Skip to main content

Application of adipose-derived stem cells in photoaging: basic science and literature review


Photoaging is mainly induced by continuous exposure to sun light, causing multiple unwanted skin characters and accelerating skin aging. Adipose-derived stem cells(ADSCs) are promising in supporting skin repair because of their significant antioxidant capacity and strong proliferation, differentiation, and migration ability, as well as their enriched secretome containing various growth factors and cytokines. The identification of the mechanisms by which ADSCs perform these functions for photoaging has great potential to explore therapeutic applications and combat skin aging. We also review the basic mechanisms of UV-induced skin aging and recent improvement in pre-clinical applications of ADSCs associated with photoaging. Results showed that ADSCs are potential to address photoaging problem and might treat skin cancer. Compared with ADSCs alone, the secretome-based approaches and different preconditionings of ADSCs are more promising to overcome the current limitations and enhance the anti-photoaging capacity.


The skin is our largest organ by weight and extent. It not only protects us from environment factors, but also synthesizes, processes, and metabolizes structural biomolecules such as lipid, protein, and glycan [1]. As a multifaceted organ, the skin also has sensory function and exerts pivotal role in esthetic appearance.

Skin aging is a culmination of intrinsic and extrinsic elements, which result in decreased structural integrity and disruption of normal physiological function. Extrinsic factors such as solar radiation, cigarette [2], or other pollution factors could induce skin aging. Among them, exposure to UV (long wavelength ultraviolet radiations (UVA) and medium wavelength ultraviolet radiations (UVB) exposure) radiation (UVR) is the major source of extrinsic skin aging, which is also known as photoaging.

Photoaging accounts for nearly 80% of facial aging [3]. It is characterized by fine wrinkles, dryness, laxity, rough texture, decreased elasticity, impaired wound healing, and benign and malignant growths [47]. It also exaggerates or accelerates the destruction of physiologic structure and the loss of various protective capacities, remaining an unsolved problem worldwide. In daily life, the condition of the skin is an important element used to estimate people’s age and health [8]. With the development of modern society and increasing life expectancy, maintaining a youthful and vigorous appearance is highly desired, which has facilitated the dramatic growth of the cosmeceutical industry.

Plant extracts [9], antioxidants [10], growth factors and cytokines [11], and stem cells [12] can be used to treat photoaging. Recently, stem cell therapy has attracted great attention because it can improve the regeneration ability of various tissues [1214]. It is reported that stem cells and their derivatives are able to ameliorate skin conditions to some extent [15]. People are quite interested in the application of adipose-derived stem cells (ADSCs) in fields of dermatological and esthetic medicine, because they can be isolated and expanded easily and have clear multi-lineage differentiation [1618]. Furthermore, it is reported that ADSCs can synthesize and secrete a lot of biologically active substances, mainly including antioxidants and cytokines that can be extracted and stored safely for a long time [19]. There are several reports in the past illustrated that ADSCs and their secretome can treat photoaging both in vivo and in vitro [2022].

ADSCs improve conditions of photoaged skin, but their anti-photoaging mechanism is still elusive. The mechanism of ADSCs contributing to inflammation, wound healing, cancer has already been reviewed [2325]. ADSCs against photoaging may share same molecular interactions and pathways with them because photoaging is related to inflammation, is similar to skin wound progress [26] and may result in skin cancer. This article reviews the mechanisms by which skin aging prevails following exposure to UV radiation as well as the recent research developments on the anti-photoaging effects of ADSCs and ADSC secretome. An overview of established and emerging treatment capacity of ADSCs and ADSC secretome, which have been proven or at least have demonstrated potential to inhibit or recupe- rate the unwanted clinical manifestations of photoaging, will be explored. Current research has come up with many new fascinating approaches to modify ADSCs or combine them with other materials to improve their treating ability. These novel ideas will be rendered in the manuscript(Table 1).

Table 1 Different preconditionings of ADSCs and their functions

Molecular, cellular, and histological alternation of skin in photoaging

The aged condition of photoaged skin is induced by molecular, cellular, and histological alternation and damage to the skin structure. UVR accelerates skin aging by causing direct and indirect damage to multiple skin structures. The simplified diagram of the general model of UV-induced skin aging is shown in Fig. 1.

Fig. 1

UV-induced skin aging model

Direct damage induced by UVB

Direct damage is mainly caused by UVB. A considerate part of UVB is absorbed in the stratum corneum, and the rest part of UVB is absorbed in epidermal cells [27], inducing biological alternation in DNA, RNA, protein. DNA alternation is the most crucial one because accumulations of DNA damage can cause cell senescence and apoptosis. What is more, DNA alternation can damage the apoptotic capacity of skin cells and increase the possibility of malignancies [28].

Reactive oxygen species (ROS)-related indirect damage

UVR can also cause physiological damage and accelerate skin aging indirectly via endogenous or exogenous photosensitizers that absorb solar radiations. The progress generates free radicals and ROS that induce skin inflammation. The inflammation progress can produce ROS by phagocytic cells and polynuclear lymphocytes [29]. Besides, inflammatory progress and ROS induce oxidative damage to DNA, cellular proteins, lipids, and carbohydrates [42], which in turn leads to more ROS production, resulting in a negative feedback loop [43]. Lipids are important targets of ROS and ROS can react with them in the cellular membrane to produce more reactive oxygen intermediates [44]. In addition, damage to the membrane lipids can induce structural damage in cell, cellular components leakage and eventually cell death [42].

Besides, ROS can cause indirect damage to DNA by oxidation products. For example, singlet oxygen, as the product of ROS, can turn guanine into 8-oxoguanine [45]. Low level of ROS can lead to mutation, medium levels can induce cell cycle arrest, and high levels can result in apoptosis and cell death [46]. UVR can also accelerate telomere shortening and lead to activation of p53. P53 is a tumor suppressor protein that can induce cell cycle arrest and apoptosis [47]. The apoptosis of stem cells in the basal layer induced by UVR is suggested to cause epidermal atrophy, slow wound healing, and depigmented pseudoscars [48]. On the other hand, some studies illustrated that UV-induced cell apoptosis exerts a protective function in UV injury [4951]. After acute DNA damage, fibroblasts are more likely to undergo senescence rather than apoptosis and the dermis of photoaged skin does contain senescent fibroblasts that express senescence-associated β -galactosidase(SA- β- Gal) positivity [52]. Senescence reduces cell metabolic activity. Thus, the synthesis of elastic fibers and collagen fibers in the dermis is reduced. It finally results in weakened elasticity, and wrinkles of the skin [6, 53]. The greater melanin produced by senescent melanocytes could be related to the permanent “tan” noted in photoaged skin of people with darker complexions [54]. However, the molecular details associated with freckling, lentigines, and other pigment alternations of photoaged skin remain elusive [48].

Nevertheless, there are antioxidants in our body to maintain the oxygen homeostasis. Glutathione peroxidase (GPx) is the most essential antioxidant enzymes that remove free radicals. GPx can facilitate a reaction with the thiol-group of glutathione to eliminate singlet oxygen, hydrogen peroxide, and other peroxides [55]. Superoxide dismutase (SOD) and catalase can also remove superoxide radicals or hydrogen peroxide. However, the photoaged skin is reported to have reduced levels of natural enzymatic and non-enzymatic antioxidants [56], together with increased neutrophil infiltration and inflammation [57].

Extracellular matrix(ECM) degradation

Lots of damage happens in the connective tissue, which is also known as the dermal ECM. Collagen, elastin, and glycosaminoglycans (GAGs) are the most critical and abundant substance of the dermal ECM. Features of photoaged skin include the accumulation of abnormal elastin fibers and GAGs, as well as collagen damage and reduction [58]. UVR-induced ROS stimulates the matrix-degenerating metalloproteases (MMPs) synthesis [42] that can induce the degradation of ECM. Alternatively, ROS can damage ECM indirectly by the oxidation products of DNA, lipid, and protein. Subsequently, several intracellular kinases such as mitogen-activated protein kinase (MAPK) and extracellular regulated protein kinases (ERK) will become activated. Ultimately, transcription factor complexes activator protein 1 (AP-1) and nuclear factor-kappaB (NF- κB) will be produced and activate MMP transcription. Therefore, ROS can increase collagen degradation and aberrant elastin accumulation by altering gene expression pathways. Besides, heme oxygenase-1 (HO-1) can be induced by activated AP-1 and NF- κB [59]. It can elevate free irons concentration and promote further ROS production through Fenton reaction [60]. Activated NF- κB in fibroblasts can induce the transcription of proinflammatory cytokines interleukin (IL)-1, IL-6, vascular endothelial growth factor (VEGF), and tumor necrosis factor- α (TNF- α) [28], thus stimulating the inflammatory cells infiltration. These qualitative and quantitative alternations of ECM eventually lead to decreased tensile strength and recoil capacity, as well as wrinkle formation, dryness, wound healing damage, and an increase in brittleness. [61].

ADSCs mechanisms in photoaging

Oxidative stress

Oxidative stress is a major cause of photoaging [62]. It is defined as the imbalance between ROS and antioxidants. Some studies support the protective function of ADSCs and secretome of ADSCs during oxidative injury (Fig. 2). For example, HGF (hepatocyte growth factor) is reported to protect the retinal pigment epithelium [63], the heart [64], and the liver [65] against oxidative stress. VEGF leads to great decrease of renal ischemia-reperfusion (I/R)-induced oxidative stress in mice [66]. IL-6 attenuates oxidative stress by activating the downstream signal transducer and activator of transcription 3 (STAT3), nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant pathway and upregulating manganese superoxide dismutase (Mn-SOD) [67, 68]. However, TNF- α can induce ROS generation in retinal pigment epithelial [69]. It may be induced by proinflammatory effect of TNF- α. In addition, it is reported that conditioned medium from ADSCs (ADSC-CM) and exosome of ADSCs(ADSC-Exo) protect alveolar epithelial cells [70], keratinocytes [71], human dermal fibroblasts (HDF)s [7173], dermal papilla cells [19] against oxidative stress. Specifically, the antioxidant capacity of the ADSC-CM is 1.8 times higher than that of the standard medium [74]. Mitochondrial-derived reactive oxygen species (mtROS) is associated with inflammasome activation [75]. Elevated ROS levels will lead to increase in mitochondrial lipid peroxidation. It is reported that ADSCs are able to suppressing mtROS levels in stressed recipient cells [76]. However, glycoprotein A repetitions predominant (GARP) silencing in ADSCs increased their activation of transforming growth factor- β (TGF- β) that augmented the levels of mtROS [30].

Fig. 2

Schematic representation of the effects of ADSCs on photoaging

ADSCs fight against oxidative stress through higher antioxidant enzymes expression such as GPx [72], SOD [72, 77], catalase [78]. They also upregulate antioxidant response element such as phase II gene HO-1 [71] and suppress the production of myeloperoxidase (MPO) [79] that can induce lipid peroxidation, reactive chlorinating and brominating species, NADPH oxidase (NOX)1 and 4 [80], and malondialdehyde (MDA), the most commonly used marker for lipid peroxidation [77, 81, 82]. ADSCs depend on Nrf2 to downregulate NOX1 and NOX4 and upregulate HO-1 [80]. In wound beds, overexpressed Nrf2 of ADSC-Exo promoted granulation tissue formation, angiogenesis, increased the expression of growth factor, and decreased proteins related to inflammation and oxidation [31]. However, the specific mechanism of how ADSCs react on these enzymes and the precise pathway is yet to be determined.

DNA damage

One of the major types of oxidative DNA damage products induced by free radicals is 8-hydrox-2 -deoxyguanosine (8-OHdG), and ADSCs can significantly suppress the 8-OHdG levels in the rat model [83]. Attenuated level of oxidative stress definitely contribute to reducing DNA damage. Besides, ADSCs can downregulate the expression of phosphorylated histone family 2A variant (γH2AX) protein, which responses to DNA double strand breaks in irradiated cells [84]. Besides, ADSCs with overexpressed hypoxia-inducible factor (HIF)1 α can decrease oxidative stress and subsequent DNA damage efficiently [32]. Reduced DNA damage level can ameliorate oxidative stress in turn and exert protective capacity.

It is generally accepted that UV-induced apoptosis is generated by UV-mediated DNA damage [85]. Therefore, decrease of DNA damage has an important impact on apoptosis inhibition. Studies showed that ADSC-CM inhibited the apoptotic cell death induced by UVB and it is illustrated by the reduced sub-G1 phase of HDF [86]. Furthermore, ADSCs inhibit apoptosis by transporting and regulating proteins. For example, ADSCs-Exo not only remarkably reduced hypoxia and serum deprivation (H/SD)-induced apoptosis in murine long bone osteocyte (MLO)-Y4 cells [87], but also promoted cell proliferation and migration of human keratinocytes (HaCaT) cells, and decreased cell apoptosis of HaCaT cells, both via upregulating the radio of B cell lymphoma-2 (Bcl-2)/Bcl-2 associated X(Bax) [88]. In a skin flap transplantation model, H2O2-treated ADSC-Exo group had fewer apoptosis cells, resulting in higher mean percentage of skin flap survival area after I/R injury [33]. In the mean time, apoptotic biomarkers (Bax/caspase-3/poly ADP-ribose polymerase) were significantly reduced through the combination of ADSC-Exo and ADSCs in another acute kidney I/R injury model [89]. In addition, hypoxia-treated ADSCs downregulated the expression of pro-apoptotic gene such as CASP9, BAX, BID, and BLK and upregulated the expression of anti-apoptotic gene BCL-2 in hepatocytes [90]. Last but not the least, it is reported that ADSCs can convert necrotic or late apoptotic cells to early apoptotic cells in photoaged fibroblasts depending on paracrine capability [22].

Senescence is a state of stable cell growth arrest in the G1-phase [91]. The major inducer of the cell cycle arrest is p21, which is downregulated by ADSCs in fibroblasts [34]. ADSC-CM treatment decreased cellular senescence induced by UVB and SA- β-Gal in HDFs [92], which can be explained by the reduced oxidative stress and attenuated DNA damage based on the oxidative stress theory. Besides, overexpression of VEGF in ADSCs promoted the function of ADSCs on downregulating SA- β-Gal and inhibiting senescence in fibroblasts injured by UVR [34]. It is reported that p53 were significantly downregulated in hematopoietic stem cells (HSCs) cultured on ADSCs, which may contribute to the capacity of ADSCs for inhibiting apoptosis and senescence [93].

Extracellular matrix

Collagen is a primary element in ECM. When exposed to UVR, it will be degraded mostly because of increased activity of MMPs caused by ROS production [71]. The molecular interaction between fibroblasts and the ECM is obstructed due to the decrease of collagen, which eventually results in the damage of fibroblast function and further collagen decrease [94]. It is reported that ADSC-Exo can promote the migration ability of HDFs irradiated by UVB [95], suppress the overexpression of MMP-1 [95, 96], MMP-2 [95, 97], MMP-3 [95, 96], MMP-9 [92, 95] and MMP-13 [97] caused by UVB. Moreover, it can increase collagen I, II, III, and V and elastin expression [92, 95]. Inhibitor of metalloproteinase (TIMP)-1 and TGF- β1 that are critical factors contributing to suppressing MMP and synthesizing ECM were upregulated in extracellular vesicles from ADSCs (ADSC-EV)-treated HDFs after UVB exposure [95]. Injection of ADSCs in nude mice promoted collagen density, fibroblast number, and skin thickness [35]. Besides, procollagen type I protein that accounts for the synthesis of dermal collagen increased noticeably [98].

Elastic fibers accumulate abnormally in sun-aged skin. Subcutaneous injection of ADSCs significantly decreased elastosis and resulted in new oxytalan elastic fiber production in the papillary dermis. It also promoted the tridimensional architecture in the reticular dermis and a richer microvascular bed structure [99], concomitant with activation of cathepsin K and matrix MMP 12 [100].

Hyaluronic acid (HA) is one type of GAGs, which decreases in photoaged skin [101]. HA composes proteoglycan (PG) aggregates that are large compound of HA and PGs bound to HA. Their combination with other matrix proteins, like collagen networks, leads to the formation of supermolecular structures and increases the hardness of the tissue [102]. HA production and degradation modulation are important for ECM homeostasis maintenance. ADSCs produce TGF- β1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF)-BB, which promote the expression of HA synthase in fibroblast [103].

ECM is secreted mainly by fibroblasts. As already mentioned, ADSC-CM reduced cellular senescence and apoptosis in irradiated HDFs. And it is demonstrated that ADSC-CM plays a protective role in preventing HDFs from extrinsic aging damages. Among them, PDGF-AA may promote the function of ADSC-CM with some other elements [92]. Moreover, in in vitro and in vivo experiments, the Wnt/ β-catenin signaling pathway can promote the activation of skin fibroblasts through the transplantation of ADSCs. The combination of ADSCs and fractional CO2 laser can further strengthen the dermal fibroblast activity [21]. ADSC-Exos can be absorbed by fibroblasts and enhance their ability to proliferate and migrate, as well as promote the deposition of collagen type I and III through the PI3K/Akt signaling pathway [104]. ADSC-CM is currently under clinical study to treat skin aging due to its ability to promote fibroblast migration and collagen synthesis [105].

It is also found that ADSC-CM can suppress the activation of the MAPK [71] and ERK1 [73] signaling pathway induced by UVB, promote TGF- β, suppress IL-6, and inhibit activation of AP-1 and NF- κB [71] signaling molecules induced by UVB. They all showed that in the early UVB responsive stage, ADSC-CM can regulate relative molecules to exert its function.

Some research suggested that UVB causes photoaging by changing skin stem cell niches that are mainly composed of ECM and other regulatory factors [106]. Transferred ADSCs can influence the BMP signaling pathway and differentiate into skin stem cells to remodel the niches, as a supplement to the paracrine mechanism of the protective function of ADSCs.

Inflammatory response

Attenuated oxidative stress is concomitant with reduced inflammation because oxidative stress occurs after UVR results in glucocorticoid resistance and the subsequent progress of skin inflammation [107]. What is more, accumulation of senescent cells causes the increase of proinflammatory molecules such as IL-6, IL-8, and TNF- α that are closely related to chronic inflammation [24]. ADSC can reduce senescent cells and may alleviate the inflammatory responses in this way.

Besides, ADSCs can mediate inflammatory response directly. ADSCs are able to ameliorate inflammatory and immune responses [108], which is illustrated in several types of cells, such as natural killer T cells [109], regulatory T cells [110], T cells [111], and dendritic cells [112]. In the injured area, ADSCs were aggregated and relocate by increasing CXCR-4 expression. What is more, in this way, the inflammatory phenotype of immune cells will be transferred into anti-inflammatory cells [24]. In vitro, ADSC-Exo had an inhibitory effect on the differentiation of CD4+ or CD8+ T cells toward effector or memory cell phenotypes, regulated by anti-CD3/CD2/ CD28 stimulation[113]. Moreover, ADSCs increased macrophage recruitment and promoted macrophage polarization toward anti-inflammatory M2 phenotypes by secreting TGF- β, IL-1 β, and IL-6 [114, 115]. In activated macrophages, the generation of pro-inflammatory cytokines like TNF- α and IL-12 and the trend of apoptosis can be suppressed by ADSCs [116]. What is more, regulatory T cells’ differentiation and proliferation are suppressed by ADSCs while regulatory T cells’ are enhanced. It seems that the anti-inflammatory function of ADSCs is associated with the phenotypic differentiation of T cells [116].

In fact, ADSC secretome includes various proinflammatory and anti-inflammatory components including growth differentiation factor (GDF)11, TGF- β, bFGF, VEGF, toll-like receptor (TLR)2, TLR4, IL-10, and MMP [117122]. The final outcome is determined by the balance of these anti-inflammatory and pro-inflammatory molecules. In pig models with both I/R and hemihepatectomy, ADSCs transplantation successfully improved high concentrations of pro-inflammatory cytokines such as IL-1 β, IL-6, and TNF- α induced histopathological injury [123]. Moreover, ADSCs promoted the expression of IL-10, regenerative molecules like HGF, Cyclin D1, proliferatory molecules such as VEGF, angiotensin (ANG)-1, and ANG-2 [123]. Recently, microRNA (miR)-146a-transfected ADSCs and the secretome containing abundant miR greatly demonstrated their angiogenic and anti-inflammatory abilities [36].

Furthermore, it is reported that ADSCs can modulate the UVB-induced inflammatory signaling pathways. UVB improved the inflammatory molecules expression such as phospho-NF- κB p65, nod-like receptor protein (Nlrp)3, vascular cell adhesion molecule (VCAM)-1, COX2, and TNF- α, while ADSCs transplantation repressed the overexpression of these genes [97].

Inflammation and apoptosis are considered to be the main features of skin photoaging [124, 125], while ADSCs can suppress this inflammatory progress. These findings about ADSCs could provide effective strategies to deal with photoaging.

Potential applications of ADSCs and ADSC secretome in photoaging and photocarcinogenesis

Recent clinical research suggested that ADSCs can be applied to ameliorate multiple skin conditions, because they can stimulate injured skin to regenerate [126]. The efficacy of ADSCs under multiple skin aging conditions have been presented and confirmed and are significant in potential therapeutic applications development, such as anti-wrinkling, dermal thickness improvement, skin whitening, UV-induced skin injury regulation, and tumor applications. A randomized controlled trial study showed that protein extracts of ADSC-CM via microneedles presented a critical improvement for melanin levels, brightness, skin gloss, roughness, elasticity, and wrinkles without the unfavorable side of the skin. Besides, more than 70% of the participants of the participants said that in the test surface, wrinkles, firmness, elasticity, hydration, whitening, and brilliance were noticeably improved [127].

Next, the therapeutic potential as well as the current limitations of ADSCs in photoaging and photocarcinogenesis will be described in multiple aspects. The pre-clinical studies of ADSCs and their secretome in photoaging and photocarcinogenesis are listed in Table 2.

Table 2 Pre-clinical studies of ADSCs and their secretome in photoaging and photocarcinogenesis

Anti-wrinkling and skin thickness improvement

Although the mechanism of wrinkle formation is not well understood, there is general atrophy of the ECM, fewer fibroblasts, and reduced synthetic ability [131, 132]. The generation of wrinkles is modulated by genetic factors, but the amount of exposure to UVR is also a significant component. UVR increases the degradation of collagen and elastic fibers, thereby leading to photoaging through the wrinkle formation and the skin elasticity loss [133].

Photoaging is a complicated process that is similar to dermal wounds pathologically [26]. Dermal fibroblasts communicate with keratinocytes, adipose cells, and mast cells, exerting essential functions in these progress. Meanwhile, they also synthesize ECM proteins, glycoproteins, adhesive molecules, and various cytokines [134]. Dermal fibroblasts play an important role in the fibroblast-keratinocyte-endothelium complex by providing these factors and promoting interactions between cells, which promotes wound repair as well as keeps the dermal integrity and skin youth. Normal applications dealing with dermal aging like laser and topical regimens usually promote the synthesis of ECM through activation of fibroblast. It was reported that ADSCs activated HDF through the generation of various growth factors which promote the proliferation and relocation of HDF and regulate the secretion of collagen in HDF [86]. It was also reported that ADSCs have anti-wrinkle functions in animal models based on the capacity of activating fibroblast. For example, ADSCs augmented skin thickness and stimulated the proliferation of dermal fibroblast on the photoaged skin by the Wnt/ β-catenin signaling pathway in both vitro and vivo experiment [21]. In an experimental study using mice, treated with ADSC-CM, UVB-induced wrinkles in nude mice were noticeably ameliorated, which is mainly regulated by the decrease of apoptosis induced by UVB and increase of collagen synthesis in HDF [86]. Collagen synthesis by fibroblasts is promoted by multiple factors including insulin-like growth factor (IGF), EGF, IL-1, and TNF- α, but TGF- β seems to be the most important stimulator in vivo [135, 136].

In a comparative study, both ADSC group and fibroblast group showed decreased wrinkle area. Compared with ADSCs, fibroblasts promoted more collagen expression, but they also augmented the expression of MMPs, while ADSCs reduced MMP expression [20]. ADSCs also stimulated higher collagen density and had high levels of tropoelastin and fibrillin-1 than fibroblast group, which indicates the superior regeneration capacity of ADSC.

Besides, in an athymic mouse model of photoaging, injection of ADSCs combined with HA gel ablated photoinduced skin wrinkles [37]. In a porcine acute wound model, ADSCs seeded onto collagen scaffolds increased dermal thickness and increased ECM in comparison to scaffold only and unprocessed porcine skin [38]. Moreover, the wrinkles in the areas injected with the stromal vascular fraction (SVF)/ADSC-concentrated nanofats were significantly attenuated and photoaged condition of hairless mice skin was greatly improved [35]. In addition, ADSCs and fat graft have a wrinkle-reducing effect in aged mice by synergistically affecting collagen synthesis and neovascularization [39]. Combination of ADSCs with other material or graft offers the skin a consistent and stable volume fill, which tends to augment skin thickness and reduce wrinkles more significantly.

What is more, low-level laser (LLL) preconditioning enhanced ADSCs proliferation and increased their growth factors generation and the dermal thickness of photoaged mouse skin[40], which indicated LLL might improve the clinical therapeutic potential of ADSCs. Nevertheless, the key point should be highly considered is that therapies based on stem cells still have some concerns related to safety and immune rejection [137]. Several days after transplantation, stem cells are likely to undergo apoptosis [138]. However, their secretome contains a variety of bioactive factors, such as cytokines, growth factors, and chemokines. They can function as paracrine tools and are more potential than cell transplantation. Therefore, more cell-free studies associated with ADSC-CM or ADSC-Exo can be done to fill the void.

Skin whitening

Most of UVR stress can be defended by melanin pigmentation, but threatening health and esthetic problems will be induced by abnormal pigmentation like melasma, freckles, and senile lentigines [133]. One of the most common skin disorders is hyperpigmentation that affects all ethnic groups, mainly caused by UV exposure and skin inflammation [139]. Upon exposure of the skin to UVR, melanogenesis is facilitated by the stimulation of tyrosinase. Tyrosinase is a rate-limiting enzyme in the melanin biosynthesis cascade, which catalyzes the hydroxylation of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and the subsequent oxidation of L-DOPA to dopaquinone [140]. In the absence of thiols, dopaquinone can undergo cyclization into dopachrome and turn to dihydroxyindole-2-carboxylic acid-melanin. By the activation of tyrosinase-related proteins 1 and 2 (TYRP1, TYRP2), the dark brown-black insoluble type of melanin finally forms [141].

Conventional methods dealing with hyperpigmentation such as acid peels and topically used hydroquinone creams can cause acute contact dermatitis or skin pigment spots. Besides, chemical peels do not work on deep wrinkles or pigmentations [142]. However, ADSCs are more potential to treat aged skin by stimulating skin regeneration ability and inhibiting melanin, as well as overcoming current clinical limitations. It is reported that ADSCs can exert as whitening agents via a paracrine function or their own presence [128, 129]. For example, ADSCs can secrete various factors, mainly TGF- β1, to exert their whitening effect in vitro. The tyrosinase and TRP1 expression are downregulated by TGF- β1 in B16 melanoma cells [129]. However, the accurate mechanism and molecular pathway about how TGF- β1 regulates melanin synthesis are still not quite explicit. Other cytokines can also suppress pigmentation by interacting with tyrosinase. Nevertheless, the concentrations of these components in ADSC-CM are far from reaching the half-maximal inhibitory concentration (IC50) value of inhibition [72, 129]. Moreover, the skin tanning induced by UVB in mice can be ameliorated by subcutaneous ADSCs injection, which is effected by suppression of tyrosinase activity and DOPA-positive melanocytes [130]. What is more, it is reported that antioxidants suppress the formation of melanin and the transfer of melanosome as well as alter the melanin type [129, 143]. And it has already been demonstrated above that ADSC-CM has great antioxidant capacity. In a word, ADSCs could exert whitening functions as antioxidants and TGF- β1 also plays an important role.

UV-induced skin injury regulation

Overexposure to UVR leads to acute skin injury that triggers the relocating of the activated immune cells into the injured skin site [144]. It forms a localized inflammatory environment and further exacerbates inflammation, resulting in delayed wound healing [145]. What is more, in C57BL/6 mice, UVR can deteriorate skin wound healing [146]. The cytokine and growth factor secreted by ADSCs function importantly in all three phases of wound healing. The first phase engages TGF- β, TNF- α, PDGF, IL-1, and IL-6, which balance the progress of inflammation [147]. In the second stage, FGFs, TGF- β, PDGF, HGF, IGF-1, and EGF, together with IL6, IL8, and TNF- α, play a critical role [148154]. In the third phase, TGF- β, TNF- α, EGF, and IL-1 contribute to remodeling the injured site. [155160]. Besides, ADSCs are able to migrate to injured sites effectively and boost adjacent cell to regenerate. Moreover, ADSCs have been shown to differentiate into lots of skin cells such as keratinocytes and dermal fibroblasts (DF) [161163].

In a UV-injured mice model, skin appearance of ADSCs group was noticeably improved with less wrinkles, pigmentation, or erythema and the skin recovered from the injury caused by UVR better [34]. As we all know, VEGF exerts angiogenesis function by interacting with vascular endothelial cells and promoting blood vessels proliferation. Overexpression of VEGF in ADSCs further allowed the skin to resist photoaging. The VEGF group almost recovered from the UVR-induced injury and their skin conditions looked like those in the negative control group [34].

There were already plenty of studies of ADSCs in wound healing applications [164, 165], but only a few reports on the UV-induced skin injury. Therefore, more studies could be done to investigate the potential application of ADSC in UV-induced skin injury.

Skin cancer inhibition

Photoaging and skin cancer are triggered mainly by UVR from chronic sun exposure. And they share lots of mutual molecular and histological changes. For instance, mutation in p53 gene, an essential factor in photoaging model, has also been recognized as a significant biomarker in skin cancer induced by UVR [166] and been found in different skin cancers, especially squamous cell carcinomas [167] and basal cell carcinoma [168]. Besides, ROS contributes to the progress of skin cancer, while its exact role in skin cancer has not been thoroughly elucidated [169]. Moreover, inflammatory responses induced by photoaging could be caused by photocarcinogenesis and degradation in ECM could be responsible for tumor dissemination [170], while ADSCs can ameliorate the inflammatory response and inhibit the degradation in ECM. These results might offer us potential methods to inhibit photoaging and photocarcinogenesis.

Multiple studies are interested in the interaction of ADSCs and the oncogenic process. Indeed, mesenchymal stem cells (MSCs) can regulate cancer indirectly or exert a direct function by transforming malignantly [171]. Contradictory results have been presented that ADSCs can exert pro-tumor or anti-tumor function, both in vitro and in vivo. For example, in a mouse model of xenotransplantation of human breast cancer, the study presented that ADSCs injected into a tumor can promote tumor growth. However, when injected around the tumor, ADSCs inhibited tumor growth, suggesting that distinct influences the effect of ADSCs in different tumor microenvironments [172]. A study in vitro showed that ADSC-EV promoted Wnt/ β-catenin signaling to facilitate MCF7 human breast carcinoma cell proliferating and migrating [172], although effects of angiogenesis were not assessed. Another in vitro study illustrated that ADSCs-CM can slow down liver cancer cells growth through suppressing cell proliferation and increasing cell apoptosis, as well as inhibiting cell motility, adhesive ability, migration, and invasion [173]. Besides, it is also reported that human glioblastoma cancer stem cell subpopulations are not affected by ADSC-CM [174]. Therefore, before drawing conclusions, further detailed research in this area is needed.

As for skin cancer, a study illustrated that ADSC-CM greatly suppressed the migration capacity of B16 melanoma cells and reduced the volume of the tumor mass [175]. ADSCs can restore skin barrier by ameliorating the downregulation of α6 integrin, CD34, and collagen I by UVB, reducing the overexpression of COX2 and TNF- α induced by UVB [97]. ADSCs engineered to express interferon (IFN)- β and combined with cisplatin can migrate to the tumor sites and inhibit the growth of melanoma more effectively, as well as led to extended survival time. It suggested that ADSC can be used as a powerful cell-based delivery vehicle to release therapeutic drugs to tumor lesions [41]. Besides, it is already illustrated above that ADSCs can suppress photoaging- and photocarcinogenesis-related inflammatory responses and ECM degradation [97]. Collectively, ADSCs and their secretome are quite potential as a therapeutic anti-skin cancer medicine or a delivery vehicle. However, more basic research and clinical trial must be conducted to find out molecular mechanism details.

Conclusion and perspective

Photoaging is a complex process triggered mainly by UVR from chronic sun exposure. This leads to DNA damage and ROS production, which initiates an inflammatory response altering cell structure and function. The harmful effects of oxidative stress exert through a variety of mechanisms, which involve changes in proteins and lipids, induction of inflammation, immune suppression, DNA damage, and activation of signal transduction pathways that affect gene transcription, cell cycle, and proliferation. And it finally leads to cell death, apoptosis and senescence, degradation of dermal collagen, and degeneration of elastic fibers as well as chronic inflammation and skin cancer.

In regard to photoaging, the treating strategies aim to ensure patient satisfaction in fields of esthetic appearance and functionality. ADSCs can reduce oxidative stress, inhibit cell apoptosis and senescence, improve ECM synthesis and skin regeneration, and regulate the inflammation progress. Besides, studies have demonstrated that ADSCs may have multiple clinical therapeutic applications, such as tissue regeneration, anti-wrinkle, tumors, and depigmentation. ADSCs are thought to be “immuno-privileged” and reliable in culturing for a long time [176], thereby exerting an outstanding advantage in dermatological field. In conclusion, these promising consequences showed that ADSCs might be potential cosmo-therapeutic tools addressing photoaging problem.

However, there are many problems with the applications of ADSC in dermatology, such as lack of details on how ADSC affects keratinocytes, fibroblasts, and endothelial cells or acts as a carrier for the secretion of soluble factors. [1]. Additionally, systemic and local delivery may have effects in multiple cell types simultaneously, sometimes with opposing outcomes. Thus, possible side effects should be taken into account and the safe doses should be determined personally. Moreover, the application of ADSCs could be impaired by some limitations. It is reported that the formation of tumor can be induced by transportation of MSCs into normal tissues [177]. ADSC-CM was especially known for high level of factors involved in cancer progression and may have unexpected side effects. Recent studies have also demonstrated that ADSCs after transplantation do not survive for a very long time. Besides, Pap cervical smear used for obtaining human uterine cervical stem cells (hUCESCs) is less invasive and less painful than liposuction used for obtaining ADSCs [178].

In terms of manufacturing, storage, handling, and safety, secretome-based approaches using conditioned medium or exosomes may bring huge potential benefits than living cells [178]. We can expect that cell-free secretomes rather than ADSCs are more potential in treatment of skin aging. What is more, inducing secretory modifications in ADSCs are promising to overcome the current limitations and enhance the anti-photoaging capacity.

Further study about the molecular details regarding the involvement of ADSCs in photoaging applications need to be carried out in order to increase our understanding and open the way to therapeutic approaches. Besides, in order to establish the optimal, durable, and safe strategy for ADSCs and ADSC secretome in the treatment of patients with symptoms of photoaging and aging, long-term and extensive in vivo studies are absolutely necessary.





Adipose-derived stem cell


Conditioned medium from ADSC


Extracellular vesicles from ADSC


Exosome of ADSC




Activator protein 1


BCL-2 associated X


B cell lymphoma-2


Basic fibroblast growth factor


C-X-C chemokine receptor


Dermal fibroblasts


Extracellular matrix


Epidermal growth factor


Extracellular regulated protein kinases




glycoprotein A repetitions predominant


Growth differentiation factor


Glutathione peroxidase


Hypoxia and serum deprivation


Hyaluronic acid


Human keratinocytes


Human dermal fibroblast


Hepatocyte growth factor


Hypoxia-inducible factor


Heme oxygenase-1


Hematopoietic stem cell


Human uterine cervical stem cell




Half-maximal inhibitory concentration




Insulin-like growth factor






Low-level laser


Mitogen-activated protein kinase






Murine long bone osteocyte


Matrix metalloprotease


Manganese superoxide dismutase




Mesenchymal stem cell


Mitochondrial-derived reactive oxygen species

NF- κB:

Nuclear factor-kappaB


Nod-like receptor protein


NADPH oxidase


Nuclear factor erythroid 2-related factor 2


Platelet-derived growth factor




Reactive oxygen species

SA- β- Gal:

Senescence-associated β- galactosidase


Superoxide dismutase


Signal transducer and activator of transcription 3


Stromal vascular fraction

TGF- β :

Transforming growth factor- β


Tissue inhibitor of metalloproteinase


Toll-like receptor

TNF- α :

Tumor necrosis factor- α


Tyrosinase-related proteins




Long wavelength ultraviolet radiations


Medium wavelength ultraviolet radiations


Vascular cell adhesion molecule


Vascular endothelial growth factor


Phosphorylated histone family 2A variant


  1. 1

    Gaur M, Dobke M, Lunyak VV. Mesenchymal stem cells from adipose tissue in clinical applications for dermatological indications and skin aging. Int J Mol Sci. 2017; 18(1):208.

    PubMed Central  Article  CAS  Google Scholar 

  2. 2

    Bernhard D, Moser C, Backovic A, Wick G. Cigarette smoke–an aging accelerator?Exp Gerontol. 2007; 42(3):160–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    Friedman O. Changes associated with the aging face. Facial Plast Surg Clin. 2005; 13(3):371–80.

    Article  Google Scholar 

  4. 4

    Helfrich YR, Sachs DL, Voorhees JJ. Overview of skin aging and photoaging. Dermatol Nurs. 2008; 20(3):177.

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Silva SAME, Michniak-Kohn B, Leonardi GR, et al.An overview about oxidation in clinical practice of skin aging. An Bras Dermatol. 2017; 92(3):367–74.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Wölfle U, Seelinger G, Bauer G, Meinke MC, Lademann J, Schempp CM. Reactive molecule species and antioxidative mechanisms in normal skin and skin aging. Skin Pharmacol Physiol. 2014; 27(6):316–32.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  7. 7

    Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron T. The skin aging exposome. J Dermatol Sci. 2017; 85(3):152–61.

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8

    Lorencini M, Brohem CA, Dieamant GC, Zanchin NI, Maibach HI. Active ingredients against human epidermal aging. Ageing Res Rev. 2014; 15:100–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9

    Cavinato M, Waltenberger B, Baraldo G, Grade CV, Stuppner H, Jansen-Dürr P. Plant extracts and natural compounds used against UVB-induced photoaging. Biogerontology. 2017; 18(4):499–516.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Koh EK, Kim JE, Go J, Song SH, Sung JE, Son HJ, Jung YJ, Kim BH, Jung YS, Hwang DY. Protective effects of the antioxidant extract collected from Styela clava tunics on UV radiation-induced skin aging in hairless mice. Int J Mol Med. 2016; 38(5):1565–77.

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Ha J-H, Kim H-N, Moon K-B, Jeon J-H, Jung D-H, Kim S-J, Mason HS, Shin S-Y, Kim H-S, Park K-M. Recombinant human acidic fibroblast growth factor (aFGF) expressed in Nicotiana benthamiana potentially inhibits skin photoaging. Planta Med. 2017; 83(10):862–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12

    Xu Y, Deng M, Cai Y, Zheng H, Wang X, Yu Z, Zhang W, Li W. Cell-free fat extract increases dermal thickness by enhancing angiogenesis and extracellular matrix production in nude mice. Aesthet Surg J. 2020; 40(8):904–13.

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13

    Assis-Ribas T, Forni MF, Winnischofer SMB, Sogayar MC, Trombetta-Lima M. Extracellular matrix dynamics during mesenchymal stem cells differentiation. Dev Biol. 2018; 437(2):63–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Kariminekoo S, Movassaghpour A, Rahimzadeh A, Talebi M, Shamsasenjan K, Akbarzadeh A. Implications of mesenchymal stem cells in regenerative medicine. Artif Cells Nanomedicine Biotechnol. 2016; 44(3):749–57.

    CAS  Article  Google Scholar 

  15. 15

    Mojallal A, Lequeux C, Shipkov C, Breton P, Foyatier J-L, Braye F, Damour O. Improvement of skin quality after fat grafting: clinical observation and an animal study. Plast Reconstr Surg. 2009; 124(3):765–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002; 13(12):4279–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004; 36(4):568–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

    Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005; 54(3):132–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19

    Won CH, Park G-H, Wu X, Tran T-N, Park K. -y., Park B-S, Kim DY, Kwon O, Kim K-H. The basic mechanism of hair growth stimulation by adipose-derived stem cells and their secretory factors. Curr Stem Cell Res Ther. 2017; 12(7):535–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20

    Jeong JH, Fan Y, You GY, Choi TH, Kim S. Improvement of photoaged skin wrinkles with cultured human fibroblasts and adipose-derived stem cells: a comparative study. J Plast Reconstr Aesthet Surg. 2015; 68(3):372–81.

    PubMed  Article  PubMed Central  Google Scholar 

  21. 21

    Xu X, Wang H-y, Zhang Y, Liu Y, Li Y-q, Tao K, Wu C-T, Liu X-y, et al. Adipose-derived stem cells cooperate with fractional carbon dioxide laser in antagonizing photoaging: a potential role of Wnt and β-catenin signaling. Cell Biosci. 2014; 4(1):24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22

    Song SY, Jung JE, Jeon YR, Tark KC, Lew DH. Determination of adipose-derived stem cell application on photo-aged fibroblasts, based on paracrine function. Cytotherapy. 2011; 13(3):378–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23

    Ti D, Hao H, Fu X, Han W. Mesenchymal stem cells-derived exosomal micrornas contribute to wound inflammation. Sci China Life Sci. 2016; 59(12):1305–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24

    Mazini L, Rochette L, Admou B, Amal S, Malka G. Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing. Int J Mol Sci. 2020; 21(4):1306.

    CAS  PubMed Central  Article  Google Scholar 

  25. 25

    Scioli MG, Storti G, D’Amico F., Gentile P, Kim B-S, Cervelli V., Orlandi A. Adipose-derived stem cells in cancer progression: new perspectives and opportunities. Int J Mol Sci. 2019; 20(13):3296.

    CAS  PubMed Central  Article  Google Scholar 

  26. 26

    Watson RE, Griffiths CE. Pathogenic aspects of cutaneous photoaging. J Cosmet Dermatol. 2005; 4(4):230–6.

    PubMed  Article  PubMed Central  Google Scholar 

  27. 27

    Hussein MR. Ultraviolet radiation and skin cancer: molecular mechanisms. J Cutan Pathol. 2005; 32(3):191–205.

    PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Kammeyer A, Luiten R. Oxidation events and skin aging. Ageing Res Rev. 2015; 21:16–29.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29

    Trenam CW, Blake DR, Morris CJ. Skin inflammation: reactive oxygen species and the role of iron. J Investig Dermatol. 1992; 99(6):675–82.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30

    Carrillo-Gálvez AB, Gálvez-Peisl S, González-Correa JE, de Haro-Carrillo M, Ayllón V, Carmona-Sáez P, Ramos-Mejía V, Galindo-Moreno P, Cara FE, Granados-Principal S, et al. GARP is a key molecule for mesenchymal stromal cell responses to TGF- β and fundamental to control mitochondrial ROS levels. Stem Cells Transl Med. 2020; 9(5):636–50.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31

    Li X, Xie X, Lian W, Shi R, Han S, Zhang H, Lu L, Li M. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 2018; 50(4):29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Xu J, Liu X, Zhao F, Zhang Y, Wang Z. Hif1 α overexpression enhances diabetic wound closure in high glucose and low oxygen conditions by promoting adipose-derived stem cell paracrine function and survival. Stem Cell Res Ther. 2020; 11:1–13.

    Article  CAS  Google Scholar 

  33. 33

    Bai Y, Yan XL, Ren J, Zeng Q, Li XD, Pei XT, Han Y, et al. Adipose mesenchymal stem cell-derived exosomes stimulated by hydrogen peroxide enhanced skin flap recovery in ischemia-reperfusion injury. Biochem Biophys Res Commun. 2018; 500(2):310–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34

    Xie X, Wang Y, Xia Y, Mao Y. Overexpressed vascular endothelial growth factor in adipose derived stem cells attenuates fibroblasts and skin injuries by ultraviolet radiation. Biosci Rep. 2019;39(7).

  35. 35

    Zheng H, Qiu L, Su Y, Yi C. Conventional nanofat and SVF/ADSC-concentrated nanofat: a comparative study on improving photoaging of nude mice skin. Aesthet Surg J. 2019; 39(11):1241–50.

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36

    Waters R, Subham S, Pacelli S, Modaresi S, Chakravarti AR, Paul A. Development of MicroRNA-146a-enriched stem cell secretome for wound-healing applications. Mol Pharm. 2019; 16(10):4302–12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Altman AM, Khalek FJA, Seidensticker M, Pinilla S, Yan Y, Coleman M, Song YH, Butler CE, Alt EU. Human tissue-resident stem cells combined with hyaluronic acid gel provide fibrovascular-integrated soft-tissue augmentation in a murine photoaged skin model. Plast Reconstr Surg. 2010; 125(1):63–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38

    Lequeux C, Oni G, Wong C, Damour O, Rohrich R, Mojallal A, Brown SA. Subcutaneous fat tissue engineering using autologous adipose-derived stem cells seeded onto a collagen scaffold. Plast Reconstr Surg. 2012; 130(6):1208–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Kim K, Fan Y, Lin G, Park YK, Pak CS, Jeong JH, Kim S. Synergistic effect of adipose-derived stem cells and fat graft on wrinkles in aged mice. Plast Reconstr Surg. 2019; 143(6):1637–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40

    Liao X, Li SH, Xie GH, Xie S, Xiao LL, Song JX, Liu HW. Preconditioning with low-level laser irradiation enhances the therapeutic potential of human adipose-derived stem cells in a mouse model of photoaged skin. Photochem Photobiol. 2018; 94(4):780–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Seo KW, Lee HW, Oh YI, Ahn JO, Koh YR, Oh SH, Kang SK, Youn HY. Anti-tumor effects of canine adipose tissue-derived mesenchymal stromal cell-based interferon- β gene therapy and cisplatin in a mouse melanoma model. Cytotherapy. 2011; 13(8):944–55.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    Pillai S, Oresajo C, Hayward J. Ultraviolet radiation and skin aging: roles of reactive oxygen species, inflammation and protease activation, and strategies for prevention of inflammation-induced matrix degradation–a review. Int J Cosmet Sci. 2005; 27(1):17–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43

    Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015; 5(2):545–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Miller JD, Arteca RN, Pell EJ. Senescence-associated gene expression during ozone-induced leaf senescence in arabidopsis. Plant Physiol. 1999; 120(4):1015–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Kasai H, Crain P, Kuchino Y, Nishimura S, Ootsuyama A, Tanooka H. Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis. 1986; 7(11):1849–51.

    CAS  PubMed  Article  Google Scholar 

  46. 46

    McCord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000; 108(8):652–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47

    Kosmadaki M, Gilchrest B. The role of telomeres in skin aging/photoaging. Micron. 2004; 35(3):155–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48

    Gilchrest BA. Photoaging. J Investig Dermatol. 2013; 133(E1):2.

    Article  Google Scholar 

  49. 49

    Neades R, Cox L, Pelling JC. S-phase arrest in mouse keratinocytes exposed to multiple doses of ultraviolet B/A radiation. Mol Carcinog Published Cooperation Univ Tex MD Anderson Cancer Cent. 1998; 23(3):159–67.

    CAS  Google Scholar 

  50. 50

    Li G, Ho V. p53-dependent DNA repair and apoptosis respond differently to high-and low-dose ultraviolet radiation. Br J Dermatol. 1998; 139(1):3–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51

    Chow J, Tron VA. Molecular aspects of ultraviolet radiation-induced apoptosis in the skin. J Cutan Med Surg. 2005; 9(6):289–95.

    PubMed  Article  PubMed Central  Google Scholar 

  52. 52

    Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, LINskENs M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci. 1995; 92(20):9363–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53

    LUBOWE II. Topical use of placenta-extract gel (non-estrogenic) in the treatment of aging skin. J Am Geriatr Soc. 1963; 11(9):914–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54

    Bandyopadhyay D, Medrano EE. Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/PRB and E2F1. Ann N Y Acad Sci. 2000; 908(1):71–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55

    Tyrrell RM, Pidoux M. Endogenous glutathione protects human skin fibroblasts against the cytotoxic action of UVB, UVA and near-visible radiations. Photochem Photobiol. 1986; 44(5):561–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56

    Rhie G. -e., Shin MH, Seo JY, Choi WW, Cho KH, Kim KH, Park KC, Eun HC, Chung JH. Aging-and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J Investig Dermatol. 2001; 117(5):1212–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57

    Katiyar SK, Mukhtar H. Green tea polyphenol (-)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes, depletion of antigen-presenting cells, and oxidative stress. J Leukoc Biol. 2001; 69(5):719–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Scharffetter–Kochanek K, Brenneisen P, Wenk J, Herrmann G, Ma W, Kuhr L, Meewes C, Wlaschek M. Photoaging of the skin from phenotype to mechanisms. Exp Gerontol. 2000; 35(3):307–16,.

    PubMed  Article  PubMed Central  Google Scholar 

  59. 59

    Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees JJ. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002; 138(11):1462–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60

    Whitmarsh A, Davis R. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med. 1996; 74(10):589–607.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61

    Poljšak B, Dahmane R. Free radicals and extrinsic skin aging. Dermatol Res Pract. 2012;2012.

  62. 62

    Iriondo-DeHond A, Martorell P, Genovés S, Ramón D, Stamatakis K, Fresno M, Molina A, Del Castillo MD. Coffee silverskin extract protects against accelerated aging caused by oxidative agents. Molecules. 2016; 21(6):721.

    PubMed Central  Article  CAS  Google Scholar 

  63. 63

    Shibuki H, Katai N, Kuroiwa S, Kurokawa T, Arai J, Matsumoto K, Nakamura T, Yoshimura N. Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia–reperfusion injury. Investig Ophthalmol Vis Sci. 2002; 43(2):528–36.

    Google Scholar 

  64. 64

    Suzuki YJ. Growth factor signaling for cardioprotection against oxidative stress-induced apoptosis. Antioxid Redox Signal. 2003; 5(6):741–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65

    Enriquez-Cortina C, Almonte-Becerril M, Clavijo-Cornejo D, Palestino-Domínguez M, Bello-Monroy O, Nuño N, López A, Bucio L, Souza V, Hernández-Pando R, et al. Hepatocyte growth factor protects against isoniazid/rifampicin-induced oxidative liver damage. Toxicol Sci. 2013; 135(1):26–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

    Liu Z, Yang Q, Wei Q, Chang Y, Qu M, Yu L. The protective effect of miR-377 inhibitor against renal ischemia-reperfusion injury through inhibition of inflammation and oxidative stress via a VEGF-dependent mechanism in mice. Mol Immunol. 2019; 106:153–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67

    Matsuoka Y, Nakayama H, Yoshida R, Hirosue A, Nagata M, Tanaka T, Kawahara K, Sakata J, Arita H, Nakashima H, et al. IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma. Br J Cancer. 2016; 115(10):1234–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Tamari Y, Kashino G, Mori H. Acquisition of radioresistance by IL-6 treatment is caused by suppression of oxidative stress derived from mitochondria after γ-irradiation. J Radiat Res. 2017; 58(4):412–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Wang H, Han X, Wittchen ES, Hartnett ME. TNF- α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation. Mol Vis. 2016; 22:116.

    PubMed  PubMed Central  Google Scholar 

  70. 70

    Gao Y, Sun J, Dong C, Zhao M, Hu Y, Jin F. Extracellular vesicles derived from adipose mesenchymal stem cells alleviate PM2. 5-induced lung injury and pulmonary fibrosis. Med Sci Monit Int Med J Exp Clin Res. 2020; 26:922782–1.

    Google Scholar 

  71. 71

    Li L, Ngo HT, Hwang E, Wei X, Liu Y, Liu J, Yi T-H. Conditioned medium from human adipose-derived mesenchymal stem cell culture prevents UVB-induced skin aging in human keratinocytes and dermal fibroblasts. Int J Mol Sci. 2020; 21(1):49.

    CAS  Article  Google Scholar 

  72. 72

    Kim WS, Park BS, Kim HK, Park JS, Kim KJ, Choi JS, Chung SJ, Kim DD, Sung JH. Evidence supporting antioxidant action of adipose-derived stem cells: protection of human dermal fibroblasts from oxidative stress. J Dermatol Sci. 2008; 49(2):133–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73

    Chae YB, Lee JS, Park HJ, Park IH, Kim MM, Park YH, Kim DS, Lee JH. Advanced adipose-derived stem cell protein extracts with antioxidant activity modulates matrix metalloproteinases in human dermal fibroblasts. Environ Toxicol Pharmacol. 2012; 34(2):263–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

    Palomares T, Cordero M, Bruzos-Cidon C, Torrecilla M, Ugedo L, Alonso-Varona A. The neuroprotective effect of conditioned medium from human adipose-derived mesenchymal stem cells is impaired by N-acetyl cysteine supplementation. Mol Neurobiol. 2018; 55(1):13–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75

    Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469(7329):221–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76

    Paliwal S, Chaudhuri R, Agrawal A, Mohanty S. Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Stem Cell Res Ther. 2018; 9(1):1–9.

    Article  Google Scholar 

  77. 77

    Pan F, Liao N, Zheng Y, Wang Y, Gao Y, Wang S, Jiang Y, Liu X. Intrahepatic transplantation of adipose-derived stem cells attenuates the progression of non-alcoholic fatty liver disease in rats. Mol Med Rep. 2015; 12(3):3725–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78

    Hong H-E, Kim O-H, Kwak BJ, Choi HJ, Ahn J, Kim S-J, et al. Antioxidant action of hypoxic conditioned media from adipose-derived stem cells in the hepatic injury of expressing higher reactive oxygen species. Ann Surg Treat Res. 2019; 97(4):159–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Ge Y, Zhang Q, Jiao Z, Li H, Bai G, Wang H. Adipose-derived stem cells reduce liver oxidative stress and autophagy induced by ischemia-reperfusion and hepatectomy injury in swine. Life Sci. 2018; 214:62–69.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80

    Chen X, Yan L, Guo Z, Chen Z, Chen Y, Li M, Huang C, Zhang X, Chen L. Adipose-derived mesenchymal stem cells promote the survival of fat grafts via crosstalk between the Nrf2 and TLR4 pathways. Cell Death Dis. 2016; 7(9):2369–9.

    Article  CAS  Google Scholar 

  81. 81

    Yang J, Zhang Y, Zang G, Wang T, Yu Z, Wang S, Tang Z, Liu J. Adipose-derived stem cells improve erectile function partially through the secretion of IGF-1, BFGF, and VEGF in aged rats. Andrology. 2018; 6(3):498–509.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82

    Sheashaa H, Lotfy A, Elhusseini F, Aziz AA, Baiomy A, Awad S, Alsayed A, El-Gilany AH, Saad M-AA, Mahmoud K, et al. Protective effect of adipose-derived mesenchymal stem cells against acute kidney injury induced by ischemia-reperfusion in Sprague-Dawley rats. Ex Ther Med. 2016; 11(5):1573–80.

    CAS  Article  Google Scholar 

  83. 83

    Huang YC, Kuo YH, Huang YH, Chen CS, Ho DR, Shi CS. The effects of adipose-derived stem cells in a rat model of tobacco-associated erectile dysfunction. PloS ONE. 2016; 11(6):0156725.

    Google Scholar 

  84. 84

    Zhang J, Liu Z, Tang W, Xiong X, Zhang Z, Cao W, Li X. Repair effects of rat adipose-derived stem cells on DNA damage induced by ultraviolet in chondrocytes. Chin J Reparative Reconstr Surg. 2017; 31(5):600–6.

    Google Scholar 

  85. 85

    Kulms D, Pöppelmann B, Yarosh D, Luger TA, Krutmann J, Schwarz T. Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation. Proc Natl Acad Sci. 1999; 96(14):7974–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86

    Kim W-S, Park B-S, Park S-H, Kim H-K, Sung J-H. Antiwrinkle effect of adipose-derived stem cell: activation of dermal fibroblast by secretory factors. J Dermatol Sci. 2009; 53(2):96–102.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87

    Ren L, Song ZJ, Cai QW, Chen RX, Zou Y, Fu Q, Ma YY. Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. Biochem Biophys Res Commun. 2019; 508(1):138–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88

    Ma T, Fu B, Yang X, Xiao Y, Pan M. Adipose mesenchymal stem cell-derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt/ β-catenin signaling in cutaneous wound healing. J Cell Biochem. 2019; 120(6):10847–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89

    Lin KC, Yip HK, Shao PL, Wu SC, Chen KH, Chen YT, Yang CC, Sun CK, Kao GS, Chen SY, et al. Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia–reperfusion injury. Int J Cardiol. 2016; 216:173–85.

    PubMed  Article  PubMed Central  Google Scholar 

  90. 90

    Qin HH, Filippi C, Sun S, Lehec S, Dhawan A, Hughes RD. Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes. Stem Cell Res Ther. 2015; 6(1):1–12.

    Article  CAS  Google Scholar 

  91. 91

    Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25(3):585–621.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Guo S, Wang T, Zhang S, Chen P, Cao Z, Lian W, Guo J, Kang Y. Adipose-derived stem cell-conditioned medium protects fibroblasts at different senescent degrees from UVB irradiation damages. Mol Cell Biochem. 2020; 463(1-2):67–78.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93

    Foroutan T, Farhadi A, Abroun S, Soltani BM. Adipose derived stem cells affect miR-145 and p53 expressions of co-cultured hematopoietic stem cells. Cell J (Yakhteh). 2018; 19(4):654.

    Google Scholar 

  94. 94

    Shin JW, Kwon SH, Choi JY, Na JI, Huh CH, Choi HR, Park KC. Molecular mechanisms of dermal aging and antiaging approaches. Int J Mol Sci. 2019; 20(9):2126.

    CAS  PubMed Central  Article  Google Scholar 

  95. 95

    Choi JS, Cho WL, Choi YJ, Kim JD, Park HA, Kim SY, Park JH, Jo DG, Cho YW. Functional recovery in photo-damaged human dermal fibroblasts by human adipose-derived stem cell extracellular vesicles. J Extracellular Vesicles. 2019; 8(1):1565885.

    CAS  Article  Google Scholar 

  96. 96

    Fan F, Li Y, Liu Y, Shao L, Yu J, Li Z. Overexpression of klotho in adipose-derived stem cells protects against UVB-induced photoaging in co-cultured human fibroblasts. Mol Med Rep. 2018; 18(6):5473–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Gong M, Zhai X, Yu L, Li C, Ma X, Shen Q, Han Y, Yang D. ADSCs inhibit photoaging-and photocarcinogenesis-related inflammatory responses and extracellular matrix degradation. J Cell Biochem. 2020; 121(2):1205–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98

    Kim J-H, Jung M, Kim H-S, Kim Y-M, Choi E-H. Adipose-derived stem cells as a new therapeutic modality for ageing skin. Exp Dermatol. 2011; 20(5):383–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99

    Charles-de-Sá L, Gontijo-de-Amorim NF, Takiya CM, Borojevic R, Benati D, Bernardi P, Sbarbati A, Rigotti G. Antiaging treatment of the facial skin by fat graft and adipose-derived stem cells. Plast Reconstr Surg. 2015; 135(4):999–1009.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  100. 100

    Charles-de-Sá L, Gontijo-de-Amorim NF, Rigotti G, Sbarbati A, Bernardi P, Benati D, Carias RBV, Takiya CM, Borojevic R. Photoaged skin therapy with adipose-derived stem cells. Plast Reconstr Surg. 2020; 145(6):1037–49.

    Article  CAS  Google Scholar 

  101. 101

    Makrantonaki E, Zouboulis C. Molecular mechanisms of skin aging: state of the art. Ann N Y Acad Sci. 2007; 1119(1):40–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102

    Lee DH, Oh JH, Chung JH. Glycosaminoglycan and proteoglycan in skin aging. J Dermatol Sci. 2016; 83(3):174–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103

    Nagaoka A, Yoshida H, Nakamura S, Morikawa T, Kawabata K, Kobayashi M, Sakai S, Takahashi Y, Okada Y, Inoue S. Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts. J Biol Chem. 2015; 290(52):30910–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104

    Zhang W, Bai X, Zhao B, Li Y, Zhang Y, Li Z, Wang X, Luo L, Han F, Zhang J, et al. Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway. Exp Cell Res. 2018; 370(2):333–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105

    Jung H, Kim HH, Lee DH, Hwang YS, Yang HC, Park JC. Transforming growth factor-beta 1 in adipose derived stem cells conditioned medium is a dominant paracrine mediator determines hyaluronic acid and collagen expression profile. Cytotechnology. 2011; 63(1):57–66.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106

    Gong M, Zhang P, Li C, Ma X, Yang D. Protective mechanism of adipose-derived stem cells in remodelling of the skin stem cell niche during photoaging. Cell Physiol Biochem. 2018; 51(5):2456–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107

    Li J, Liu D, Wu J, Zhang D, Cheng B, Zhang Y, Yin Z, Wang Y, Du J, Ling C. Ginsenoside Rg1 attenuates ultraviolet B-induced glucocortisides resistance in keratinocytes via Nrf2/HDAC2 signalling. Sci Rep. 2016; 6:39336.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Chang CL, Sung PH, Chen KH, Shao PL, Yang CC, Cheng BC, Lin KC, Chen CH, Chai HT, Chang HW, et al. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am J Transl Res. 2018; 10(4):1053.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Ning H, Lei HE, Xu YD, Guan RL, Venstrom JM, Lin G, Lue TF, Xin Z, Lin CS. Conversion of adipose-derived stem cells into natural killer-like cells with anti-tumor activities in nude mice. PLoS ONE. 2014; 9(8):106246.

    Article  CAS  Google Scholar 

  110. 110

    Zhang Y, Meng Q, Zhang Y, Chen X, Wang Y. Adipose-derived mesenchymal stem cells suppress of acute rejection in small bowel transplantation. Saudi J Gastroenterol Off J Saudi Gastroenterol Assoc. 2017; 23(6):323.

    Article  Google Scholar 

  111. 111

    Baharlou R, Rashidi N, Ahmadi-Vasmehjani A, Khoubyari M, Sheikh M, Erfanian S. Immunomodulatory effects of human adipose tissue-derived mesenchymal stem cells on T cell subsets in patients with rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2019; 18(1):114–9.

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Chia JJ, Zhu T, Chyou S, Dasoveanu DC, Carballo C, Tian S, Magro CM, Rodeo S, Spiera RF, Ruddle NH, et al. Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis. J Clin Investig. 2016; 126(11):4331–45.

    PubMed  Article  PubMed Central  Google Scholar 

  113. 113

    Blazquez R, Sanchez-Margallo FM, de la Rosa O, Dalemans W, Álvarez V, Tarazona R, Casado JG. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol. 2014; 5:556.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114

    Hong SJ, Jia SX, Xie P, Xu W, Leung KP, Mustoe TA, Galiano RD. Topically delivered adipose derived stem cells show an activated-fibroblast phenotype and enhance granulation tissue formation in skin wounds. PloS ONE. 2013; 8(1):55640.

    Article  CAS  Google Scholar 

  115. 115

    Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, Zhang Q, Guo C, Zhang L, Wang Q. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018; 67(2):235–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116

    Kotani T, Masutani R, Suzuka T, Oda K, Makino S, Ii M. Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia. Sci Rep. 2017; 7(1):1–10.

    CAS  Article  Google Scholar 

  117. 117

    Bachmann S, Jennewein M, Bubel M, Guthörl S, Pohlemann T, Oberringer M. Interacting adipose-derived stem cells and microvascular endothelial cells provide a beneficial milieu for soft tissue healing. Mol Biol Rep. 2020; 47(1):111–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118

    Dabrowski FA, Burdzinska A, Kulesza A, Sladowska A, Zolocinska A, Gala K, Paczek L, Wielgos M. Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. J Obstet Gynaecol Res. 2017; 43(11):1758–68.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119

    Komaki M, Numata Y, Morioka C, Honda I, Tooi M, Yokoyama N, Ayame H, Iwasaki K, Taki A, Oshima N, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther. 2017; 8(1):1–12.

    Article  CAS  Google Scholar 

  120. 120

    Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg. 2004; 187(5):11–16.

    Article  CAS  Google Scholar 

  121. 121

    Othmani A, Rouam S, Abbad A, Erraoui C, Harriba S, Boukind H, Nourlil J, Malka G, Mazini L. Cryopreservation impacts cell functionality of long term expanded adipose-derived stem cells. J Stem Cell Res Ther. 2019; 9:445.

    Article  Google Scholar 

  122. 122

    Anderson PH. Vitamin D activity and metabolism in bone. Curr Osteoporos Rep. 2017; 15(5):443–9.

    PubMed  Article  PubMed Central  Google Scholar 

  123. 123

    Jiao Z, Ma Y, Liu X, Ge Y, Zhang Q, Liu B, Wang H. Adipose-derived stem cell transplantation attenuates inflammation and promotes liver regeneration after ischemia-reperfusion and hemihepatectomy in swine. Stem Cells Int. 2019;2019.

  124. 124

    Xu H, Yan Y, Li L, Peng S, Qu T, Wang B. Ultraviolet B-induced apoptosis of human skin fibroblasts involves activation of caspase-8 and-3 with increased expression of vimentin. Photodermatol Photoimmunol Photomed. 2010; 26(4):198–204.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125

    Lee CH, Wu SB, Hong CH, Yu HS, Wei YH. Molecular mechanisms of UV-induced apoptosis and its effects on skin residential cells: the implication in UV-based phototherapy. Int J Mol Sci. 2013; 14(3):6414–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126

    Camilleri ET, Gustafson MP, Dudakovic A, Riester SM, Garces CG, Paradise CR, Takai H, Karperien M, Cool S, Im Sampen HJ, et al. Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production. Stem Cell Res Ther. 2016; 7(1):107.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127

    Wang X, Shu X, Huo W, Zou L, Li L. Efficacy of protein extracts from medium of adipose-derived stem cells via microneedles on Asian skin. J Cosmet Laser Ther. 2018; 20(4):237–44.

    PubMed  Article  PubMed Central  Google Scholar 

  128. 128

    Chang H, Park JH, Min KH, Lee RS, Kim EK. Whitening effects of adipose-derived stem cells: a preliminary in vivo study. Aesthet Plast Surg. 2014; 38(1):230–3.

    Article  Google Scholar 

  129. 129

    Kim WS, Park SH, Ahn SJ, Kim HK, Park JS, Lee GY, Kim KJ, Whang KK, Kang SH, Park BS, et al. Whitening effect of adipose-derived stem cells: a critical role of tgf- β1. Biol Pharm Bull. 2008; 31(4):606–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130

    Jeon BJ, Kim DW, Kim MS, Park SH, Dhong ES, Yoon ES, Lee BI, Hwang NH. Protective effects of adipose-derived stem cells against UVB-induced skin pigmentation. J Plast Surg Hand Surg. 2016; 50(6):336–42.

    PubMed  Article  PubMed Central  Google Scholar 

  131. 131

    Makrantonaki E, Zouboulis CC. Characteristics and pathomechanisms of endogenously aged skin. Dermatology. 2007; 214(4):352–60.

    PubMed  Article  PubMed Central  Google Scholar 

  132. 132

    Varani J, Spearman D, Perone P, Fligiel SE, Datta SC, Wang ZQ, Shao Y, Kang S, Fisher GJ, Voorhees JJ. Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. Am J Pathol. 2001; 158(3):931–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Roh E, Kim JE, Kwon JY, Park JS, Bode AM, Dong Z, Lee KW. Molecular mechanisms of green tea polyphenols with protective effects against skin photoaging. Crit Rev Food Sci Nutr. 2017; 57(8):1631–7.

    PubMed  Article  PubMed Central  Google Scholar 

  134. 134

    Pillouer-Prost AL. Fibroblasts: what’s new in cellular biology?J Cosmet Laser Ther. 2003; 5(3-4):232–8.

    PubMed  Article  PubMed Central  Google Scholar 

  135. 135

    Fitzpatrick RE, Rostan EF. Reversal of photodamage with topical growth factors: a pilot study. J Cosmet Laser Ther. 2003; 5(1):25–34.

    PubMed  Article  PubMed Central  Google Scholar 

  136. 136

    Pierce GF, Brown D, Mustoe TA. Quantitative analysis of inflammatory cell influx, procollagen type I synthesis, and collagen cross-linking in incisional wounds: influence of PDGF-BB and TGF- β1 therapy. J Lab Clin Med. 1991; 117(5):373–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Abdelkrim H, Juan D-B, Jane W, Mohamed A, Bernat S. The immune boundaries for stem cell based therapies: problems and prospective solutions. J Cell Mol Med. 2009; 13(8a):1464–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Seo YS, Ko IO, Park H, Jeong YJ, Park JA, Kim KS, Park MJ, Lee HJ. Radiation-induced changes in tumor vessels and microenvironment contribute to therapeutic resistance in glioblastoma. Front Oncol. 2019;9.

  139. 139

    Ephrem E, Elaissari H, Greige-Gerges H. Improvement of skin whitening agents efficiency through encapsulation: Current state of knowledge. Int J Pharm. 2017; 526(1-2):50–68.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140

    Hearing VJ, Tsukamoto K. Enzymatic control of pigmentation in mammals. FASEB J. 1991; 5(14):2902–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141

    Cichorek M, Wachulska M, Stasiewicz A, Tymińska A. Skin melanocytes: biology and development. Adv Dermatol Allergol/Postepy Dermatologii I Alergologii. 2013; 30(1):30.

    Article  Google Scholar 

  142. 142

    Sharad J. Glycolic acid peel therapy–a current review. Clin Cosmet Investig Dermatol. 2013; 6:281.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143

    Quevedo Jr WC, Holstein TJ, Dyckman J, McDonald CJ, Isaacson EL. Inhibition of UVR-induced tanning and immunosuppression by topical applications of vitamins C and E to the skin of hairless (hr/hr) mice 1. Pigment Cell Res. 2000; 13(2):89–98.

    CAS  Article  Google Scholar 

  144. 144

    Ryser S, Schuppli M, Gauthier B, Hernandez DR, Roye O, Hohl D, German B, Holzwarth JA, Moodycliffe AM. UVB-induced skin inflammation and cutaneous tissue injury is dependent on the MHC class I-like protein, CD1d. J Investig Dermatol. 2014; 134(1):192–202.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 145

    Faustin B, Reed JC. Sunburned skin activates inflammasomes. Trends Cell Biol. 2008; 18(1):4–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146

    Liu H, Yue J, Lei Q, Gou X, Chen SY, He YY, Wu X. Ultraviolet B inhibits skin wound healing by affecting focal adhesion dynamics. Photochem Photobiol. 2015; 91(4):909–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147

    Eming SA, Werner S, Bugnon P, Wickenhauser C, Siewe L, Utermöhlen O, Davidson JM, Krieg T, Roers A. Accelerated wound closure in mice deficient for interleukin-10. Am J Pathol. 2007; 170(1):188–202.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148

    Jackson WM, Nesti LJ, Tuan RS. Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med. 2012; 1(1):44–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  149. 149

    Kato J, Kamiya H, Himeno T, Shibata T, Kondo M, Okawa T, Fujiya A, Fukami A, Uenishi E, Seino Y, et al. Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats. J Diabetes Complicat. 2014; 28(5):588–95.

    Article  Google Scholar 

  150. 150

    Matias MA, Saunus JM, Ivanovski S, Walsh LJ, Farah CS. Accelerated wound healing phenotype in interleukin 12/23 deficient mice. J Inflamm. 2011; 8(1):39.

    CAS  Article  Google Scholar 

  151. 151

    McCartney-Francis N, Mizel D, Wong H, Wahl L, Wahl S. TGF- β regulates production of growth factors and TGF- β by human peripheral blood monocytes. Growth Factors. 1990; 4(1):27–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152

    Kiritsy CP, Lynch SE. Role of growth factors in cutaneous wound healing: a review. Crit Rev Oral Biol Med. 1993; 4(5):729–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153

    Mateo RB, Reichner JS, Albina JE. Interleukin-6 activity in wounds. Am J Physiol Regul Integr Comp Physiol. 1994; 266(6):1840–4.

    Article  Google Scholar 

  154. 154

    Moulin V. Growth factors in skin wound healing. Eur J Cell Biol. 1995; 68(1):1–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Peplow PV, Chatterjee MP. A review of the influence of growth factors and cytokines in in vitro human keratinocyte migration. Cytokine. 2013; 62(1):1–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156

    Werner S, Krieg T, Smola H. Keratinocyte–fibroblast interactions in wound healing. J Investig Dermatol. 2007; 127(5):998–1008.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157

    Ansel J, Perry P, Brown J, Damm D, Phan T, Hart C, Luger T, Hefeneider S. Cytokine modulation of keratinocyte cytokines. J Investig Dermatol. 1990; 94(6):101–7.

    Article  Google Scholar 

  158. 158

    Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989; 245(4919):752–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159

    Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, Kupper TS, Sehgal PB, Gottlieb AB. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci. 1989; 86(16):6367–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160

    Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M. Keratins and the keratinocyte activation cycle. J Investig Dermatol. 2001; 116(5):633–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161

    Marfia G, Navone SE, Di Vito C, Ughi N, Tabano S, Miozzo M, Tremolada C, Bolla G, Crotti C, Ingegnoli F, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 2015; 11(4):183–206.

    PubMed  PubMed Central  Article  Google Scholar 

  162. 162

    Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180(4):2581–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163

    Cuevas-Diaz Duran R, González-Garza MT, Cardenas-Lopez A, Chavez-Castilla L, Cruz-Vega DE, Moreno-Cuevas JE. Age-related yield of adipose-derived stem cells bearing the low-affinity nerve growth factor receptor. Stem Cells Int. 2013;2013.

  164. 164

    Condé-Green A, Marano AA, Lee ES, Reisler T, Price LA, Milner SM, Granick MS. Fat grafting and adipose-derived regenerative cells in burn wound healing and scarring: a systematic review of the literature. Plast Reconstr Surg. 2016; 137(1):302–12.

    PubMed  Article  CAS  Google Scholar 

  165. 165

    Luu CA, Larson E, Rankin TM, Pappalardo JL, Slepian MJ, Armstrong DG. Plantar fat grafting and tendon balancing for the diabetic foot ulcer in remission. Plast Reconstr Surg Glob Open. 2016; 4(7).

  166. 166

    Weasel SLH. Molecular epidemiology in environmental health: the potential of tumor suppressor gene p53 as a biomarker. Environ Health Perspect. 1997; 105:155–63.

    PubMed  PubMed Central  Google Scholar 

  167. 167

    Brash DE SJLAGMBHHAPJ Rudolph JA. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A. 1991; 88:10124–8.

    PubMed  PubMed Central  Article  Google Scholar 

  168. 168

    Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA, Halperin AJ, Baden HP, Shapiro PE, Bale AE, et al.Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancer. Proc Natl Acad Sci. 1993; 90(9):4216–20.

    CAS  PubMed  Article  Google Scholar 

  169. 169

    Xian D, Lai R, Song J, Xiong X, Zhong J. Emerging perspective: role of increased ROS and redox imbalance in skin carcinogenesis. Oxidative Med Cell Longev. 2019; 2019:1–11.

    Google Scholar 

  170. 170

    Wäster P, Orfanidis K, Eriksson I, Rosdahl I, Seifert O, Öllinger K. UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins–TGF- β1–FAP- α. Br J Cancer. 2017; 117(4):535–44.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171

    Wong RS. Mesenchymal stem cells: angels or demons?J Biomed Biotechnol. 2011;2011.

  172. 172

    Yves-Gerard Illouz M. Breast cancer treatment by adipose-derived stem cells: an experimental study. J Stem Cells. 2014; 9(4):211.

    PubMed  PubMed Central  Google Scholar 

  173. 173

    Xie H, Liao N, Lan F, Cai Z, Liu X, Liu J. 3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition. Int J Mol Med. 2018; 41(3):1385–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Onzi GR, Ledur PF, Hainzenreder LD, Bertoni APS, Silva AO, Lenz G, Wink MR. Analysis of the safety of mesenchymal stromal cells secretome for glioblastoma treatment. Cytotherapy. 2016; 18(7):828–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. 175

    Lee JH, Park CH, Chun KH, Hong SS. Effect of adipose-derived stem cell-conditioned medium on the proliferation and migration of B16 melanoma cells. Oncol Lett. 2015; 10(2):730–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176

    Zarei F, Abbaszadeh A. Application of cell therapy for anti-aging facial skin. Curr Stem Cell Res Ther. 2019; 14(3):244–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177

    Attar-Schneider O, Zismanov V, Drucker L, Gottfried M. Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation. Tumor Biol. 2016; 37(4):4755–65.

    CAS  Article  Google Scholar 

  178. 178

    Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017; 18(9):1852.

    PubMed Central  Article  CAS  Google Scholar 

Download references


Not appliacable.


The project is supported by the National Natural Science Foundation of China (Grant No. 81873937) and the National Science Foundation for Post-doctoral Scientists of China (Grant No. 2019M662073).

Author information




CSD summarized the references and was the major contributor in writing the manuscript. HZG and XJH made substantial contributions to the conception, design, and critical revision of the manuscript. All authors read and approved the final manuscript and agreed to be responsible for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

Corresponding authors

Correspondence to Zhigang He or Jinghong Xu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, S., He, Z. & Xu, J. Application of adipose-derived stem cells in photoaging: basic science and literature review. Stem Cell Res Ther 11, 491 (2020).

Download citation


  • Adipose-derived stem cell
  • Photoaging
  • Exosome
  • Conditioned medium
  • Reactive oxygen species
  • Aging
  • Secretome
  • Skin aging