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Review

Potential of Plant Stem Cells as Helpful Agents for Skin Disorders—A Narrative Review

by
Anastasia Aliesa Hermosaningtyas
1,2,
Justyna Chanaj-Kaczmarek
2,
Małgorzata Kikowska
2,
Justyna Gornowicz-Porowska
2,*,
Anna Budzianowska
2 and
Mariola Pawlaczyk
2
1
Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznań, Poland
2
Department and Division of Practical Cosmetology and Skin Diseases Prophylaxis, Poznan University of Medical Sciences, Collegium Pharmaceuticum, 3 Rokietnicka St., 60-806 Poznań, Poland
*
Author to whom correspondence should be addressed.
Appl. Sci. 2024, 14(16), 7402; https://doi.org/10.3390/app14167402 (registering DOI)
Submission received: 26 May 2024 / Revised: 19 August 2024 / Accepted: 20 August 2024 / Published: 22 August 2024
(This article belongs to the Special Issue Antioxidants in Natural Plant Products: From Biological Activities to Applied Efficiency Evaluation)
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Abstract

:
Recently, cellular senescence has been of great interest due to its pleiotropic nature and association with both physiological (e.g., aging) and pathological conditions. Excessive accumulation of reactive oxygen species (ROS) can induce inflammation, which accelerates skin aging (also premature aging) and may cause several dermatoses. It has been postulated that plant-derived antioxidants, especially plant stem cells, may prevent cell damage by preserving stemness and reducing cellular senescence by ROS targeting. Therefore, this paper aims to review and summarize recent developments and innovative techniques associated with plant-derived stem cells in relation to skin senescence. This review also presents the possible pathways involved in this process. Particular attention was paid to the potential applications of plant stem cells as senostatics/senomorphics produced by modern plant biotechnology methods. Furthermore, the advantages, limitations, and future directions of this technology are also discussed. This knowledge allows the development of personalized strategies to create a healthy balance in skin care. Plant stem cells could be a more feasible and practical approach to combating the adverse effects of skin senescence processes.

1. Introduction

The Latin term ‘senex’ is used to denote an ‘older adult’ or ‘old age’ and the adjective ‘senectus’ is the root of the English term ‘senescence’, which describes the process of gradual deterioration following development and maturation [1]. Hayflick and Moorhead were the first to formally describe the process of cellular senescence, which they observed in in vitro human diploid cells that reached their maximum proliferative capacity and ceased cellular division without any signs of cell death [2].
The skin, the human body’s biggest organ, consists of three layers: the epidermis, the dermis, and the hypodermis (subcutaneous tissue) [3,4,5,6]. It is also the most accessible organ, reacting to the external and internal environments, which affects its aging process [7,8]. The exposomes which may accelerate the aging of the skin include environmental pollutants, tobacco smoke, and ultraviolet radiation (UVR). UVR has been estimated to account for over 80% of senescence caused by the external factors [9,10].
The process of skin aging is intricate and encompasses all layers of the skin. It is coupled with the build-up of senescent cells and a phenomenon known as “senescence-associated secretory phenotype” (SASP) [11]. Senescent cells are irreversibly cell-cycle arrested via the p53–p21CIP1 or the p16INK4a–Rb axis, accumulate senescence-associated β-galactosidase activity (SA-β-gal), and exhibit typical morphology [1,12]. SASP is defined as a combination of growth hormones, chemokines, cytokines, and proteases that promotes tumor development and inflammation [12]. Senescence, as a pleiotropic process, is discussed both in physiological conditions as well as in various, mainly age-related, skin disorders, e.g., skin cancers, psoriasis, pigmentation disorders, bullous pemphigoid, cutaneous lupus erythematosus, and alopecia areata [7,13]. Although the senescent cells positively affect wound healing and tissue repair, over time, their continuous presence and accumulation might be harmful [12]. Importantly, it should be emphasized that senescence and aging are closely connected but not synonymous processes [7]. Senescence contributes to aging and age-related diseases, but as a pleiotropic process, it is also linked with various physiological and pathological stages.
It is crucial to identify and develop effective as well as safe senolytics/senostatics for topical therapy. Therefore, compounds attenuating or reversing senescence could be promising agents for anti-aging skin treatments. Apart from specific drugs whose anti-aging effectiveness has been observed, skin senescence can also be suppressed with natural bioactive products and medicinal plants [14,15,16,17,18]. The study of plant resources as natural antioxidants and enzyme inhibitors has focused on their relationship to skin barrier disturbance, inflammation, melanin hyperpigmentation, and different skin disorders. They have become valuable components of cosmetic formulations that aim to inhibit or impede senescent processes in the skin [19].
The use of plant extracts or organs (leaves, fruits, flowers, bark, and roots) in pharmaceutical and cosmetic contexts dates back to ancient times [20]. Active plant constituents are responsible for several features, including moisturizing, nourishing, photoprotection, antioxidation, anti-wrinkling, astringency, cleaning, and whitening [16,19,21,22,23,24,25]. Worldwide interest in natural-based products has led to an increase in demand for these products and has developed a fast-growing market. It is estimated that the world’s herb production reached 0.5 million tons per year, occupying around 70,000 hectares of cultivation area. However, conventional production of plant raw materials is highly dependent on climate conditions, soil composition, and the genetic makeup of the plants themselves. Thus, it is more difficult to obtain uniform raw materials for pharmaceutical and cosmetic production [26]. Owing to technological advances, modern biotechnology allows the production of biomass, which is independent of climate, seasonal, and geographical factors, and the controlled extraction process of these valuable compounds from plant stem cells. This approach ensures a high-quality, fast, consistent, and increased yield of secondary metabolite compounds while still providing a uniform biomass, complying with good laboratory practices and good manufacturing practices [27].
This study provides an overview of the latest advancements and scientific research conducted between 2013 and 2023 on plant-derived stem cells in relation to age-related skin senescence. The production of plant stem cells from different plant species was highlighted in this review. Moreover, attention was paid to the possible applications of plant stem cells as senostatics/senomorphics produced by plant biotechnology.

2. Methodology

A review of the literature was conducted to provide an overview of the data about the role of plant stem cells in skin senescence. The findings are shown in the format of a topical overview. Publications were retrieved from the academic search engines PubMed, Google Scholar, Scopus, and ScienceDirect, and the standard search engine Google. Multiple search terms were used, including ‘skin’, ‘senescence’, ‘plant’, and ‘stem cells’. A hand search of relevant journals and reference lists was also conducted. The abstracts were read to assess their relevance. Studies about the properties and application of plant stem cells in cosmetology, published between 2013 and 2023, were selected based on the experimental workflow, starting cell culture production on in vitro or in vivo studies on skin-derived cells. Using this method, 28 papers were identified. Each publication was then read and analyzed, allowing the identification of the relevant references, and an additional 75 relevant papers were included in this review.

3. Divide and Conquer: Harnessing Biotechnology for Plant Stem Cell Cultivation

Plants are totipotent, which means they can grow, develop (self-renewability), and differentiate cells to regenerate whole plant bodies for an unlimited period of time [28,29]. That ability is lost by some animal cells after the embryonic phase. Primary stem cells in intact plants are established during the process of embryogenesis. They are later localized in the specialized meristem structure in the shoot (shoot apical meristem—SAM), root (root apical meristem—RAM), and (pro)cambium [28,30,31]. A transit-amplifying matrix cell population in the meristem peripheral zone surrounds the stem cells in the shoots. Meanwhile, stem cells in the root rely on the quiescent center as the source of the maintenance signal [30]. Secondary meristems established during the post-embryogenesis phase include cambium, phellogen, and traumatic meristem (callus). As seen in Figure 1, the callus, a collective unorganized cell mass, can still be generated by the whole plant body in response to stressors (physical, chemical, or biological) [28,32].
Stable cell suspension cultures can be generated when undifferentiated cells/calluses are propagated under a controlled liquid media environment. Biotechnological methods for the development of plant cell culture offer a renewable and environmentally sustainable alternative to extracting bioactive compounds [33]. The workflow for obtaining cell culture is presented in Figure 2.
Until recently, cosmetic industries have been using extracts or compounds isolated from plants traditionally grown in the ground or harvested from various natural sites. However, the provision of fresh materials, regardless of the season and the plant reproductive cycle, has always been the source of limitations to their application in both the pharmaceutical and cosmetic industries, e.g., instability of cultivating some taxa, low metabolite content in the raw materials, and challenges associated with the extraction process [27]. Thus, the novel approach to producing quality-controlled anti-senescence plant-derived bioactive components—in vitro plant tissue and cell culture—will be perceived as a valid alternative. Callus development in plants is triggered by robust stimulation of the meristem, which hosts plant stem cells and serves as the primary origin of all plant tissues [34].
Not only are the products obtained using biotechnology methods reproducible, but they also meet the requirements of good manufacturing (GMP) and laboratory practices (GLPs). Standardized and controlled conditions allow the achievement of repeatable conditions, regardless of the geophysical properties, and avoid environmental contamination [27,35,36]. The development of plant cell cultures using biotechnology methods provides better quality secondary metabolite compounds, continuous production, higher production yield, and phytochemically uniform biomass [27,37]. Some publications have reported in vitro plant systems producing secondary metabolites [38,39,40,41], and these promising compounds are beneficial for skin health and aesthetics [33,42,43,44,45,46,47]. Species for which phytochemical and skin activity studies were conducted simultaneously in recent years were selected and are presented in Table 1. Moreover, plant stem cell extracts have been studied for their cosmetic properties, with the extracts often being formulated into creams for topical application. Research shows that these extracts have positive effects on skin physiology, as summarized in Table 2.

4. Mechanistic Insights into the Skin Aging of Plant-Derived Stem Cells

Because of its strategic placement, human skin is susceptible to intrinsic and extrinsic aging. Internal/endogenous factors, such as genetic makeup, hormone changes, or inflammation, often impact intrinsic aging, resulting in stem cell failure and senescent cell accumulation. Extrinsic aging is caused by exogenous causes such as pollution, sunlight exposure, lifestyle, stress, and cellular oxidative stress [73,74]. Figure 3 depicts the external and endogenous factors that contribute to skin aging.
The mechanisms of action of natural senolytics (eliminate senescence cells) or senomorphics (adjust characteristics of senescent cells to mitigate senescence symptoms, without cell elimination) are different and must be fully understood. The role of plant stem cell extracts in preventing cellular senescence is related mainly to oxidative stress, inflammation, and autophagy.

4.1. Antioxidant Activity

Oxidative stress has long been considered one of the significant causes of premature aging [75]. The reactive molecule species, known as oxidants, cause damage to the structure and function of DNA, proteins, and lipids. Moreover, they have negative effects on particular regulatory systems and signaling pathways in cell metabolism [76]. Excessive accumulation of reactive oxygen species (ROS) can induce inflammation by triggering the signaling of the inflammatory process via nuclear factor kappa B (NF-ĸB) and secretion of the pro-inflammatory cytokines, e.g., interleukin 6 (IL-6) cellular senescence, which accelerates skin aging and may be the cause of several dermatoses [55,77,78,79]. Moreover, ROS plays a major role in intrinsic skin aging, and this process is mostly dependent on transcription factors that activate and upregulate the MMP-1, MMP-3, and MMP-9 expression [76]. This way, fibroblasts reduce their proliferative activity, downregulate the extracellular matrix protein synthesis, and become senescent cells [55,79]. The degradation of existing tissue, as well as a decline in the ability of keratinocytes to renew and differentiate, contributes to the aging process [76].
It has been postulated that plant-derived antioxidants, especially plant stem cells, may prevent cell damage by preserving stemness and reducing cellular senescence by ROS targeting [50,80]. Guidoni et al. observed that flavonoids and phenolic compounds in plant stem cell extracts exhibit antioxidant and anti-inflammatory properties by stimulating fibroblasts, increasing their proliferative capacity and migration, and inhibiting the NF-ĸB signaling pathway [55]. Several known plant-derived phenolic acids and vitamins with important antioxidant properties are listed in Table 3 below. However, Kornienko et al. demonstrated that the senolytic effect of antioxidants depends on their dose and the type of target cells [45].
UV irradiation is one of the important factors in extrinsic skin aging. This process is caused by UV-A, UV-B, and infrared radiation. UV-B rays can cause DNA breaks in the epidermis and cause immunosuppressive and inflammatory effects [76]. Therefore, many cosmeceutical products promote UV protection activity. The cell extract of Dolichos biflorus was evaluated in vitro against fibroblasts and keratinocytes. It exhibits the ability to mitigate cellular damage caused by UV-B radiation by reducing interleukin expression. Furthermore, it decreases the production of MMP-1 and MMP-3 caused by UV-A radiation [56]. A similar result was also obtained from Aster yomena and Tiarella polyphylla in the in vitro fibroblast assay [48,70].

4.2. Anti-Inflammatory Activity

Various plant-derived metabolites, such as flavonoid glycosides, phenolic acids, sterols, triterpenes, and lignans, have been proven to exhibit anti-inflammatory activity. It has been demonstrated that the hydrosoluble Rubus ideaus cell culture extract demonstrates significant anti-inflammatory properties, primarily attributed to high concentrations of flavonoids and anthocyanins. This is confirmed by a marked reduction in the expression of inducible Nitric Oxide Synthase 2 (iNOS2) and Cyclo-oxygenase 2 (COX2) [68]. Cho et al. observed that the anti-inflammation activity of the Edelweiss cell extract suppressed iNOS2 and COX2 expression in UV-induced inflammation in a non-dose-dependent manner [22]. Phenolic acid contents in the Cirsium eriophorum cell extract were discovered to play a role in the regulation of the inflammatory response, negatively modulating the overexpression of pro-inflammatory cytokines IL-1α, IL-1β, IL-8, and tumor necrosis factor alpha (TNF-α) in keratinocytes, due to microbial aggression [53]. All in all, the findings of the abovementioned studies indicate that plant stem cell extracts are effective anti-inflammatory agents in UV-induced and bacterial inflammation.

4.3. Regulation of Gene Expression

As cell aging progresses, the synthesis of genes related to collagen fiber production decreases, while the presence of matrix metalloproteinases (MMPs), cytokines, chemokines, and growth factors becomes more pronounced [90]. Interactions between plant stem cell extracts, with the proteins involved in the transcription and expression of genes related to cell metabolism, proliferation, inflammation, as well as growth, lead to the elimination of the senescent cells and neutralization of SASP. Plant callus extracts have demonstrated substantial benefits in the treatment of animal cells. A recent study showed that the Swiss apple callus extract stimulated the growth of human stem cells, protected umbilical cord blood stem cells from UV radiation-induced cell death, and reversed the aging process in fibroblasts, resulting in an extended lifetime of human skin cells [72]. Further studies demonstrated that plant stem cell extracts inhibit the activity of elastase [48,61,63], tyrosinase [52], hyaluronidase [61,63], collagenase/MMP-1 [48,56,70], and gelatinase/MMP-2,9 [22,50], thus maintaining skin integrity and containing skin alterations such as skin tones, deep wrinkles, and loss of resilience [61,63]. Higher MMP-2 expression is one of the biomarkers for skin senescence, as it leads to the degradation of the extracellular matrix, causing wrinkles and loss of elasticity [91]. Inhibition of that gene resulted in improved skin elasticity, dermal density, and periorbital wrinkles [22]. Of note, a positive correlation was found between higher MMP-2 expression and longevity, which might be indicative of a link between inflammaging and longevity [92]. Ceramide production through the expression of glucocerebrosidase (GBA) and sphingomyelin phosphodiesterase 1 (Smpd1) increased significantly in keratinocyte cells treated with raspberry stem cell extract. Moreover, the extract also increased the expression of the genes involved in skin hydration, suggesting the effectiveness of the raspberry stem cell extract in maintaining skin hydration and preventing excessive water loss in aged skin [68]. These results indicated that the extract of plant stem cells might effectively exhibit a protective effect in UV-induced photo-aged or photodamaged models [10]. Recently, a combined therapy with plant stem cells has been proposed. Ji et al. reported that plasma-treated plant stem cells showed increased expression of collagen synthesis protein-related genes, resulting in skin regeneration [93].

4.4. Improving Cell Proliferation

During the process of wound healing, the tissue undergoes four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. The hemostasis and the inflammation phases occur immediately after injury and are associated with the removal of dead cells [90]. The occurrence of tissue injury initiates the activation of immune cells, resulting in the generation of pro-inflammatory cytokines. These include potent initiators of fibrogenesis such as IL-1β, TNF-α, and transforming growth factor beta (TGF-β) [94]. Cells treated with Daphne odora and Coffea canephora stem cell extracts suppressed pro-inflammatory cytokines TNF-α and IL-6 as well as IL-1β and IL-8, respectively [21,55]. Moreover, the Coffea canephora extract inhibited the NF-κB transcription factor. The results suggest that the flavonoids, phenolic acids, and lignan components from the stem cells of these species are valuable anti-inflammatory and anti-fibrotic agents in skin wound healing. Anti-fibrotic activity was also reported for the dipeptide Gly-Pro (GP) isolated from the Hibiscus sabdariffa cell culture. It is postulated that the activity was achieved by regulating the TGF-β1-ATF4-serine/glycine biosynthesis pathway [59].
Mechanical stress and TGF-β signaling at the proliferation stage cause the cells to migrate into the wound site. Under the regulation of TGF-β, fibroblasts could multiply and secrete collagens I and III and fibronectin [95,96]. It was further shown that senescent cells accelerate wound closure by inducing myofibroblast differentiation through platelet-derived growth factor AA (PDGF-AA) secretion [95] and restricting fibrosis formation due to matricellular protein CCN1 expression in the wound site [83]. Plant stem cell extracts can accelerate healing of the skin cells during the proliferation phase. The mechanism of wound healing through fibroblast or keratinocyte proliferation was shown to be stimulated by Fitzroya cupressoides [57], Citrus junos [52], Coffea canephora [54,55], Pueraria candollei [66], and Pyrus pyrifolia [19] from their scratch test assay. Moreover, these extracts also induce cell migration [19,55,64,69], resulting in accelerated wound closure. The deposition of the extracellular matrix proteins and cellular adhesion through fibronectin synthesis was also observed after treatment with Daphne odora [21] and Hibiscus syriacus [60]. However, a detailed understanding of how plant stem cell extracts improve wound healing at the molecular level remains to be fully elucidated.

5. Promising Agent for Skin Aging Treatment: Extracellular Vesicles

Extracellular vesicles (EVs) have received a significant amount of attention, emerging as potential agents for the treatment of skin aging [97,98,99,100,101] and facilitators of intercellular communication through biomolecules. Despite restricted understanding, plant-derived EVs show promise in skin rejuvenation because they exhibit favorable biological characteristics for treating age-related skin conditions [102]. It is postulated that plant stem cells release exosome-like structures when cultured in vitro and that these vesicles may harbor anti-inflammatory and potentially regenerative functions. Recent findings indicate that exosome-like structures from plant stem cells might stimulate skin fibroblast proliferation, collagen production, and in vitro wound healing. Furthermore, they can reduce pigmentation of the melanocytes and decrease anti-inflammatory function in the macrophages [103]. EVs are small lipid bilayer nanoparticles released into the extracellular space by various cell types. They may be classified into three types based on size and biogenesis: exosomes (50–200 nm), microvesicles (100–1000 nm), and apoptotic bodies (500–5000 nm) [104,105,106]. Interestingly, several sources reported that callus-derived EVs seemed promising as far as skin aging therapies were concerned [62]. The mechanism of anti-senescence action of callus-derived EVs involves inhibition of ROS production, reduction in melanin production, and increased expression of essential skin proteins (filaggrin—FLG, aquaporin 3—AQP3, collagen type 1—COL1) in fibroblasts [62]. Further characterization and functional studies of exosomes derived from plant stem cells are necessary.

6. Large-Scale Production of Plant Cell Cultures

The research on cultivating plant cells and organs continued to advance to acquire a greater phytochemical output, particularly for industrial-scale manufacturing. Routien and Nickell discovered a method of cultivating plants in liquid culture under submerged and aerated conditions, which was followed by the production of secondary metabolites from Lithospermum erythrorhizon Sieb. et Zucc. and Coptis japonica (Thunb.) Makino using suspension culture systems of a mass of undifferentiated cells for shikonin and berberine production [107]. A breakthrough in cosmetic application and production from plant stem cells began with the publication of the findings of the research on Malus domesticus stem cells for skin and hair longevity [72]. Since then, knowledge and understanding of the manufacturing process based on plant cell culture improved greatly and found its way into the cosmetic industry.
Stirred-tank and wave bioreactors are effective systems for producing plant cell cultures. A stirred-tank bioreactor is the most common because it provides simple scalability, high oxygen transfer capability, a proper fluid mixing system, and a wide range of alternative impellers [108]. The process of Paclitaxel production uses stainless steel bioreactors with a capacity of up to 75,000 L, demonstrating the robustness and capability of mass-scale production [37]. This type of bioreactor is widely used in cosmetic industries, e.g., for the cell cultures of cloudberry [109], marigolds [33], Japanese aster [48], Asiatic pennywort [50], Edelweiss [22] and sacred lotus [23], as shown in Table 1.
Wave bioreactors adopt the mixing mechanism based on the rocking wave-like movement of a disposable inflated bag-like container. The motion also promotes oxygenation and bulk mixing with shear, stress-free characteristics. Moreover, a wave bioreactor is easy to operate and time-effective (no preparation, cleaning, or sterilization is required). Also, it increases biomass productivity, does not change cell morphology, and has low contamination risk [110,111]. A wave bioreactor is used to produce pharmaceutically important isoflavones from Glycine max (L.) Merr. and Nicotiana tabacum L. suspension cells up to 70 and 100 L working volume [112]. Wave bioreactors have also found practical applications in the production of cellular biomass, which is an ingredient of cosmetic formulations containing such valuable taxa as Malus domestica Borkh. [24,72], Vitis vinifera L., Argania spinosa (L.) Sheels, and Rhododendron ferrugineum L. [37,113].

7. Limitations

Although plant stem cells could overcome conventional challenges associated with plant material, such as limited plant quantities, undomesticated species, and sometimes rare plant sources, they are not without limitations and drawbacks. Plant growth regulators are used for the induction and proliferation of plant stem cells, such as 2,4-D, BAP, Picloram, Dicamba, Kinetin, and NAA, as listed in Table 1. Although these regulators are potent for plant cell induction and proliferation, some are hazardous to the environment and animal biological system—for instance, 2,4-D. Previous studies on 2,4-D (growth regulator and herbicide) revealed that it polluted the soil, air, and surface water and could cause neuropathologic effects in animal models [114,115]. Therefore, additional efforts must be made to dispose of by-products and waste properly. In addition, Muselikova and Mouralova have recently reported that using 2,4-D at different concentrations leads to morphological changes in the plant model, BY-2 tobacco, and anomalous tumor-type proliferation growth [116]. Their research might explain the effectiveness of 2,4-D as an inductor and proliferator for plant stem cells. However, it also implies that the quality system frameworks are crucial. Regular testing should be done to ensure that there is no bioaccumulation of harmful and toxic compounds on the final product that may cause illness [117,118].
Research on the use of plant stem cells as an active ingredient is a relatively new trend in cosmetology. While skincare products containing plant stem cells have shown various advantageous benefits on aging skin, there are still numerous concerns that may restrict their usage. Although cosmetics do not include live stem cells, they utilize stem cell extracts to reduce wrinkles and enhance skin firmness through their action and antioxidant properties [43,44]. These extracts are commonly found in cosmetic products, but their effectiveness may be hindered by limited transdermal penetration. To address this, further research is needed to optimize formulations and overcome the skin’s natural barrier function. Additionally, the application of plant stem cells in clinical practice is a recent and emerging approach; thus, long-term side effects may still need to be discovered. Therefore, the effects of plant stem cells on aging skin still require further, better, and more profound research.
The production of valuable extracts or secondary metabolites from plant stem cells requires fulfilling the quality system frameworks, including good manufacturing practices (GMP), good laboratory practices (GLPs), quality control (QC), and quality assurance (QA) [119]. Potential challenges during plant stem cell production include ensuring product consistency and purity, controlling microbiological contaminations, and ensuring product comparability [118]. Furthermore, ethical issues must be considered when the research progresses to trials using animal models or clinical trials [119]. All these practices are essential to ensure the safety of consumers.

8. Commercial Misconceptions

A recent innovative concept from the field of cosmetology suggested using plant stem cells in cosmetic preparations, as they have similar functional characteristics to human stem cells. Studies found that cosmeceuticals (cosmetics with therapeutic effects), due to their higher content of active compounds containing plant stem cells, may stimulate epidermal stem proliferation, cell renewal, skin protection, regeneration, and anti-aging effects [24,25]. In contrast, others believe that plant stem cells can only stimulate the proliferation of other plant cells, while their impact on human cells may be negligible, and growth factors affecting plant cells may, in fact, have no effect on human cells. Regrettably, numerous manufacturers claim to use ‘plant stem cells’ in their cosmetic formulations. However, these products do not incorporate live cells. Instead, the metabolites and the active compounds are extracted from these stem cells. Substances derived from these stem cells do not function in the same way as living plant stem cells. The cell content is released by digestion of the cell wall and membrane, releasing an abundance of metabolites and active compounds. The alleged benefits of smoother and tighter skin are primarily attributed to the antioxidative properties and active compounds of the stem cell extracts. Stem cells must be incorporated as live cells in the product in order to fully realize their potential in skin-care products. The challenge lies in embedding these cells into a medium that might enable deep skin penetration and ensure real benefits for the skin [27,44].

9. Conclusions and Future Perspective

The application of plant extracts to inhibit skin senescence has been practiced for centuries. Nowadays, plant stem cell technology has gained significant attention. Plant stem cell-derived products have inherent antioxidant and anti-inflammatory activities, which are significant contributors to inhibiting cellular aging. Studies have shown that plant stem cell products work through various mechanisms, such as stimulating fibroblast proliferation, enhancing extracellular matrix production, and modulating gene expression related to skin senescence. Moreover, using biotechnological methods to cultivate plant stem cells ensures a sustainable and consistent supply of high-quality bioactive compounds.
Owing to their complex biochemical nature, with multiple active phytochemicals acting synergistically, plant-derived stem cells appear to offer much promise as far as anti-senescence skin treatment is concerned. However, so far, only a limited number of studies, mainly in vitro, have demonstrated direct anti-senescence mechanisms of plant stem cells. Further in vivo studies are needed to investigate the safety, dosing regimens, and clinical efficacy of plant stem cells. Interestingly, the use of combined therapy and chemo-herbal fusion in skin therapy, especially in skin biomaterials, has been suggested. In that way, plant stem cells could be a more feasible and practical approach to combating the negative effects of skin senescence processes.

Author Contributions

Conceptualization, J.G.-P., M.K. and M.P.; writing—original draft preparation, A.A.H., J.C.-K., A.B. and J.G.-P.; writing—review and editing, A.A.H., J.G.-P. and M.P.; visualization, A.A.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Anastasia Aliesa Hermosaningtyas participates in the Poznan University of Medical Science STER Internationalization of Doctoral Schools Programs of the NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/0014/DEC/02. Selected artwork (skin–dermatology) shown in Figure 3 was used from or adapted from pictures provided by Servier Medical Art (Servier; https://smart.servier.com/, accessed on 25 July 2024), licensed under a Creative Commons Attribution 4.0 Unported License. Selected icons (cell, cells, and chemical molecule) used in Figure 3 were extracted and modified from Flaticon.com.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Plant callus, the unorganized cell mass, which has been obtained and maintained through the use of biotechnological methods, is capable of producing a higher quality of secondary metabolite compounds and has the additional benefits of continuous production, a higher production yield, and a phytochemically uniform product. Selected lines of stabilized homogenous callus lines of (a,b) Eryngium planum, (c) Plantago ovata, (d,e) Lychnis flos-cuculi, (f) Chaenomeles japonica cultured under controlled conditions at Laboratory of Pharmaceutical Biology and Biotechnology, Collegium Pharmaceuticum, Poznan University of Medical Sciences.
Figure 1. Plant callus, the unorganized cell mass, which has been obtained and maintained through the use of biotechnological methods, is capable of producing a higher quality of secondary metabolite compounds and has the additional benefits of continuous production, a higher production yield, and a phytochemically uniform product. Selected lines of stabilized homogenous callus lines of (a,b) Eryngium planum, (c) Plantago ovata, (d,e) Lychnis flos-cuculi, (f) Chaenomeles japonica cultured under controlled conditions at Laboratory of Pharmaceutical Biology and Biotechnology, Collegium Pharmaceuticum, Poznan University of Medical Sciences.
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Figure 2. Schematic presentation of biotechnological steps in the process of obtaining plant secondary stem cells.
Figure 2. Schematic presentation of biotechnological steps in the process of obtaining plant secondary stem cells.
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Figure 3. Schematic representation of exogenous and endogenous factors that contribute to skin aging.
Figure 3. Schematic representation of exogenous and endogenous factors that contribute to skin aging.
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Table 1. Plant stem cell culture with biological activities in skin senescence (in vitro and in vivo study).
Table 1. Plant stem cell culture with biological activities in skin senescence (in vitro and in vivo study).
SpeciesCommon NameExplantCulture TypeSystemsMediumCompoundsBiological AssaysBiological Activities Associated with Age-Related Skin SenescenceRef
Aster yomena (Kitam.) Honda (Asteraceae)Japanese asterRootCallus and cell suspensionBioreactorMS + 1 mg/L 2,4-Dflavonoids (robustic acid, 3,5-Di-O-methyl-8-prenylafzelechin-4beta-ol)in vitro using keratinocytesinhibits elastase and MMP-1, promotes type I procollagen synthesis, anti-inflammatory (inhibition of TNF-α, IL-8, and IL-1β), antioxidant activity[48]
Calycophyllum spruceanum (Benth.) Hook.f. ex K.Schum. (Rubiaceae)MulateiroSeedingCallusFlaskMS + 1 mg/L NAA + 1 mg/L BAPnot specifiedin vitro using fibroblastsantioxidant activity and anti-senescence effect against oxidative damage[49]
Centella asiatica (L.) Urb (Apiaceae)Asiatic pennywortSeedlingCallusBioreactorMS + 1 mg/L NAA + 1 mg/L BAPnot specifiedin vitro using fibroblastsinhibits MMP-9 expression, antioxidant activity[50]
Chaenomeles japonica Lindl. ex Spach (Rosaceae)Flowering quince, he yuan ziLeafCallusFlaskMS + 1 mg/L 2,4-D + 0.1 mg/L KINpentacyclic triterpenoids, flavonoidsin vitro using fibroblastsantioxidant activity and stimulates fibroblast proliferation[51]
Citrus junos Siebold ex Tanaka
(Rutaceae)		Yuzu Leaf, flower, seedCallus and cell suspensionFlaskMS + 2 mg/L Picloramphenolic compounds (mainly p-hydroxycinnamoylmalic acid)in vitro using fibroblastsinhibits the activity of tyrosinase and the biosynthesis of melanin, promotes fibroblast proliferation and the synthesis of procollagen, regenerative activity, moderate antioxidant activity[52]
Cirsium eriophorum (L.) Scop. (Asteraceae)Woolly thistleLeafCell suspensionFlaskB5 + phytohormonespolyphenolsin vitro fibroblasts and keratinocytes, in vivoregulates essential markers (5α-reductase and trypsin-like serine protease Kallikrein 5) associated with sebum secretion and pore enlargements[53]
Coffea canephora Pierre ex A.Froehner (Rubiaceae)Robusta coffeeLeafCell suspensionFlask½ MS salt + B5 vitamins + 2 mg/L 2,4-D + 1 mg/L BAPnot specifiedin vivoenhances wound healing, facilitates extracellular matrix production, regulates the inflammatory response, and stimulates neovascularization.[54]
Callus and cell suspensionFlasknot specifiedflavonoids (catechin gallate, rutin), phenolic acids (caffeic acid, rosmarinic acid)in vitro using fibroblastsinhibits the NF-ĸB signaling pathway, reduces the production of cytokines (IL-6, TNF-α), increases the proliferation and migration of fibroblasts, and antioxidant activity[55]
Daphne odora Thunb.
(Thymelaeaceae) 		Jinchoge, winter daphneLeafCell suspensionFlaskB5 + 1 mg/L 2,4-D + 0.1 mg/L KINflavonoid (kaempferol and glucosidic derivatives, luteolin, daphnodorins), lignans (wikstromol, pinoresinol, and lariciresinol)in vitro using fibroblasts and keratinocytes, in vivomodulates the sebum regulator 5α reductase 1, inhibits the pro-inflammatory cytokines IL-1β and IL-8 and TNF-α, increases membrane permeability and nutrient delivery and accelerates the wound healing capacity by inducing actin and fibronectin synthesis[21]
Dolichos biflorus L. (Fabaceae)Catjang, sow-peaLeafCell suspensionFlaskB5 + 1 mg/L 2,4-D + 0.1 mg/L KINisoflavonesin vitro using fibroblasts and keratinocytes, in vivoprevents damage on a cellular level by decreasing the UVB-induced interleukin expression, reduces the UVA-induced expression of MMP-1 and MMP-3 enzymes[56]
Fitzroya cupressoides (Molina) I.M.Johnst (Cupressaceae)AlerceNeedleCallusFlask½ LP + 1.5 mg/L 2,4-D + 0.75 mg/L of BAP + 1% sucrosenot specifiedin vitro using fibroblasts and melanocytesstimulates cell division in human skin epidermal cells in wound repair mechanism[57]
Hibiscus sabdariffa L. (Malvaceae)Red-sorrel, roselle, sereniSeedingCallusFlaskMS + 1 mg/L 2,4-Dpeptidesin vitro using keratinocytesanti-melanogenic effects, functions for skin barrier, antioxidant activity, promotes healing of radiation-injured skin cells[58]
LeafCallusFlasknot specifieddipeptidein vitro using fibroblastsexhibits potent anti-fibrotic effects[59]
Hibiscus syriacus L. (Malvaceae)Rose of SharonLeafCell suspensionFlaskB5 + 1 mg/L 2,4-D + 0.1 mg/L KINflavonoids, coumarins, naphthalene carbaldehydein vitro fibroblasts and keratinocytesaccelerates the wound healing activity (epithelium formation and fibronectin production), increases the expression of genes involved in skin hydration and homeostasis[60]
Isodon rugosus (Wall. ex Benth.) Codd (Lamiaceae)Deciduous shrubStem, leafCallusFlaskMS + NAA or TDZ or BAPpentacyclic triterpenoids (plectranthoic acid,
oleanolic acid, betulinic acid), phenolic acids (caffeic acid, rosmarinic acid)		in vitroinhibits degradation of collagen, elastase, hyaluronic acid melanin production, antioxidant activity[61]
Leontopodium alpinum Colmeiro ex Willk. & Lange (Asteraceae)EdelweissLeafCell suspensionBioreactorMS + BAP + 2,4-Dnot specifiedin vitro using fibroblasts and keratinocytesdecreases COX-2 and iNOS gene expression, antioxidant activity, anti-wrinkle activity[22]
Stem, leafCell suspensionFlaskMS + 0.3 mg/L 2,4-D + 0.5 mg/L BAPextracellular vesiclesin vitro using fibroblast, keratinocytes and murine-derived melanomaantioxidant activity, reducing melanin production, increasing filaggrin, aquaporin 2, and collagen production[62]
Linum usitatissimum L.
(Linaceae) 		FlaxHypocotyl, cotyledon, rootCell suspensionFlaskMS + 2 mg/L BAP + 0.5 mg/L NAAneolignan, phenolic acid, furofuran, furan, dibenzylbutanein vitroinhibits tyrosinase and elastase, antioxidant activity[63]
Nelumbo nucifera Gaertn.
(Nelombonaceae)		Sacred lotusLeafCell suspensionBioreactorMS + 0.05 mg/L NAAnot specifiedin vitro using melanoma, in vivoantioxidant activity and skin-soothing properties, skin-whitening effect[23]
Oryza sativa L. (Poaceae)RiceSeedCell suspensionFlaskChu N6phenolic compoundsin vitro using fibroblastspromotes the migration of fibroblasts to facilitate tissue regeneration and wound healing[64]
CallusFlaskMS + 2 mg/L 2,4-D + 1 mg/L NAA + 1 mg/L BAPphenolic compounds, amino acidsin vitro using keratinocytespromotes keratinocyte proliferation, inhibits degradation of collagen and melanin production, antioxidant activity, anti-inflammatory activity[65]
Pueraria candollei var. mirifica (Airy Shaw & Suvat.) Niyomdham
(Fabaceae)		Thai kudzuSeedlingCell suspensionFlaskMS + 0.2 mg/L 2,4-Disoflavonoid (daidzein)in vitro using fibroblastspromotes fibroblast proliferation, oxidative damage prevention[66]
Pyrus pyrifolia (Burm.f.) Nakai (Rosaceae)KumoiLeafCell suspensionFlaskMS + 2 mg/L Picloramuridine, adenosine, and guanosinein vitro using fibroblasts and keratinocytespromotes keratinocyte proliferation and migration, increases procollagen synthesis in fibroblasts; inhibits biosynthesis of melanin, antioxidant activity[19]
CotyledonCell suspensionFlaskMS + 2 mg/L Picloramphenolic compounds, flavonoidsin vitro using fibroblast[67]
Rubus idaeus L.
(Rosaceae)		European raspberry, red raspberryLeafCell suspensionFlaskB5 + 1 mg/L 2,4-D + 0.1 mg/L KINfatty acids (palmitic, stearic, oleic, linoleic, α-linolenic acids, arachidic, arachidonic), phenolic acids (coumaric, ferulic acid), flavonoids (kaempferol)in vitro using fibroblasts and keratinocytes, in vivoinduces the genes responsible for skin hydration (aquaporin 3, filaggrin, involucrin, and hyaluronic acid synthase), stimulates the expression and activity of glucocerebrosidase for ceramide production[68]
Rhus coriaria L.
(Anacardiaceae) 		Sicilian sumac, Tanner’s sumacLeafCell suspensionFlaskB5 + 0.5 mg/L NAA + 0.2 mg/L IAA + 0.02 mg/L KIN + 4% sucrosegallic acidin vitro using fibroblasts and keratinocytesinduces significant keratinocyte migration and wound closure[69]
Tiarella polyphylla D.Don (Saxifragaceae)Foam flowersStemCallusFlask½ MS + 1 mg/L BAP + 0.3 mg/L 2,4-Dnicotiflorin, astragalin, quercitrin, myricitriin vitro using fibroblastsanti-aging via regulation of the type I procollagen reduction and MMP-1 (collagenase-1) secretion in dermal fibroblasts by UVB irradiation[70]
Woodfordia fruticosa Kurz.
(Lythraceae) 		Fire flame bushLeafCallusFlask½ MS + 0.25 mg/L 2,4,5-T + 0.10 mg/L BAPpolyphenolsin vitro using human and murine fibroblastincreases the synthesis of collagen-I and elastin[71]
2,4-D—2,4-dichlorophenoxyacetic acid; 2,4,5-T—2,4,5-trichlorophenoxy acetic acid; B5—Gamborg B5 medium; BAP—N6-benzyladenine; GDF11—Growth Differentiation Factor 11; IAA—indole-3-acetic acid; IL—interleukin; KIN—kinetin; MMP—matrix metalloproteinase; MS—Murashige and Skoog medium; NAA—1-aphthaleneacetic acid; LP—Quorin and LePoivre medium; TDZ—thidiazuron; TNF-α—tumor necrosis factor-alpha; UVA/B—Ultraviolet A/B.
Table 2. Clinical applications of plant stem cells against skin aging.
Table 2. Clinical applications of plant stem cells against skin aging.
Plant SourcesParticipants
(n; Age Range)		Formulation/ApplicationClinical EffectsRef
Cirsium eriophorum40 (20–40)Cream (0.5%)/twice daily for 4 weeks
  • reduced the sebum production
  • reduction in the number of visible pores
  • reduced transepidermal water loss
  • enhanced epidermal moisture level
[53]
Daphne odora20 (18–65)Cream (0.002%)/twice daily for 4 weeks
  • increased hydration
  • decreased transepidermal water loss
[21]
Leontopodium alpinum21 (48)Cream (1%)/twice daily for 4 weeks
  • decreased roughness parameters of periorbital wrinkles
  • increased skin elasticity parameters
  • increased dermal density and skin thickness
[22]
Malus domestica20 (37–64)Cream (2%)/twice daily for 4 weeksreduction in wrinkles[72]
Table 3. Effect of topically applied major classes of phytoantioxidants on human skin.
Table 3. Effect of topically applied major classes of phytoantioxidants on human skin.
CompoundFunction as an AntioxidantRef
Polyphenols, especially flavonoids and phenolic acidsProtection against oxidative stress-induced cellular damage through inhibition of reactive oxygen and nitrogen species (RONS) and the ability to chelate transition metal ions such as Fe (II) and Cu (II),
Reduction in the expression of matrix metalloproteinases that catalyze the degradation of skin proteins in epidermal keratinocytes and dermal fibroblasts
Protection of other antioxidants, such as vitamin C in the cytosol or vitamin E in biological membranes
Protection against UV-induced peroxidation of cell membrane lipid acids, reduction in oxidative stress caused by sunlight and oxygen		[16,81,82,83,84]
Vitamin CROS scavenger
Protection of the viability of cell membranes by promoting the expression of genes encoding antioxidant enzymes
Inhibition of lipid peroxidation by regenerating fat-soluble vitamin E
Reduction in UVA-induced oxidative stress		[16,85,86]
Vitamin EInhibition of lipid peroxidation and formation of 8-hydroxydeoxyguanosine—a biomarker of oxidative DNA damage
Protection against the damage of UVB-radiation		[16,87]
CarotenoidsProtection of cell membranes and lipoproteins from oxidative damage by ROS scavengers
Regeneration of tocopherol from the tocopheroxyl radical
Prevention of photooxidative damage		[88,89]
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Hermosaningtyas, A.A.; Chanaj-Kaczmarek, J.; Kikowska, M.; Gornowicz-Porowska, J.; Budzianowska, A.; Pawlaczyk, M. Potential of Plant Stem Cells as Helpful Agents for Skin Disorders—A Narrative Review. Appl. Sci. 2024, 14, 7402. https://doi.org/10.3390/app14167402

AMA Style

Hermosaningtyas AA, Chanaj-Kaczmarek J, Kikowska M, Gornowicz-Porowska J, Budzianowska A, Pawlaczyk M. Potential of Plant Stem Cells as Helpful Agents for Skin Disorders—A Narrative Review. Applied Sciences. 2024; 14(16):7402. https://doi.org/10.3390/app14167402

Chicago/Turabian Style

Hermosaningtyas, Anastasia Aliesa, Justyna Chanaj-Kaczmarek, Małgorzata Kikowska, Justyna Gornowicz-Porowska, Anna Budzianowska, and Mariola Pawlaczyk. 2024. "Potential of Plant Stem Cells as Helpful Agents for Skin Disorders—A Narrative Review" Applied Sciences 14, no. 16: 7402. https://doi.org/10.3390/app14167402

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