The biggest multipurpose organ in the human body, the skin, acts as a barrier to keep out harmful materials and creatures from the external environment, such as toxins and physical assaults (Yang J. et al., 2020). A wound is a physical harm that happens when the skin deforms due to damage to the skin’s internal and exterior components (Ayavoo et al., 2021). Wound healing can be impacted by several variables, including infection, foreign substances, necrosis, and comorbidities, even though the skin can restore itself to its normal condition and function (Falanga, 2005; Han and Ceilley, 2017). Prolonged wound closure raises the possibility of bacterial colonization, invasion, and even sepsis, all of which can be fatal for patients (Lemsanni et al., 2021; Soh, 2021).

Traditional wound treatment options comprise the application of antibiotics, various dressings, debridement, laser therapy, biological scaffolds, topical administration of specific growth factors, skin/flap grafting, gene therapy, and negative-pressure suction. These techniques have certain drawbacks, such as the lengthy treatment duration, high cost, and significant psychological and financial stress placed on patients (Qin et al., 2023). The initiation of tissue regeneration and repair is commonly attributed to the activation of the inflammatory response (Zhu et al., 2023). During the whole healing process, the initial stage is the inflammatory reaction. Inflammation is caused by the invasion of an area by inflammatory cells, which activates both the innate and adaptive immune systems (Gentek and Hoeffel, 2017; Rieckmann et al., 2019). Excessive inflammatory reactions can lead to severe pathological changes, including scarring and impeded wound healing. In contrast, well-controlled inflammation often promotes wound healing (Xu et al., 2012; Ogawa, 2017; Wang Z.-C. et al., 2020; Yu et al., 2021; Zhang et al., 2021). Thus, it is critical for wound healing to identify a treatment regimen that effectively modulates immune-related cells and cytokines at the site of damage to reduce inflammation at the appropriate time point (Hong et al., 2023).

Recent years have seen a notable advancement in the field of study on mesenchymal stem cells’ (MSCs) ability to promote wound healing. A subset of pluripotent stem cells known as MSCs was found in the bone marrow stroma during the 1960s. When transplanted into ectopic areas, these cells may be able to generate new bone (Friedenstein et al., 1970; Bianco et al., 2013). MSCs are thought to be the best seed cells for tissue engineering, according to recent research (Tsiapalis and O’Driscoll, 2020; Khayambashi et al., 2021). They may be extracted from a variety of tissues, such as the skin, bone marrow, adipose, umbilical cord, and dental pulp. In tissue injury, it not only has an extremely strong self-proliferation, multidirectional differentiation ability, and powerful secretion ability, but more importantly, it has an immunomodulatory function that can form a favorable inflammatory microenvironment at the site of tissue injury, release growth factors, and activate endogenous tissue repair (Wang et al., 2014; Wang et al., 2022). Existing evidence suggests that MSCs-based therapies can control and reduce inflammation but not replace damaged cells. MSCs have been used, for example, to alter organ inflammation at different tissue locations in the early stages of treating acute and chronic liver damage. For COVID-19, intravenous infusion of MSCs has also been suggested as a treatment to suppress inflammatory storms in the lungs (Verkhratsky et al., 2020). As a result, the use of MSCs in regenerative medicine must highlight both their limited ability to differentiate and their role in immunomodulation, which entails establishing a supportive immune environment and secreting growth factors to promote endogenous tissue healing (Wang et al., 2014).

However, the relationship between MSCs and inflammation is complex. It has been suggested that the immune regulation of MSCs is not intrinsic but is triggered by inflammation and is dynamically influenced by the type and amount of inflammatory cytokines (Ren et al., 2008; Wang et al., 2014). As an alternative, MSCs might respond to changes in tissue pathophysiological signals in an active manner. This would mobilize many components of the tissue immune microenvironment to achieve inflammation control, which would then aid in tissue regeneration and repair (Wang et al., 2014; Gao et al., 2021; Soliman et al., 2021). Currently, in vitro-amplified MSCs are a hotspot for therapeutic research, but there are still some outstanding problems. It has been discovered that in vitro-amplified MSCs are quickly identified and eliminated by the host’s immune system upon exogenous delivery. In addition, when MSCs are administered to some tissues with low inflammatory status, changes in their inflammatory microenvironment may lead to unstable efficacy of MSCs. These problems are considerable obstacles to its application. Therefore, knowing how to treat in vitro-expanded MSCs before transplantation is significant to improve their clinical efficacy. To increase the therapeutic effects of MSCs, many researchers have recently investigated diverse bioengineering methodologies and approaches for optimizing and pre-treating MSCs (Wang et al., 2022).

We have reviewed recent studies on the mechanisms of the role of MSCs in wound healing. In particular, we focused on the immunomodulatory role mediated by MSCs during the inflammatory phase. This article also presents a review of studies that strive to increase the therapeutic potential of MSCs and analyzes their implications for optimizing MSCs usage for tissue regeneration in clinical settings.

Dynamic and multifaceted interactions between a variety of cells, growth factors, cytokines, chemokines, and other chemicals are necessary for wound healing. Three stages are involved in the recovery of wounds: proliferative, remodeling, and hemostatic/inflammatory (Gurtner et al., 2008; Hong et al., 2023). These stages occur sequentially, although they also overlap. To initiate tissue repair and regeneration, the hemostatic/inflammatory phase is essential (Zhu et al., 2023). The sudden creation of a platelet-fibrin clot at the wound site is known as hemostasis, and it is triggered by severe skin damage. It involves almost immediate platelet aggregation and vasoconstriction (Clark, 2003; Zeng and Liu, 2021). This clot stops blood flow, lessens subsequent blood loss, and acts as a scaffold for the migration of immune and resident skin cells (Reish and Eriksson, 2008). Therefore, the histamine, bradykinin, and leukotrienes produced by nearby mast cells draw immune cells and widen blood vessels (Hong et al., 2023). Neutrophils are activated after skin injury as “first responders” by recruiting “find me” signals from the blood (Zhu et al., 2023). Several signals are produced by the wounded or infected area, including lipid mediators, hydrogen peroxide, damage-associated molecular patterns (DAMPs), calcium waves, and chemokines (Su and Richmond, 2015). Many tactics are used by activated neutrophils to degrade pathogens by proteolytic hydrolysis and oxidative bursts of microbicidal reactive oxygen species (ROS) released. This process is known as neutrophil extracellular traps (NETs) formation (Clark et al., 2007; Kolaczkowska and Kubes, 2013; Lood et al., 2016). Activated neutrophils also use phagocytosis and expel DNA decorated with particles from proteolytic hydrolysis to immobilize and eventually kill pathogens. Macrocytizing macrophages phagocytize neutrophils that have undergone extensive apoptosis in the final stages of inflammation. Inflammatory monocytes are drawn from the peripheral circulation 48–96 h after injury, and when they get to the site of damage, they change into macrophages (Geissmann et al., 2010). Macrophages (also called M1 type) are essential during the early stages of wound healing because they help promote angiogenesis and fibroplasia, synthesize nitric oxide (NO), and move the wound from an inflammatory to a proliferative phase. By producing pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6, they can also fight off infection. Reducing inflammation and restoring tissue homeostasis is made possible by macrophages’ ability to develop anti-inflammatory qualities and support tissue healing. The anti-inflammatory type M2 phenotype is developed as a result of this change. In response to IL-4/IL-13 or apoptotic neutrophils, type M2 macrophages produce platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), which encourages the proliferation of keratinocytes and fibroblasts (Russell et al., 2019). Dendritic cells (DCs) provide antigens, which stimulate T-cell responses. Helper T-cells 1 (Th1), which have proinflammatory effects during the acute inflammatory phase of the wound, are primarily driven by interferon-γ (IFN-γ). The T cells get more and more polarized throughout the inflammatory phase, which eventually turns into a Th2 response. These cells produce IL-4, IL-5, IL-10, and IL-13, which are anti-inflammatory and also have significant pro-fibrotic effects (Wallace et al., 1994; Ong et al., 1999). Th17 cells induce an immune response that overlaps with Th1 and Th2 immune responses, promoting follicular neogenesis and pro-inflammatory effects through neutrophil recruitment and wound re-epithelialization (Zhu et al., 2023). Moreover, it has been found that regulatory T cells (Tregs) promote tissue homeostasis and regeneration after tissue injury by reducing excessive inflammation (Zhu et al., 2023) Figure 1.

While an overabundance of inflammation leads to scarring, delayed wound healing, and perhaps severe pathological changes, a moderate amount of inflammation encourages wound repair (Xu et al., 2012; Ogawa, 2017; Wang Z.-C. et al., 2020; Yu et al., 2021; Zhang et al., 2021). Inflammation is a necessary component in the healing of wounds. The length and severity of the inflammatory response affect how well the lesion heals. Consequently, in order to facilitate wound healing, it is crucial to preserve a suitable and timely balance between the inflammatory and reparative phases (Hong et al., 2023). Targeting pathways that either lower inflammation or trigger repair has been the focus of intense research over the past 30 years in an effort to enhance the prognosis of wound healing/. Examples of these efforts include the use of curcumin (Akbik et al., 2014), neurotensin (NT) (Liu et al., 2019), photodynamic therapy (PDT) (Yang T. et al., 2020), silver nanoparticles (AgNPs) (Choudhury et al., 2020), and others.

Curcumin’s ability to lower inflammation is supported by the majority of research (Akbik et al., 2014). By inhibiting the synthesis of TNF-α and IL-1 as well as the activation of the nuclear factor κ light chain enhancer (NF- κ B) in activated B-cells, curcumin controls inflammation in wounds (Joe et al., 2004). As the primary source of inflammation during wound healing activity, Gopinath et al. (2004) discovered that curcumin had a scavenging impact on ROS. Unfortunately, curcumin’s quick metabolism, low solubility, high photosensitivity, and low bioavailability restrict its medicinal usefulness (Akbik et al., 2014).

NT is also a critical immunomodulator that modulates cellular functions in innate and adaptive immunity (Evers et al., 1994; Ramez et al., 2001; Bernatchez et al., 2013). Moura et al. (2014) showed that the expression of IL-1β was reduced in mice treated with NT and NT-loaded collagen, which promoted wound healing. Additional research is required to address this issue as NT therapy alone has little therapeutic potential, as does NT-collagen loading treatment. However, it dramatically accelerates wound healing and leaves more noticeable scars once recovery is complete (Moura et al. (2014).

PDT has drawn a lot of interest as a wound therapy method in recent years. Research has indicated that PDT creates pro-inflammatory cytokines such as IL-1, lipids, and a local acute inflammatory response (Gollnick et al., 2006; Brackett and Gollnick, 2011; Anzengruber et al., 2015). It also dramatically influences neutrophil activation. However, 5-aminolevulinic acid (ALA) -PDT treatment was effective in diminishing inflammatory infiltration with relatively low expression levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-23, according to Yang et al. (2021). In the mid-to-late phases of the wound-healing process, PDT therapy can decrease chronic inflammation and increase acute inflammation early in the healing phase (Yang T. et al., 2020). This indicates that PDT therapy can regulate inflammation and facilitate wound healing. However, PDT has some limitations, including pain and discomfort during treatment, long treatment duration, and instability of treatment results (Cottrell et al., 2008; Syed Azhar et al., 2018; Kaw et al., 2020), and its limited optical depth limits its application in deep tissue therapy (Li and Lin, 2022).

The anti-inflammatory activity of AgNPs has also been demonstrated in skin wounds (Tian et al., 2007; Nadworny et al., 2008; Liu X. et al., 2014; Wasef et al., 2020). It has been found that increased expression of type I collagen alpha 1 chain (Col1A1) suppressed inflammatory cytokines (IL-1α and IL-6), and inflammation was maintained at low equilibrium levels after treatment with AgNPs, effectively facilitating the healing process and decreasing the risk of chronicity in wounds (Shahverdi et al., 2007). The keratinocyte growth factor/p38 mitogen-activated protein kinase (KGF-2/p38MAPK) signaling pathway, which AgNPs mediate, controls the inflammatory response by promoting the production of early pro-inflammatory cytokines while inhibiting the early phase of the skin wound anti-inflammatory cytokine, IL-10, following injury. Zhang et al. (2020) showed that while early inflammation is crucial, prolonged inflammation is harmful to wound healing. In fact, giving mice a little late injection of AgNPs to reduce inflammation actually aided in their ability to repair wounds. However, in wounds, cell types are diverse, and the microenvironment is spatially heterogeneous, so targeting specific inflammatory factors or signaling pathways does not achieve great effectiveness (Gurtner et al., 2008; Forrester et al., 2009; Wang et al., 2022).

Therefore, the modulation of the inflammatory microenvironment is crucial in promoting wound healing. MSCs are gradually becoming the focus of promoting wound repair by modulating the inflammatory microenvironment of wounds from multiple mechanisms.

Previous research has indicated that MSCs’ primary capacity to facilitate wound healing may stem from their secretion of pro-regenerative cytokines (Garg et al., 2014). As per the latest research, MSCs could suppress immune responses in the presence of enriched inflammatory cytokines, including infection, trauma, or immune-mediated diseases. These immunomodulatory properties were discovered in preclinical and clinical trials (Margiana et al., 2022). Therefore, when it comes to the use of in vitro-expanded MSCs in regenerative medicine, we shouldn’t overemphasize their limited differentiation potential (“cell replacement”). Instead, we should concentrate on a range of responses that MSCs have to injury signals, such as migration, immunomodulation, growth factor release, tissue remodeling, etc. Growth factors are released to start endogenous tissue healing (“cellular empowerment”) and to create an environment that is favorable for the immune system (Wang et al., 2014). Specifically, MSCs exert their inflammatory modulatory effects mainly relying on direct cell-to-cell communication and paracrine secretion (Keshtkar et al., 2018). Almost all immune cells, including mast cells, natural killer (NK) cells, DCs, T lymphocytes, and so on, can interact with and change the activity of MSCs in order to restore immunological homeostasis and prevent the immune response from spiraling out of control (Wang et al., 2014; Shi et al., 2018a; Han et al., 2022). Paracrine effects are thought to be the primary mechanism of their immunomodulation (Qiu et al., 2018; Qin et al., 2023). By releasing a range of growth factors, inflammatory modulators, and extracellular vesicles (e.g., exosomes (Exos)), the local inflammatory response can be regulated by MSCs after they enter an inflammatory environment (Shi et al., 2018b). MSCs positively impact wound healing, which is supported by their capacity to control the inflammatory response to wounds. The number of inflammatory cells and pro-inflammatory cytokines was dramatically reduced by human umbilical cord-derived MSCs (e.g., IL-1, IL-6, and TNF-α) in a rat model of severe burns, according to Liu L. et al. (2014). Crucially, these wounds also showed the higher speed of healing and shorter recovery periods (Liu L. et al., 2014). Further studies have shown that Exos in the MSCs secretome are increasingly recognized as critical intercellular mediators for transmitting biological signals rather than wasted products initially thought to be processed by cells. Numerous studies have demonstrated that Exos produced from MSCs actively participate in every step of wound healing (Qin et al., 2023) Figure 2

Stem cells exhibit the capacity to repair tissue and heal wounds. Studies in both the clinic and the laboratory have shown that MSCs-based inflammatory regulation treatment is a successful tactic for accelerating wound healing. Nonetheless, the primary issue limiting their practical use is the limited survival and retention of cells following implantation. Current research emphasizes how critical it is to control inflammation early in the healing process and how MSCs can help heal wounds by influencing the local inflammatory milieu through primary immunomodulatory action. Furthermore, the adaptability of MSCs’ immunomodulation is highlighted, and methods to boost MSCs’ therapeutic effectiveness—which has been demonstrated to raise MSCs migration and survival, encourage angiogenic potential, improve immunomodulation, and increase overall efficacy—are further explored. These findings hold potential for the advancement of MSCs-based treatment approaches. In the clinical management of wounds, clinicians tend to administer antimicrobial and anti-inflammatory treatments immediately after trauma to prevent excessive inflammatory responses. In contrast, the need for inflammation may vary during different periods of wound healing. Thus, to advance the realization of precision therapy in the clinic, more thorough research is still needed to understand the molecular mechanisms underlying the interactions between MSCs and each type of immune cell, particularly the distinct requirements for inflammation regulation for different kinds of wounds and varying periods of wound healing. Future research endeavors may expand upon this study and offer valuable perspectives on the practical applications of these results.