ASC derivatives. Comella et al. reported the first case study of intravenous SVF implantation in psoriasis. The patient benefited from a significant decrease in symptoms and skin quality appearance without safety concerns or severe adverse events [131]. Furthermore, Park et al. underscored the therapeutic potential of ASC-Exos for AD patients. Two patients with AD and refractory dupilumab facial redness were successfully improved with ASC-Exos. Importantly, this trial did not use autologous ASC-Exos, confirming that clinical application of allogeneic ASCs-Exos does not cause immune rejection, making ASCs derivatives an ideal material for allogeneic applications [132].

However, some reports suggest a dualistic function of ASCs in SSc as ASCs could function as an additional pathogenic source of pro-fibrotic myofibroblasts via adipocyte-to-myofibroblast transition, resulting in lack of therapeutic effect or even potential aggravation of SSc [133]. A prior study might support this theory. A double-blind, multicenter, phase II trial assessed the efficacy of SVF vs placebo injection into the fingers in improvement of hand disability in 40 patients, showing no additional therapeutic effects for SVF over time. The author indicated that studies of more patients with the same phenotype should be conducted to more accurately assess the benefits of ASC treatment [134].

The means for ASC induction to exert the desired immunomodulatory and therapeutic effects in different stages of different immune-related skin diseases remains a major barrier to treatment. Because the immunomodulatory effects of ASCs are regulated primarily by paracrine mechanisms, multiple strategies to regulate ASC paracrine effects have been evaluated [135]. A prior study used fibrous-engineered scaffolds to induce ASC expression of higher levels of anti-inflammatory factors via a mechanotransduction pathway [136]. Additionally, using chitosan film as a 3D culture strategy significantly affects ASC production of immunosuppressive factors in vitro through increased secretion of TGF-β and IL-10 and increased Arg activity [137]. ASC-Exos combined with hydrogels are more easily absorbed by the body, alleviating early inflammation and promoting tissue repair [138]. Thus, the combination with materials increases duration of action, induces sustained release, and changes the route of drug administration, increasing the range and efficacy of ASC applications. Although the above strategies are presently still in the research stage, their potential for clinical application is worth expecting.

Challenges and adverse reactions during clinical application of ASCs

In recent years, the techniques used to harvest, isolate, and inject ASCs have been studied and standardized. However, challenges remain with respect to clinical application. Differences in donor age, sex, body mass index, and donor site lead to heterogeneity of ASCs, which makes treatment efficacy unpredictable. In addition, the research and clinical application of human stem cells must follow strict guidelines and pass ethical reviews, which limits clinical application of ASCs.

We cannot ignore the existence of adverse reactions associated with ASC-based therapies. Current concerns related to the clinical application of ASCs focus mainly on embolism caused by intravascular injection, and possible tumorigenicity, which gives rise to ethical problems. Although an increasing number of clinical studies have refuted these concerns, further work is needed [152,153,154].

Although some of the interactions between ASCs and immune cells mentioned in this review have not been confirmed in models of immune-related skin diseases, they have been verified in many models of autoimmune disease, a field in which ASCs are likely to be used as a treatment. We expect that these interactions will be examined in models of immune-related skin diseases in the future. In addition, most of the current research on the use of ASCs as a treatment for various disorders is at the experimental stage; large-scale clinical trials should be the ultimate focus of our future efforts.

Conclusions

ASCs directly or indirectly alleviate immune-related skin diseases via direct interaction with immune cells and paracrine mechanisms. ASCs affect immune cells involved in both the innate and adaptive immune responses to inhibit their pro-inflammatory functions. ASCs also mediate immune pathways by secreting cytokines, growth factors, anti-inflammatory mediators, and active enzymes. Presently, most clinical research focuses on their efficacy and safety in human body, while animal studies are devoted to explored underlying mechanisms of the interaction of ASCs with immune cells and immune factors. The immunomodulatory effect of ASCs has been reported in multiple clinical trials, but these applications need to be further explored and refined, including more standardized preparation methods, higher numbers of patients, and more stringent inclusion criteria. ASC therapy is thus a promising candidate for treatment of immune-related skin diseases and is expected to suppress disease progression and improve patient quality of life.

Availability of data and material

Not applicable.

Abbreviations

ASC:

Adipose-derived stem cell

MSC:

Mesenchymal stem cell

DC:

Dendritic cell

NK cell:

Natural killer cell

EV:

Extracellular vesicle

BM-MSCs:

Bone marrow mesenchymal stem cells

Treg cell:

Regulatory T cell

Th1:

Type 1 helper T cell

Th2:

Type 2 helper T cell

Th17:

Type 17 helper T cell

CTL:

Cytotoxic T lymphocyte

Breg cell:

Regulatory B cell

IL:

Interleukin

TGF:

Transforming growth factor

MLRs:

Mixed lymphocyte reactions

HGF:

Hepatocyte growth factor

VEGF:

Vascular endothelial growth factor

PGE2 :

Prostaglandin E2

TSG-6:

Tumor necrosis factor alpha induced protein-6

IDO:

Indoleamine-pyrrole 2,3,-dioxygenase

NOS:

Nitric oxide synthase

Arg:

Arginase

CM:

Conditioned medium

Exos:

Exosomes

AD:

Atopic dermatitis

PBMC:

Peripheral blood mononuclear cell

SLE:

Systemic lupus erythematosus

TNF-α :

Tumor necrosis factor-α

SSc:

Systemic scleroderma

IFN-γ :

Interferon-γ

Exos:

Exosomes

Scl-GvHD:

Chronic sclerodermatous graft-versus-host disease

SVF:

Stromal vascular fraction

hSVF:

Human stromal vascular fraction

hASCs:

Human adipose-derived stem cells

mASCs:

Mouse adipose-derived stem cells

dASCs:

Dog adipose-derived stem cells

rASCs:

Rat adipose-derived stem cells

α-SMA:

α-Smooth muscle actin

MMP1:

Matrix metalloproteinase 1

TIMP1:

Tissue inhibitor of metalloproteinase-1 protein

COX-2:

Cyclo-oxygenase

dcSSC:

Diffuse cutaneous SSc

PRP:

Platelet-rich plasma

References

  1. Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012;11(3):226–30. https://doi.org/10.1016/j.autrev.2011.05.017.

    Article  CAS  PubMed  Google Scholar 

  2. Braegelmann C, Niebel D, Wenzel J. Targeted therapies in autoimmune skin diseases. J Invest Dermatol. 2022;142(3):969–75. https://doi.org/10.1016/j.jid.2021.08.439.

    Article  CAS  PubMed  Google Scholar 

  3. Torres Crigna A, Uhlig S, Elvers-Hornung S, et al. Human adipose tissue-derived stromal cells suppress human, but not murine lymphocyte proliferation, via indoleamine 2,3-dioxygenase activity. Cells. 2020;9(11):2419. https://doi.org/10.3390/cells9112419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14(8):493–507. https://doi.org/10.1038/s41581-018-0023-5.

    Article  CAS  PubMed  Google Scholar 

  5. Ribeiro A, Laranjeira P, Mendes S, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther. 2013;4(5):1–16. https://doi.org/10.1186/scrt336.

    Article  CAS  Google Scholar 

  6. Strioga M, Viswanathan S, Darinskas A, et al. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724–2452. https://doi.org/10.1089/scd.2011.0722.

    Article  CAS  PubMed  Google Scholar 

  7. Hoang D, Pham P, Bach T, et al. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022;7(1):272. https://doi.org/10.1038/s41392-022-01134-4.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stevens N, Cowin A, Kopecki Z. Skin barrier and autoimmunity-mechanisms and novel therapeutic approaches for autoimmune blistering diseases of the skin. Front Immunol. 2019;10:1089. https://doi.org/10.3389/fimmu.2019.01089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ceccarelli SEA, Napoli C, et al. Immunomodulatory effect of adipose-derived stem cells: the cutting edge of clinical application. Front Cell Dev Biol. 2020;8:236. https://doi.org/10.3389/fcell.2020.00236.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Al-Ghadban S, Bunnell BA. Adipose tissue-derived stem cells: immunomodulatory effects and therapeutic potential. Physiology. 2020;35(2):125–33. https://doi.org/10.1152/physiol.00021.2019.

    Article  CAS  PubMed  Google Scholar 

  11. Malko D, Elmzzahi T, Beyer M. Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology. Front Immunol. 2022;13:954798. https://doi.org/10.3389/fimmu.2022.954798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu O, Xu J, Wang F, et al. Adipose-mesenchymal stromal cells suppress experimental Sjögren syndrome by IL-33-driven expansion of ST2(+) regulatory T cells. Science. 2021;24(5):102446. https://doi.org/10.1016/j.isci.2021.102446.

    Article  CAS  Google Scholar 

  13. Fiori A, Uhlig S, Klüter H, et al. Human adipose tissue-derived mesenchymal stromal cells inhibit CD4+ T cell proliferation and induce regulatory T cells as well as CD127 expression on CD4+CD25+ T cells. Cells. 2021;10(1):58. https://doi.org/10.3390/cells10010058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Teshima T, Yuchi Y, Suzuki R, et al. Immunomodulatory effects of canine adipose tissue mesenchymal stem cell-derived extracellular vesicles on stimulated CD4+ T Cells isolated from peripheral blood mononuclear cells. J Immunol Res. 2021. https://doi.org/10.1155/2021/2993043.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bowles A, Wise R, Gerstein B, et al. Adipose stromal vascular fraction attenuates TH1 cell-mediated pathology in a model of multiple sclerosis. J Neuroinflammation. 2018;15(1):1–12. https://doi.org/10.1186/s12974-018-1099-3.

    Article  CAS  Google Scholar 

  16. Dai R, Yu Y, Yan G, et al. Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model. BMC Pulm Med. 2018;18(1):1–9. https://doi.org/10.1186/s12890-018-0701-x.

    Article  CAS  Google Scholar 

  17. Fu Z, Zhang Z, Ge H. Mesenteric injection of adipose-derived mesenchymal stem cells relieves experimentally-induced colitis in rats by regulating Th17/Treg cell balance. Am J Transl Res. 2018;10(1):54.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Najar M, Lombard C, Fayyad-Kazan H, et al. Th17 immune response to adipose tissue-derived mesenchymal stromal cells. J Cell Physiol. 2019;234(11):21145–52. https://doi.org/10.1002/jcp.28717.

    Article  CAS  PubMed  Google Scholar 

  19. Alves V, de Sousa B, Fonseca M, et al. A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis. Clin Exp Immunol. 2019;196(2):139–54. https://doi.org/10.1111/cei.13262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bi Y, Lin X, Liang H, et al. Human adipose tissue-derived mesenchymal stem cells in Parkinson’s disease: inhibition of T helper 17 cell differentiation and regulation of immune balance towards a regulatory T cell phenotype. Clin Interv Aging. 2020;15:1383–91. https://doi.org/10.2147/CIA.S259762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kuca-Warnawin E, Plebańczyk M, Bonek K, et al. Inhibition of allogeneic and autologous T cell proliferation by adipose-derived mesenchymal stem cells of ankylosing spondylitis patients. Stem Cells Int. 2021. https://doi.org/10.1155/2021/6637328.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kuca-Warnawin E, Olesińska M, Szczȩsny P, et al. Impact and possible mechanism(s) of adipose tissue-derived mesenchymal stem cells on T-cell proliferation in patients with rheumatic disease. Front Physiol. 2022;12:749481. https://doi.org/10.3389/fphys.2021.749481.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yuan Y, Ni S, Zhuge A, et al. Adipose-derived mesenchymal stem cells reprogram M1 macrophage metabolism via PHD2/HIF-1α pathway in colitis mice. Front Immunol. 2022;13:859806. https://doi.org/10.3389/fimmu.2022.859806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen L, Chen P, Tang C, et al. Adipose-derived stromal cells reverse insulin resistance through inhibition of M1 expression in a type 2 diabetes mellitus mouse model. Stem Cell Res Ther. 2022;13(1):1–16. https://doi.org/10.1186/s13287-022-03046-0.

    Article  MathSciNet  CAS  Google Scholar 

  25. Ghahremani Piraghaj M, Soudi S, Ghanbarian H, et al. Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function. Life Sci. 2018;212:203–12. https://doi.org/10.1016/j.lfs.2018.09.052.

    Article  CAS  PubMed  Google Scholar 

  26. Lee T, Harn H, Chiou T, et al. Remote transplantation of human adipose-derived stem cells induces regression of cardiac hypertrophy by regulating the macrophage polarization in spontaneously hypertensive rats. Redox Biol. 2019;27:101170. https://doi.org/10.1016/j.redox.2019.101170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang W-C, Qin F, Wang X-J, et al. Adipose-derived stromal cells attenuate adipose inflammation in obesity through adipocyte browning and polarization of M2 macrophages. Mediators Inflamm. 2019;2019:1731540. https://doi.org/10.1155/2019/1731540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu J, Qin J, Wu X, et al. Allogeneic adipose-derived stem cells promote ischemic muscle repair by inducing M2 macrophage polarization via the HIF-1α/IL-10 pathway. Stem Cells Dayt Ohio. 2020;38(10):1307–20. https://doi.org/10.1002/stem.3250.

    Article  CAS  Google Scholar 

  29. Mehdipour F, Razmkhah M, Rezaeifard S, et al. Mesenchymal stem cells induced anti-inflammatory features in B cells from breast tumor draining lymph nodes. Cell Biol Int. 2018;42(12):1658–69. https://doi.org/10.1002/cbin.11062.

    Article  CAS  PubMed  Google Scholar 

  30. Wagner J, Reinkemeier F, Wallner C, et al. Adipose-derived stromal cells are capable of restoring bone regeneration after post-traumatic osteomyelitis and modulate B-cell response. Stem Cells Transl Med. 2019;8(10):1084–91. https://doi.org/10.1002/sctm.18-0266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen C-C, Chen R-F, Shao J-S, et al. Adipose-derived stromal cells modulating composite allotransplant survival is correlated with B cell regulation in a rodent hind-limb allotransplantation model. Stem Cell Res Ther. 2020;11(1):478–478. https://doi.org/10.1186/s13287-020-01961-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Garcia S, Sandoval-Hellín N, Clos-Sansalvador M, et al. Mesenchymal stromal cells induced regulatory B cells are enriched in extracellular matrix genes and IL-10 independent modulators. Front Immunol. 2022;13:957797. https://doi.org/10.3389/fimmu.2022.957797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bahrami B, Hosseini A, Talei A-R, et al. Adipose derived stem cells exert immunomodulatory effects on natural killer cells in breast cancer. Cell J. 2017;19(1):137–45.

    PubMed  Google Scholar 

  34. Rezaei Kahmini F, Shahgaldi S, Moazzeni SM. Mesenchymal stem cells alter the frequency and cytokine profile of natural killer cells in abortion-prone mice. J Cell Physiol. 2020;235(10):7214–23. https://doi.org/10.1002/jcp.29620.

    Article  CAS  PubMed  Google Scholar 

  35. Shahir M, Mahmoud Hashemi S, Asadirad A, et al. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol. 2020;235(10):7043–55. https://doi.org/10.1002/jcp.29601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Juhl M, Follin B, Gad M, et al. Adipose tissue-derived stromal cells induce a highly trophic environment while reducing maturation of monocyte-derived dendritic cells. Stem Cells Int. 2020. https://doi.org/10.1155/2020/8868909.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50(4):871–91. https://doi.org/10.1016/j.immuni.2019.03.020.

    Article  CAS  PubMed  Google Scholar 

  38. Neumann C, Scheffold A. Functions and regulation of T cell-derived interleukin-10. Semin Immunol. 2019. https://doi.org/10.1016/j.smim.2019.101344.

    Article  PubMed  Google Scholar 

  39. Zhang J, Deng Z, Jin L, et al. Spleen-derived anti-inflammatory cytokine IL-10 stimulated by adipose tissue-derived stem cells protects against type 2 diabetes. Stem Cells Dev. 2017;26(24):1749–58. https://doi.org/10.1089/scd.2017.0119.

    Article  CAS  PubMed  Google Scholar 

  40. Jiang Y, Hong S, Zhu X, et al. IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension. Front Immunol. 2022;13:940093. https://doi.org/10.3389/fimmu.2022.940093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nolte M, Margadant C. Controlling immunity and inflammation through integrin-dependent regulation of TGF-β. Trends Cell Biol. 2020;30(1):49–59. https://doi.org/10.1016/j.tcb.2019.10.002.

    Article  CAS  PubMed  Google Scholar 

  42. Kamata S, Miyagawa S, Fukushima S, et al. Targeted delivery of adipocytokines into the heart by induced adipocyte cell-sheet transplantation yields immune tolerance and functional recovery in autoimmune-associated myocarditis in rats. Circ J Off J Jpn Circ Soc. 2015;79(1):169–79. https://doi.org/10.1253/circj.CJ-14-0840.

    Article  CAS  Google Scholar 

  43. Boldyreva MA, Shevchenko EK, Molokotina YD, et al. Transplantation of adipose stromal cell sheet producing hepatocyte growth factor induces pleiotropic effect in ischemic skeletal muscle. Int J Mol Sci. 2019;20(12):E3088. https://doi.org/10.3390/ijms20123088.

    Article  CAS  Google Scholar 

  44. Choi J, Chae D, Ryu H, et al. Transplantation of human adipose tissue derived-SVF enhance liver function through high anti-inflammatory property. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864(12):158526. https://doi.org/10.1016/j.bbalip.2019.158526.

    Article  CAS  PubMed  Google Scholar 

  45. Ma J, Yan X, Lin Y, et al. Hepatocyte growth factor secreted from human adipose-derived stem cells inhibits fibrosis in hypertrophic scar fibroblasts. Curr Mol Med. 2020;20(7):558–71. https://doi.org/10.2174/1566524020666200106095745.

    Article  CAS  PubMed  Google Scholar 

  46. Ntellas P, Mavroeidis L, Gkoura S, et al. Old player-new tricks: non angiogenic fffects of the VEGF/VEGFR pathway in cancer. Cancers. 2020;28:3145. https://doi.org/10.3390/cancers12113145.

    Article  CAS  Google Scholar 

  47. Chen L, Zheng Q, Liu Y, et al. Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway. Arch Biochem Biophys. 2020;8:108531.

    Article  Google Scholar 

  48. An J, Song W, Li Q, et al. Prostaglandin E2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res. 2018. https://doi.org/10.1186/s12917-018-1684-9.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Taechangam N, Iyer S, Walker N, et al. Mechanisms utilized by feline adipose-derived mesenchymal stem cells to inhibit T lymphocyte proliferation. Stem Cell Res Ther. 2019;10:1–12. https://doi.org/10.1186/s13287-019-1300-3.

    Article  CAS  Google Scholar 

  50. Ortiz-Virumbrales M, Menta R, Pérez L, et al. Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2. Stem Cell Res Ther. 2020;11(1):1–21. https://doi.org/10.1186/s13287-020-01975-2.

    Article  CAS  Google Scholar 

  51. Liu L, He Y, Liu S, et al. Enhanced effect of IL-1 β-activated adipose-derived MSCs (ADMSCs) on repair of intestinal ischemia-reperfusion injury via COX-2-PGE2 signaling. Stem Cells Int. 2020. https://doi.org/10.1155/2020/2803747.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang J, Li S, He L, et al. Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine. Burns Trauma. 2021. https://doi.org/10.1093/burnst/tkab020.

    Article  PubMed  PubMed Central  Google Scholar 

  53. An Y, Yao J, Niu X. The signaling pathway of PGE2 and its regulatory role in T cell differentiation. Mediat Inflamm. 2021. https://doi.org/10.1155/2021/9087816.

    Article  Google Scholar 

  54. Day A, Milner C. TSG-6: a multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biol J Int Soc Matrix Biol. 2019;78:60–83. https://doi.org/10.1016/j.matbio.2018.01.011.

    Article  CAS  Google Scholar 

  55. Hu Y, Li G, Zhang Y, et al. Upregulated TSG-6 expression in ADSCs inhibits the BV2 microglia-mediated inflammatory response. BioMed Res Int. 2018. https://doi.org/10.1155/2018/7239181.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Song W, Li Q, Ryu M, et al. TSG-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice. Stem Cell Res Ther. 2018;9(1):1–12. https://doi.org/10.1186/s13287-018-0841-1.

    Article  CAS  Google Scholar 

  57. An J, Li Q, Ryu M, et al. TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis. PLoS ONE. 2020;15(2):e0220756. https://doi.org/10.1371/journal.pone.0220756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao Y, Zhu X, Song T, et al. Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching. Am J Physiol Renal Physiol. 2021;320(3):454–63. https://doi.org/10.1152/ajprenal.00426.2020.

    Article  CAS  Google Scholar 

  59. Abd El-Fattah EE. IDO/kynurenine pathway in cancer: possible therapeutic approaches. J Transl Med. 2022;20(1):347. https://doi.org/10.1186/s12967-022-03554-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Merlo LMF, DuHadaway JB, Montgomery JD, et al. Differential roles of IDO1 and IDO2 in T and B cell inflammatory immune responses. Front Immunol. 2020;11:1861. https://doi.org/10.3389/fimmu.2020.01861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Heidari F, Razmkhah M, Razban V, et al. Effects of indoleamine 2, 3-dioxygenase (IDO) silencing on immunomodulatory function and cancer-promoting characteristic of adipose-derived mesenchymal stem cells (ASCs). Cell Biol Int. 2021;45(12):2544–56. https://doi.org/10.1002/cbin.11698.

    Article  CAS  PubMed  Google Scholar 

  62. Ye Y, Zhang X, Su D, et al. Therapeutic efficacy of human adipose mesenchymal stem cells in Crohn’s colon fibrosis is improved by IFN-γ and kynurenic acid priming through indoleamine 2,3-dioxygenase-1 signaling. Stem Cell Res Ther. 2022;13(1):465. https://doi.org/10.1186/s13287-022-03157-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gharavi AT, Hanjani NA, Movahed E, et al. The role of macrophage subtypes and exosomes in immunomodulation. Cell Mol Biol Lett. 2022. https://doi.org/10.1186/s11658-022-00384-y.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Young SA, Flynn LE, Amsden BG. Adipose-derived stem cells in a resilient in situ forming hydrogel modulate macrophage phenotype. Tissue Eng Part A. 2018;24(23–24):1784–97. https://doi.org/10.1089/ten.TEA.2018.0093.

    Article  CAS  PubMed  Google Scholar 

  65. Zhao H, Shang Q, Pan Z, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in White Adipose tissue. Diabetes. 2018. https://doi.org/10.2337/db17-0356.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Heidari M, Pouya S, Baghaei K, et al. The immunomodulatory effects of adipose-derived mesenchymal stem cells and mesenchymal stem cells-conditioned medium in chronic colitis. J Cell Physiol. 2018;233(11):8754–66. https://doi.org/10.1002/jcp.26765.

    Article  CAS  PubMed  Google Scholar 

  67. Guillén M, Platas J, Pérez Del Caz M, et al. Paracrine anti-inflammatory effects of adipose tissue-derived mesenchymal stem cells in human monocytes. Front Physiol. 2018;9:661. https://doi.org/10.3389/fphys.2018.00661.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Souza-Moreira L, Soares VC, da Dias SG, et al. Adipose-derived mesenchymal stromal cells modulate lipid metabolism and lipid droplet biogenesis via AKT/mTOR -PPARγ signalling in macrophages. Sci Rep. 2019;9(1):20304. https://doi.org/10.1038/s41598-019-56835-8.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  69. Filidou E, Kandilogiannakis L, Tarapatzi G, et al. Conditioned medium from a human adipose-derived stem cell line ameliorates inflammation and fibrosis in a lung experimental model of idiopathic pulmonary fibrosis. Life Sci. 2021. https://doi.org/10.1016/j.lfs.2021.120123.

    Article  PubMed  Google Scholar 

  70. Yano F, Takeda T, Kurokawa T, et al. Effects of conditioned medium obtained from human adipose-derived stem cells on skin inflammation. Regen Ther. 2022;20:72–7. https://doi.org/10.1016/j.reth.2022.03.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shi M, Yang Q, Monsel A, et al. Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles. J Extracell Vesicles. 2021;10(10):e12134. https://doi.org/10.1002/jev2.12134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shimamura Y, Furuhashi K, Tanaka A, et al. Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. Commun Biol. 2022;5(1):753. https://doi.org/10.1038/s42003-022-03712-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Heo JS, Choi Y, Kim HO. Adipose-derived mesenchymal stem cells promote M2 macrophage phenotype through exosomes. Stem Cells Int. 2019;2019:7921760. https://doi.org/10.1155/2019/7921760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen Z, Xue S, Zhang S, et al. Exosomes from donor-derived adipose mesenchymal stem cells prolong the survival of vascularized composite allografts. J Cell Physiol. 2021;236(8):5895–905. https://doi.org/10.1002/jcp.30274.

    Article  CAS  PubMed  Google Scholar 

  75. Xia L, Zhang C, Lv N, et al. AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages. Theranostics. 2022;12(6):2928. https://doi.org/10.7150/thno.69533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Das D, Akhtar S, Kurra S, et al. Emerging role of immune cell network in autoimmune skin disorders: An update on pemphigus, vitiligo and psoriasis. Cytokine Growth Factor Rev. 2019;45:35–44. https://doi.org/10.1016/j.cytogfr.2019.01.001.

    Article  CAS  PubMed  Google Scholar 

  77. Kuca-Warnawin E, Plebanczyk M, Ciechomska M, et al. Impact of adipose-derived mesenchymal stem cells (ASCs) of rheumatic disease patients on T helper cell differentiation. Int J Mol Sci. 2022;23(10):5317. https://doi.org/10.3390/ijms23105317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kim M, Lee S, Kim Y, et al. Human adipose tissue-derived mesenchymal stem cells attenuate atopic dermatitis by regulating the expression of MIP-2, miR-122a-SOCS1 axis, and Th1/Th2 responses. Front Pharmacol. 2018. https://doi.org/10.3389/fphar.2018.01175.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Park H, Son H, Choi M, et al. Adipose-derived stem cells attenuate atopic dermatitis-like skin lesions in NC/Nga mice. Exp Dermatol. 2019;28(3):300–7. https://doi.org/10.1111/exd.13895.

    Article  CAS  PubMed  Google Scholar 

  80. Choi EW, Shin IS, Song JW, et al. Transplantation of adipose tissue-derived mesenchymal stem cells prevents the development of lupus dermatitis. Stem Cells Dev. 2015;24(17):2041–51. https://doi.org/10.1089/scd.2015.0021.

    Article  CAS  PubMed  Google Scholar 

  81. Rokunohe A, Matsuzaki Y, Rokunohe D, et al. Immunosuppressive effect of adipose-derived stromal cells on imiquimod-induced psoriasis in mice. J Dermatol Sci. 2016;82(1):389. https://doi.org/10.1016/j.jdermsci.2015.12.007.

    Article  Google Scholar 

  82. Shi F, Guo L, Zhu W, et al. Human adipose tissue-derived MSCs improve psoriasis-like skin inflammation in mice by negatively regulating ROS. J Dermatol Treat. 2022;33(4):2129–36. https://doi.org/10.1080/09546634.2021.1925622.

    Article  CAS  Google Scholar 

  83. Guan J, Li Y, Lu F, et al. Adipose-derived stem cells ameliorate atopic dermatitis by suppressing the IL-17 expression of Th17 cells in an ovalbumin-induced mouse model. Stem Cell Res Ther. 2022;13(1):1–16. https://doi.org/10.1186/s13287-022-02774-7.

    Article  CAS  Google Scholar 

  84. Ho A, Kupper T. T cells and the skin: from protective immunity to inflammatory skin disorders. Nat Rev Immunol. 2019;19(8):490–502. https://doi.org/10.1038/s41577-019-0162-3.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang W, Feng Y-L, Pang C-Y, et al. Transplantation of adipose tissue-derived stem cells ameliorates autoimmune pathogenesis in MRL/lpr mice: modulation of the balance between Th17 and Treg. Z Rheumatol. 2019;78(1):82–8. https://doi.org/10.1007/s00393-018-0450-5.

    Article  CAS  PubMed  Google Scholar 

  86. Meligy F, Elgamal D, Abdelzaher L, et al. Adipose tissue-derived mesenchymal stem cells reduce endometriosis cellular proliferation through their anti-inflammatory effects. Clin Exp Reprod Med. 2021;48(4):322. https://doi.org/10.5653/cerm.2021.04357.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kamata M, Tada Y. Dendritic cells and macrophages in the pathogenesis of psoriasis. Front Immunol. 2022;13:941071. https://doi.org/10.3389/fimmu.2022.941071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lescoat A, Lecureur V, Varga J. Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: recent insights and therapeutic implications. Curr Opin Rheumatol. 2021;33(6):463–70. https://doi.org/10.1097/BOR.0000000000000835.

    Article  CAS  PubMed  Google Scholar 

  89. Okamura A, Matsushita T, Komuro A, et al. Adipose-derived stromal/stem cells successfully attenuate the fibrosis of scleroderma mouse models. Int J Rheum Dis. 2020;23(2):216–25. https://doi.org/10.1111/1756-185X.13764.

    Article  CAS  PubMed  Google Scholar 

  90. Lee J, Park L, Kim H, et al. Adipose-derived stem cells decolonize skin Staphylococcus aureus by enhancing phagocytic activity of peripheral blood mononuclear cells in the atopic rats. Korean J Physiol Pharmacol. 2022;26(4):287–95. https://doi.org/10.4196/kjpp.2022.26.4.287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Luk F, Carreras-Planella L, Korevaar SS, et al. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol. 2017;8:1042. https://doi.org/10.3389/fimmu.2017.01042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ma K, Du W, Wang X, et al. Multiple functions of B cells in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2019;20(23):6021. https://doi.org/10.3390/ijms20236021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Park M-J, Kwok S-K, Lee S-H, et al. Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. Cell Transplant. 2015;24(11):2367–77. https://doi.org/10.3727/096368914X685645.

    Article  PubMed  Google Scholar 

  94. Kim T, Kim S, Lee M. The origin of skin dendritic cell network and its role in psoriasis. Int J Mol Sci. 2017;19(1):42. https://doi.org/10.3390/ijms19010042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cai Y, Li J, Jia C, et al. Therapeutic applications of adipose cell-free derivatives: a review. Stem Cell Res Ther. 2020;11(1):312. https://doi.org/10.1186/s13287-020-01831-3.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Serratrice N, Bruzzese L, Magalon J, et al. New fat-derived products for treating skin-induced lesions of scleroderma in nude mice. Stem Cell Res Ther. 2014;5(6):1–11. https://doi.org/10.1186/scrt528.

    Article  CAS  Google Scholar 

  97. Maria A, Toupet K, Maumus M, et al. Human adipose mesenchymal stem cells as potent anti-fibrosis therapy for systemic sclerosis. J Autoimmun. 2016;70:31–9. https://doi.org/10.1016/j.jaut.2016.03.013.

    Article  CAS  PubMed  Google Scholar 

  98. Chen B, Wang X, Long X, et al. Supportive use of adipose-derived stem cells in cell-assisted lipotransfer for localized scleroderma. Plast Reconstr Surg. 2018;141(6):1395–407. https://doi.org/10.1097/PRS.0000000000004386.

    Article  CAS  PubMed  Google Scholar 

  99. Rozier P, Bony C, Sabatier F, et al. Extracellular vesicles are more potent than adipose mesenchymal stromal cells to exert an anti-fibrotic effect in an in vitro model of systemic cclerosis. Int J Mol Sci. 2021;22(13):6837. https://doi.org/10.3390/ijms22136837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Jiang W, Lin J, Jiang S, et al. Adipose-derived stem cell-enriched lipotransfer reverses skin sclerosis by suppressing dermal inflammation. Plast Reconstr Surg. 2022;150(3):578–87. https://doi.org/10.1097/PRS.0000000000009435.

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  101. Wang H, Sun E, Zhao R, et al. Adipose-derived stem cells attenuate skin fibrosis and improve fat retention of localized scleroderma mouse model. Plast Reconstr Surg. 2022. https://doi.org/10.1097/PRS.0000000000009796.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lai K, Zeng K, Zeng F, et al. Allogeneic adipose-derived stem cells suppress Th17 lymphocytes in patients with active lupus in vitro. Acta Biochim Biophys Sin. 2011;43(10):805–12. https://doi.org/10.1093/abbs/gmr077.

    Article  CAS  PubMed  Google Scholar 

  103. Choi E, Shin I, Park S, et al. Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum. 2012;64(1):243–53. https://doi.org/10.1002/art.33313.

    Article  CAS  PubMed  Google Scholar 

  104. He X, Zhang Y, Zhu A, et al. Suppression of interleukin 17 contributes to the immunomodulatory effects of adipose-derived stem cells in a murine model of systemic lupus erythematosus. Immunol Res. 2016;64(5–6):1157–67. https://doi.org/10.1007/s12026-016-8866-y.

    Article  CAS  PubMed  Google Scholar 

  105. Choi E, Lee M, Song J, et al. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE. Sci Rep. 2016;6:38237. https://doi.org/10.1038/srep38237.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  106. Wei S, Xie S, Yang Z, et al. Allogeneic adipose-derived stem cells suppress mTORC1 pathway in a murine model of systemic lupus erythematosus. Lupus. 2019;28(2):199–209. https://doi.org/10.1177/0961203318819131.

    Article  CAS  PubMed  Google Scholar 

  107. Jee MK, Im YB, Choi JI, et al. Compensation of cATSCs-derived TGFβ1 and IL10 expressions was effectively modulated atopic dermatitis. Cell Death Dis. 2013;4:e497. https://doi.org/10.1038/cddis.2013.4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Shin T-H, Lee B-C, Choi SW, et al. Human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis via regulation of B lymphocyte maturation. Oncotarget. 2017;8(1):512–22. https://doi.org/10.18632/oncotarget.13473.

    Article  PubMed  Google Scholar 

  109. Cho BS, Kim JO, Ha DH, et al. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cell Res Ther. 2018;9(1):187. https://doi.org/10.1186/s13287-018-0939-5.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  110. Shin K, Ha D, Kim J, et al. Exosomes from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing de novo synthesis of ceramides in atopic dermatitis. Cells. 2020;9(3):680. https://doi.org/10.3390/cells9030680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kim S, Yoon T, Na J, et al. Mesenchymal stem cells and extracellular vesicles derived from canine adipose tissue ameliorates inflammation, skin barrier function and pruritus by reducing JAK/STAT signaling in atopic dermatitis. Int J Mol Sci. 2022;23(9):4868. https://doi.org/10.3390/ijms23094868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yin X, Zhu R, Zhuang C, et al. Immunoregulatory effect of adipose mesenchymal stem cells on peripheral blood lymphocytes in psoriasis vulgaris patients. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018;40(6):790–6. https://doi.org/10.3881/j.issn.1000-503X.10646.

    Article  PubMed  Google Scholar 

  113. Zografou A, Tsigris C, Papadopoulos O, et al. Improvement of skin-graft survival after autologous transplantation of adipose-derived stem cells in rats. J Plast Reconstr Aesthetic Surg JPRAS. 2011;64(12):1647–56. https://doi.org/10.1016/j.bjps.2011.07.009.

    Article  CAS  Google Scholar 

  114. Roemeling-van Rhijn M, Khairoun M, Korevaar S, et al. Human bone marrow- and adipose tissue-derived mesenchymal stromal cells are immunosuppressive in vitro and in a humanized allograft rejection model. J Stem Cell Res Ther. 2013. https://doi.org/10.4172/2157-7633.S6-001.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wang J, Hao H, Huang H, et al. The effect of adipose-derived stem cells on full-thickness skin grafts. BioMed Res Int. 2016. https://doi.org/10.1155/2016/1464725.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hu J, Kim B, Yu N, et al. Impact of injection frequency of adipose-derived stem cells on allogeneic skin graft survival outcomes in mice. Cell Transplant. 2021. https://doi.org/10.1177/09636897211041966.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Lim J, Ryu D, Kim T, et al. CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model. Stem Cell Res Ther. 2020;11(1):1–12. https://doi.org/10.1186/s13287-020-01768-7.

    Article  CAS  Google Scholar 

  118. Wang Y-C, Chen R-F, Brandacher G, et al. The suppression effect of dendritic cells maturation by adipose-derived stem cells through TGF-β1 related pathway. Exp Cell Res. 2018;370(2):708–17. https://doi.org/10.1016/j.yexcr.2018.07.037.

    Article  CAS  PubMed  Google Scholar 

  119. Suzuka T, Kotani T, Saito T, et al. Therapeutic effects of adipose-derived mesenchymal stem/stromal cells with enhanced migration ability and hepatocyte growth factor secretion by low-molecular-weight heparin treatment in bleomycin-induced mouse models of systemic sclerosis. Arthritis Res Ther. 2022;24(1):228. https://doi.org/10.1186/s13075-022-02915-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res. 2019;25(18):5449–57. https://doi.org/10.1158/1078-0432.CCR-18-1543.

    Article  CAS  PubMed  Google Scholar 

  121. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol. 2018;9:978. https://doi.org/10.3389/fimmu.2018.00978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Harizi H. Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology. Cell Mol Immunol. 2013;10(3):213–21. https://doi.org/10.1038/cmi.2013.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lu X, Zhao Y, et al. TSG-6 released from adipose stem cells-derived small extracellular vesicle protects against spinal cord ischemia reperfusion injury by inhibiting endoplasmic reticulum stress. Stem Cell Res Ther. 2022;13(1):291. https://doi.org/10.1186/s13287-022-02963-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28. https://doi.org/10.1038/nrm.2017.125.

    Article  CAS  PubMed  Google Scholar 

  125. Cavallo C, Merli G, Borzì RM, et al. Small extracellular vesicles from adipose derived stromal cells significantly attenuate in vitro the NF-κB dependent inflammatory/catabolic environment of osteoarthritis. Sci Rep. 2021;11(1):1053. https://doi.org/10.1038/s41598-020-80032-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):6977. https://doi.org/10.1126/science.aau6977.

    Article  CAS  Google Scholar 

  127. Ramos-E-Silva M, Secchin P, Trope B. The life-threatening eruption in HIV and immunosuppression. Clin Dermatol. 2020;38(1):52–62. https://doi.org/10.1016/j.clindermatol.2019.10.014.

    Article  PubMed  Google Scholar 

  128. Liu C, Gu L, Ding J, et al. Autophagy in skin barrier and immune-related skin diseases. J Dermatol. 2021;48(12):1827–37. https://doi.org/10.1111/1346-8138.16185.

    Article  CAS  PubMed  Google Scholar 

  129. Scuderi N, Ceccarelli S, Onesti M, et al. Human adipose-derived stromal cells for cell-based therapies in the treatment of systemic sclerosis. Cell Transplant. 2013;22(5):779–95. https://doi.org/10.3727/096368912X639017.

    Article  PubMed  Google Scholar 

  130. Khanna D, Caldron P, Martin R, et al. Adipose-derived regenerative cell transplantation for the treatment of hand dysfunction in systemic sclerosis: a randomized clinical trial. Arthritis Rheumatol Hoboken NJ. 2022. https://doi.org/10.1002/art.42133.

    Article  Google Scholar 

  131. Comella K, Parlo M, Daly R, et al. First-in-man intravenous implantation of stromal vascular fraction in psoriasis: a case study. Int Med Case Rep J. 2018;11:59–64. https://doi.org/10.2147/IMCRJ.S163612.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Park K, Han H, Park J, et al. Exosomes derived from human adipose tissue-derived mesenchymal stem cells for the treatment of dupilumab-related facial redness in patients with atopic dermatitis: a report of two cases. J Cosmet Dermatol. 2022;21(2):844–9. https://doi.org/10.1111/jocd.14153.

    Article  PubMed  Google Scholar 

  133. Rosa I, Romano E, Fioretto BS, et al. Adipose-derived stem cells: pathophysiologic implications vs therapeutic potential in systemic sclerosis. World J Stem Cells. 2021;13(1):30–48. https://doi.org/10.4252/wjsc.v13.i1.30.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Daumas A, Magalon J, Jouve E, et al. Adipose tissue-derived stromal vascular fraction for treating hands of patients with systemic sclerosis: a multicentre randomized trial Autologous AD-SVF versus placebo in systemic sclerosis. Rheumatol Oxf Engl. 2022;61(5):1936–47. https://doi.org/10.1093/rheumatology/keab584.

    Article  CAS  Google Scholar 

  135. Li M, Jiang Y, Hou Q, et al. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther. 2022;13(1):146. https://doi.org/10.1186/s13287-022-02822-2.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Wan S, Fu X, Ji Y, et al. FAK- and YAP/TAZ dependent mechanotransduction pathways are required for enhanced immunomodulatory properties of adipose-derived mesenchymal stem cells induced by aligned fibrous scaffolds. Biomaterials. 2018;171:107–17. https://doi.org/10.1016/j.biomaterials.2018.04.035.

    Article  CAS  PubMed  Google Scholar 

  137. Farrokhi S, Sotoodehnejadnematalahi F, Fathollahi A, et al. The immunomodulatory potential of murine adipose-derived mesenchymal stem cells is enhanced following culture on chitosan film. Tissue Cell. 2022;74:101709. https://doi.org/10.1016/j.tice.2021.101709.

    Article  CAS  PubMed  Google Scholar 

  138. Liu H, Zhang M, Shi M, et al. Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3. Stem Cell Res Ther. 2021;12(1):338. https://doi.org/10.1186/s13287-021-02410-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Granel B, Daumas A, Jouve E, et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2015. https://doi.org/10.1136/annrheumdis-2014-205681.

    Article  PubMed  Google Scholar 

  140. Del Papa N, Di Luca G, Sambataro D, et al. Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. Cell Transplant. 2015. https://doi.org/10.3727/096368914X685636.

    Article  PubMed  Google Scholar 

  141. Onesti M, Fioramonti P, Carella S, et al. Improvement of mouth functional disability in systemic sclerosis patients over one year in a trial of fat transplantation versus adipose-derived stromal cells. Stem Cells Int. 2016. https://doi.org/10.1155/2016/2416192.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Guillaume-Jugnot P, Daumas A, Magalon J, et al. Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatol Oxf Engl. 2016;55(2):301–6. https://doi.org/10.1093/rheumatology/kev323.

    Article  Google Scholar 

  143. Song J, Volz S, Liodaki M, et al. Stem cells therapy: the future in the management of systemic sclerosis? A case report. Hell J Nucl Med. 2017;20:164.

    PubMed  Google Scholar 

  144. Virzì F, Bianca P, Giammona A, et al. Combined platelet-rich plasma and lipofilling treatment provides great improvement in facial skin-induced lesion regeneration for scleroderma patients. Stem Cell Res Ther. 2017;8(1):1–11. https://doi.org/10.1186/s13287-017-0690-3.

    Article  CAS  Google Scholar 

  145. Almadori A, Griffin M, Ryan C, et al. Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis. PLoS ONE. 2019;14(7):e0218068. https://doi.org/10.1371/journal.pone.0218068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Park Y, Lee Y, Koh J, et al. Clinical efficacy and safety of injection of stromal vascular fraction derived from autologous adipose tissues in systemic sclerosis patients with hand disability: a proof-of-concept trial. J Clin Med. 2020;9:9. https://doi.org/10.3390/jcm9093023.

    Article  CAS  Google Scholar 

  147. Wang C, Long X, Si L, et al. A pilot study on ex vivo expanded autologous adipose-derived stem cells of improving fat retention in localized scleroderma patients. Stem Cells Transl Med. 2021;10(8):1148–56. https://doi.org/10.1002/sctm.20-0419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. De Jesus M, Santiago J, Trinidad C, et al. Autologous adipose-derived mesenchymal stromal cells for the treatment of psoriasis vulgaris and psoriatic arthritis: a case report. Cell Transplant. 2016;25(11):2063–9. https://doi.org/10.3727/096368916X691998.

    Article  PubMed  Google Scholar 

  149. Seetharaman R, Mahmood A, Kshatriya P, et al. Mesenchymal stem cell conditioned media ameliorate psoriasis vulgaris: a case study. Case Rep Dermatol Med. 2019. https://doi.org/10.1155/2019/8309103.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yao D, Ye S, He Z, et al. Adipose-derived mesenchymal stem cells (AD-MSCs) in the treatment for psoriasis: results of a single-arm pilot trial. Ann Transl Med. 2021;9:22. https://doi.org/10.21037/atm-21-5028.

    Article  CAS  Google Scholar 

  151. Ranjbar A, Hassanzadeh H, Jahandoust F, et al. Allogeneic adipose-derived mesenchymal stromal cell transplantation for refractory lupus nephritis: results of a phase I clinical trial. Curr Res Transl Med. 2022;70:2. https://doi.org/10.1016/j.retram.2021.103324.

    Article  CAS  Google Scholar 

  152. Moll G, Ankrum JA, Kamhieh-Milz J, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019;25(2):149–63. https://doi.org/10.1016/j.molmed.2018.12.006.

    Article  PubMed  Google Scholar 

  153. Guillaume VGJ, Ruhl T, Boos AM, et al. The crosstalk between adipose-derived stem or stromal cells (ASC) and cancer cells and ASC-mediated effects on cancer formation and progression-ASCs: safety hazard or harmless source of tropism? Stem Cells Transl Med. 2022;11(4):394–406. https://doi.org/10.1093/stcltm/szac002.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Varghese J, Griffin M, Mosahebi A. Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Res Ther. 2017;8:1. https://doi.org/10.1186/s13287-017-0483-8.

    Article  CAS  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81801932) and the Natural Science Foundation of Guangdong Province (2022A1515011232).

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  1. Tianyi Sun and Cheng Zhou contributed equally to this study and should be considered as co-first authors.

Authors and Affiliations

  1. The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China

    Tianyi Sun, Cheng Zhou, Feng Lu, Ziqing Dong, Jianhua Gao & Bin Li

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Contributions

All authors contributed to the conception and the main idea of the work. TS and CZ drafted the main text, figures, and tables. BL, JG, FL and ZD supervised the work and provided the comments and additional scientific information. TS and CZ also reviewed and revised the text. All authors read and approved the final manuscript.

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Supplementary Information

Additional file 1: Table S1

. Preclinical studies of the immunomodulatory effect of ASCs in immune-related skin disease. This table summarizes the preclinical applications of the immunomodulatory effect of ASCs in immune-related skin diseases, which helps to understand the recent research directions.

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Sun, T., Zhou, C., Lu, F. et al. Adipose-derived stem cells in immune-related skin disease: a review of current research and underlying mechanisms. Stem Cell Res Ther 15, 37 (2024). https://doi.org/10.1186/s13287-023-03561-8

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Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512