Usually, burn wounds do not bleed right away after being injured. Still, hemostasis and vasoconstriction are the first steps in the healing process for burn wounds, just like they are for other traumas (Johnson et al., 2022). Constriction of the damaged vessels initiates hemostasis quickly after injury, preventing excessive blood loss. This process, also known as the pro-inflammatory stage, starts as soon as the damage occurs. After tissue damage, prostaglandin 2-α and thromboxane A2 are released into the injured area, leading to an extreme vasoconstrictor reaction that lasts for 5 to 10 min. The small vessels in the wound are then constricted to achieve hemostasis. Vasodilation, or the enlargement of blood vessels, comes next and reaches its peak 20 min after it. As a result, tissue hypoxia and acidosis develop, dampening the vasoconstrictive effect and heightening vascular permeability for inflammatory cells. At this point, platelets are crucial because they initiate the clotting process and release numerous signaling molecules such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibronectin, fibrinogen, histamine, serotonin, and the Von Willebrand factor (Abazari et al., 2022; Lasocka et al., 2019).

The inflammatory phase attracts more cells to the wound site, including neutrophils, mast cells, monocytes, and T lymphocytes. When a wound is this far along in its healing process, it shows changes in a number of different substances, including transforming growth factor-β (TGF-β), tumor necrosis factor alpha (TNF-α), EGF, PDGF, VEGF, FGF, IL-1, IL-6, IL-8, and IL-12. These mediators influence angiogenesis, collagen synthesis, epithelialization, and the regulation of the inflammatory process (Lasocka et al., 2019).

Macrophages stimulate cell growth and migration by secreting FGF, PDGF, VEGF, and TGF-α/TGF-β. In addition, macrophages eliminate pathogens and debris from the injury site (Bai et al., 2022). During the early phases of healing, M1 macrophages play a role in phagocytic activity, phagocytosing neutrophils, and eliminating any remaining bacteria or debris in a wound. The transition from M1 to M2 initiates fibroblast proliferation and angiogenic activity by producing anti-inflammatory mediators and extracellular matrix (ECM) (Miricescu et al., 2021). Other than leukocytes, regulatory T cells (Tregs) can control tissue inflammation by reducing the production of interferon-γ (IFN-γ) and augmenting the number of macrophages that promote inflammatory responses (Sorg et al., 2017). Once macrophages begin secreting EGF and PDGF, they create granular tissue, allowing tissue regeneration to progress into the proliferative phase (Abazari et al., 2022).

This stage involves the repair of blood vessels and the formation of granulation tissue at the wound site through a series of continuous processes, including angiogenesis, fibroblast migration, and epithelialization. It begins 4 days after the injury and lasts for 2 weeks (Abazari et al., 2022; Ayavoo et al., 2021; Fakouri et al., 2024). Angiogenesis occurs under particular conditions, such as low oxygen tension and low pH, in the wound’s area. Fibroblasts, macrophages, and epidermal cells produce bFGF, VEGF, and TGF-β, which promote it. Fibroblasts are the most common cells during the proliferative phase because they are the ones that create the new matrix needed to restore the structure and form of injured tissue. TGF-β and PDGF cause fibroblast proliferations, which are released from a hemostatic clot and migrate to the damaged arteries (Ayavoo et al., 2021). At this time, activated fibroblasts that have differentiated into myofibroblasts begin contracting the wound’s edges (Guillamat-Prats, 2021).

Fibrin, fibronectin, and collagen are all products of fibroblast cells attaching to a matrix. Tissue granulation begins at the wound site when collagen and fibronectin are secreted. Finally, epithelial cells build a full layer on the wound by increasing their mitotic activity, and they are attached to the cell matrix. The final step is the creation of the basement membrane by the aggregation of mature epithelial cells (Ayavoo et al., 2021). When the wound is fully covered and an intact epithelial barrier is reestablished, the process of epithelial migration and proliferation ends. M2 macrophages control the proliferation and migration of keratinocytes, fibroblasts, and endothelial cells, which leads to tissue regeneration and an abundance of ECM. High amounts of immature collagen type III are secreted into the matrix by fibroblasts (An et al., 2021).

In the final stage of wound healing, termed as remodeling or maturation, cellular and vascular components gradually decrease. This phase normally begins after the finalization of granulation tissue growth and lasts for a very long time, anywhere from 21 days to a year following the injury (Qin et al., 2023). Wound re-epithelization by keratinocytes and ECM deposition by fibroblasts and endothelial cells mark the beginning of the remodeling phase of wound healing (El Ayadi et al., 2020). The last stage of wound healing ends when scar formation occurs (Sorg et al., 2017), which is largely dependent on how the collagen fibers are arranged. Small, parallel bundles of collagen are characteristic of normal scars, while hypertrophic scars are characterized by thinner, more numerous, and more cross-linked collagen fibers (El Ayadi et al., 2020). In the following, collagen I begins to gradually replace collagen III (Kirby et al., 2015). Collagen I is deposited more slowly than collagen III but has greater tensile strength and thus replaces collagen III in the ECM (El Ayadi et al., 2020). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are the main factors that regulate this process (Kirby et al., 2015).

BM-MSCs are a class of heterogeneous cells made up of multipotent stem cells that Frieden first recognized (Gao et al., 2022). Just 0.002% of all stromal cells are BM-MSCs (Mazini et al., 2019). They have the capacity to differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, epithelial cells, neuron cells, fibroblasts, myofibroblasts, keratinocytes, and endothelial cells (Revilla et al., 2023). The first type of cells to be employed in burn wound therapy is BM-MSCs. It has been demonstrated that BM-MSCs have the capacity to promote angiogenesis, scarless healing, and enhanced collagen formation, all of which are crucial factors in effective wound healing.

BM-MSCs have several benefits, but low yield and restricted availability of donors are among their disadvantages (Abdul Kareem et al., 2021). Despite the traditional harvesting of stem cells from the bone marrow, which is an invasive method with low efficiency, the ability of cell fusion enables them to regenerate tissue and immunity (Francis et al., 2019). BM-MSCs have the ability to modulate the immune system. They directly inhibit the proliferation of monocytes, DCs, and inflammatory T cells. In addition, they produce mediators that reduce inflammation, including IL-1Ra, PGE2, IDO, and IL-10 (Gherghel et al., 2023) (Table 2).

In a research by Xue et al., BM-MSC was injected into 30 mice that had burn injuries. In with the control group, the recovery period shortened from 25 to 20 days (Purwanthi, n.d.). Singer et al. conducted a similar investigation using a rat model and found that injecting rat BM-MSCs intravenously can postpone the course of burn damage in a rat comb-burn model measured from the necrotic region (Singer et al., 2013). Formigli et al. (2015) used a mouse model to study what happened when BM-MSCs were transplanted onto bioengineered scaffolds that had platelet-rich plasma (PRP) in them. The test results showed evidence of improved skin regeneration quality, less collagen deposition, more neoangiogenesis, and repaired sebaceous glands and hair follicles (Formigli et al., 2015).

Aryan et al. (2019) conducted a study with the aim of determining whether hBM-MSC can enhance wound healing in deep second-degree burns in male rats. They randomly divided 32 adult male rats per time point into four groups: (1) control group, (2) sham group (DMEM), (3) common treatment group (CT), and (4) conditioned media group (CM). They reported that, relative to the control and DMEM groups, the CM and CT groups demonstrated a significant enhancement in wound closure on the 15th and 28th days after the burn injury. In addition, hBM-MSC facilitated increased cell proliferation, and it promoted both collagen synthesis and angiogenesis at the injury site (Aryan et al., 2019).

The first study to describe AD-MSCs was by Zuk in 2001, which piqued the interest of researchers (Czerwiec et al., 2023). AD-MSCs exist between adipocytes and the vascular endothelium. Adipose tissue can be used to easily separate 100% of local MSCs, and retrieval does not need cell culture. These stem cells, which can repair all layers of skin, can also be extracted from discarded burn skin (Abdul Kareem et al., 2021). Fat stem cell research on mice has demonstrated that by boosting tissue renewal and cell proliferation, it also boosts the development of new blood vessels and the control of proteins (Lukomskyj et al., 2022). Furthermore, the advantages of AD-MSCs are their high availability, minimum invasiveness, and no restrictions (Nourian Dehkordi et al., 2019). Zhu et al. (2012) demonstrated that AD-MSCs grew and doubled quicker than BM-MSCs (Abu-El-Rub et al., 2024). Compared to BM-MSCs, adipose tissue extraction has fewer risks and negative effects. They can also develop into multiple cell lineages and produce nutrients and immune-modulating substances (Goncharova et al., 2019).

The best option in regenerative medicine is AD-MSCs since they are readily available, contain macrophages, fibroblasts, and endothelial stem cells, and have incredible pluripotent potential (Abdul Kareem et al., 2021). AD-MSCs reduce the inflammatory response by upregulating chemokines and cytokines through Th cells and IL-10 (Liu et al., 2018). Zhang et al. (2018) found that AD-MSCs’ paracrine activity boosts wound healing (Jo et al., 2021). Researchers have conducted clinical studies with AD-MSCs using both autologous and allogeneic transplants. The allograft method’s low immunological rejection risk is another benefit of AD-MSCs, but there are a few drawbacks to take into account before using AD-MSCs. This specific cell population has limited ability to self-renew (Czerwiec et al., 2023).

AD-MSCs are widely used in plastic surgery, and depending on the type of adipose tissue that is harvested, they have different functions. White adipose tissue, which is extracted from visceral and subcutaneous surfaces, has the ability to store triglycerides, and brown adipose tissue is extracted from the neck, mediastinum, supraclavicular, and par scapular regions. They are involved in the production of body heat, the ability to modulate the immune system, neoangiogenesis, and endogenous repair; they cause wound regeneration; and by releasing hormones such as leptin, they can be effective in wound healing (Francis et al., 2019). Paganelli et al. (2019) used MSCs sourced from adipose tissue to construct a dermal replacement for wound healing. This substitute exhibited excellent mechanical qualities and remarkable biocompatibility (Jo et al., 2021) (Table 2).

One of the finest sources of MSCs is the umbilical cord. They include both hematopoietic and non-hematopoietic cells, as well as endothelial progenitor cells. Different stem cell types may be extracted from the numerous layers of the umbilical cord, including Wharton’s jelly, veins, arteries, the lining of the cord, and the sub meningeal and perivascular areas (Abdul Kareem et al., 2021; Phan et al., 2023). Due to their adaptability, simplicity in isolation and culture, rapid proliferation, easier differentiation, and immunosuppressive qualities, umbilical cord-derived MSCs have enormous potential as a therapeutic tool in tissue engineering and regenerative medicine (Jo et al., 2021; Phan et al., 2023).

According to the studies, it was shown that the umbilical cord stem cell has a high ability to heal burn wounds by increasing skin appendages and creating fibers. However, this source has more limited access compared to fat tissue and bone marrow (Lukomskyj et al., 2022). Umbilical cord cells have abilities such as detecting inflammatory tissues, differentiating to prevent inflammation, and performing anti-inflammatory activities. By releasing cytokines, they cause wound tissue repair and regeneration. In laboratory conditions, they have the ability to transfer to the body and differentiate into efficient cells (Atluri et al., 2020). Studies in rats indicated that UC-MSCs hastened wound healing by blocking inflammatory cell infiltration, decreasing IL-6, 1, and TNF-a, and boosting IL-10 and TSG-6 (Nourian Dehkordi et al., 2019). According to a study by Liu et al. (2016), UC-MSCs lessened acute inflammation in rats that had suffered severe burns. They demonstrated the TNF-stimulated gene/protein 6 (TSG-6) anti-inflammatory mechanism (Xiong W. et al., 2023).

An abundant supply of MSCs can be found in the umbilical cord’s Wharton’s jelly-like matrix (Nazempour et al., 2020). MSCs from Wharton’s jelly (WJ-MSCs) promote wound healing by reducing inflammation (Mansour et al., 2023). There are several advantages to using WJ-MSCs, including its accessibility to a broad pool of donors, ease of acquisition, lack of danger to the donor, lack of ethical constraints, low immunogenic potential, and high differentiation capability (Owczarczyk-Saczonek et al., 2018) (Table 2). They show significant immunomodulatory activity similar to BM-MSCs (Nazempour et al., 2020). These cells have the potential to transform into cells that gland-like cells, which speeds up the healing process of the skin (Hashemi et al., 2020). In addition, the donor is completely safe because contact with infectious pathogens is so infrequent (Owczarczyk-Saczonek et al., 2018).

Over a century has passed since placental tissue (PL) was first used to treat wounds (Azzopardi et al., 2013b). PL is an excellent source of growth factors and stem cells, which are vital to healing and creating new tissues (Teoh et al., 2023). There are several benefits associated with the placenta: the ability to obtain the maximum number of cells; the possibility of harvesting them using non-invasive techniques; a lower immune response than BM-MSCs due to their embryonic origin; and favorable immunomodulatory effects in vitro (Abd-Allah et al., 2015; Maxson et al., 2012) (Table 2).

In 2006, Chang et al. showed that PL-MSCs had a much stronger immunosuppressive impact than BM-MSCs (Malek and Bersinger, 2011). PL-MSCs differentiate into adipocytes, osteocytes, chondrocytes, endothelial cells, and neuronal cells (Maxson et al., 2012; Makhoul et al., 2013). Compared to BM-MSCs, PL-MSCs exhibit greater proliferation ability. However, Li et al. showed that BM-MSCs migrate faster than PL-MSCs, which suggests that BM-MSCs are better able to get through the endothelial blood vessel barrier (Makhoul et al., 2013). PL-MSCs’ ability to stimulate neovascularization, wound diminution, and enhanced blood flow speeds up the healing process (Shojaei et al., 2019).

Research has shown that PL-MSCs exhibit high quantities of the cell adhesion molecules programmed death ligands 1 and 2 (PD-L1 and PD-L2), which may block T-cell proliferation by stopping the cell cycle (Shojaei et al., 2019).

The amniotic membrane (AM) has been the subject of extensive studies as a cell source for regenerative therapies. This membrane is responsible for the fetus’s physical defense, pH control, and the release of anti-inflammatory substances (Miatmoko et al., 2023). The AM lacks vascular tissue and contains a three-layer structure. It consists of an epithelial cell monolayer, an acellular intermediate layer, and an outer layer that contains MSCs (Roubelakis et al., 2012). Generally, the AM includes amniotic membrane-derived MSCs (AMSCs), amniotic epithelial cells (AECs), and fibroblasts (Hu et al., 2023; Nejad et al., 2021). The AM-MSCs have the ability to differentiate into cells of the ectodermal, mesodermal, and endodermal layers (Kim et al., 2014).

The epithelium seems to be a source of biologically significant stem cells. Extracellular matrix proteins such as collagen and fibronectin make up the basement membrane. Both the stroma and the spongy layer contain vital chemicals and agents for regeneration (Pfister et al., 2023). AECs secrete several substances that suppress T and B lymphocyte proliferation as well as the chemotactic abilities of neutrophils and macrophages in inflammatory circumstances such as wounds. Another interesting finding is that AM binds to T cells and other leukocytes, preventing them from taking part in the inflammatory process (Aghayan et al., 2022).

AM-MSCs are the sources of keratinocyte growth factors (KGF) and EGF (Miatmoko et al., 2023). Since 1910, the usage of human amniotic membrane (hAM) grafts in the therapy of burn wound healing has increased significantly (Rahman et al., 2019). The AM influences wound healing through the absorption and transplantation of endogenous progenitor cells, which promotes neovascularization and wound repair. AM decreases the local inflammatory response as a result of the release of chemokines and cytokines that regulate the immune response at the site of the wound. Consequently, AM can have a favorable impact on wound healing (Pfister et al., 2023).

Studies using mouse models have demonstrated that AM usage decreases local inflammation, promotes cell renewal, and also promotes collagen formation. In addition, the use of AM was linked to a reduction in the number of bacteria in infected mouse burn wounds. In a sheep model, Fraser et al. demonstrated that AM therapy at burn sites considerably reduced the quantity of scar tissue (Pfister et al., 2023). Some advantages of using amniotic membrane stem cells in the healing process include alleviating pain, reducing inflammation, regulating fluid loss, decreasing bacterial colonization, preventing scars, the minimum ethical considerations, and low immunogenicity. All of these advantages make amniotic membrane stem cells appealing to people and give them the chance to be used in cell therapy and regenerative medicine (Hu et al., 2023; Pfister et al., 2023) (Table 2).

Amniotic fluid (AF) is a feeding and protecting liquid that helps the embryo develop normally (Harrell et al., 2019). Amniotic fluid (AF) contains high concentrations of α-defensin, lysozyme, calprotectin, and cathelicidin, as well as TGFα, TGFβ1, insulin-like growth factor 1 (IGF1), and erythropoietin (EPO) (Nyman et al., 2022). AF-MSCs were first identified as a source for wound healing in 2013 (Rahman et al., 2019). AF-MSCs are obtained from AF samples during the second trimester (16–28 weeks) through amniocentesis (Harrell et al., 2019; Anudeep et al., 2022). Many research studies have shown that volume, donor variability, and gestational stage are the three most important factors that affect the number of cells obtained from amniocentesis (Teoh et al., 2023) (Table 2).

The risks of AF harvesting during the second or third trimester include harm to the mother or fetus, infection, premature labor, and even miscarriage. Nonetheless, AF obtained following cesarean section births appears to be a non-invasive, abundant, and high-yield cell source for cell treatment (Mankuzhy et al., 2021). AF-MSCs are adult, fibroblast-like, self-renewable, multipotent stem cells with broad distinction and minimal immunogenicity (Harrell et al., 2019). AF-MSCs express a variety of antigens, such as HLA-ABC, CD73, CD44, CD105, CD166, CD117, CD29, CD49e, CD58, and CD90, but these cells do not express hematopoietic markers such as CD34, CD14, CD45, CD133, CD31, and HLA-DR (Mankuzhy et al., 2021).

The hair follicle (HF) is a dynamic little organ that supports several vital bodily biological processes. HFs are a readily available source of stem cells that may self-renew, differentiate, control hair growth, and help maintain skin homeostasis. Research has demonstrated that hair follicle stem cells (HFSC) are both multipotent and extremely proliferative in laboratory settings (Mistriotis and Andreadis, 2013). HFSCs exhibit immunological rejection, making them the ideal donors for cell-based therapies. According to Li et al.’s study, HFSCs are superior to other cell types at repairing wounds (Abdul Kareem et al., 2021).

Studies on the usage of HF-MSCs in wound healing are still limited (Ou et al., 2020). There are a number of benefits to using HF-MSCs, including an abundance of sources, ease of access, robust cell proliferation, broad differentiation potentials, low immunogenicity, lack of age limits, no ethical issues, and non-carcinogenic (Liu et al., 2024; Li S. et al., 2022; Zaki et al., 2020). They have the potential to develop into HFs, sweat glands, sebaceous glands, keratinocytes, and inter-follicular epidermis. So, it has the potential to improve the healing process of wounds (Zaki et al., 2020) (Table 2).

According to reports by Kevin et al., HF-MSCs can aid in the healing of chronic wounds (Liu et al., 2024). When HF-MSC is used to treat wounds in vivo, it accelerates the transition from fibroblasts to myofibroblasts, which in turn reduces the duration of the proliferation stage (Yang H. et al., 2023).

Because dental pulp has a high content of cells and requires relatively few invasive methods for cell separation, it has recently been regarded as a potential source of MSCs (Abbas et al., 2018). Improvements have been shown after transplantation of DP-MSCs (derived from the teeth of adult patients), which are attributed to the production of paracrine substances by these cells (Gomes et al., 2010). Through paracrine impact, the DP-MSCS may drive endogenous stem cells to regenerate damaged tissues by secreting growth factors, cytokines, chemokines, angiogenic factors, and exosomes (Ichi et al., 2023). Studies have shown that DP-MSCs have more angiogenic potential in comparison with ASCs and BMSCs. In addition, DP-MSCs have a high level of CD73 expression (Abbas et al., 2018) (Table 2).

Research has shown that the use of human MSCs extracted from burned skin accelerates the healing process in rat and pig burn models (Surowiecka et al., 2022). Amini-Nik et al. demonstrated for the first time the presence of viable mesenchymal skin stem cells in full-thickness burned skin. Furthermore, based on their reports, these cells were easily removed, expanded in vitro, and then added to wound covering in a simple and inexpensive way. The majority of patients are willing to donate these discarded tissues. Cell isolation from burned skin is a non-invasive procedure that poses no danger to the patient. Because they are the patient’s own skin stem cells, the risk of immunological response and rejection is minimal (Amini-Nik et al., 2018) (Table 2).

In another study, MSCs were extracted from the eschar by Van der Veen et al. They believed that MSCs from the burn eschar had moved from another source of MSCs, such as subcutaneous fat, into the wound region. In addition, it has been found that burn patients’ blood has higher concentrations of circulating MSCs. The function of these cells and when they are introduced to the wound site remain uncertain. These cells have the myofibroblast phenotype, which produces ECM and contracts wounds; therefore, they may aid healing (Van Der Veen et al., 2012).

Significant amounts of phosphatidylserine and tissue factor (TF) are present on the surface of MSCs and MSC-derived extracellular vesicles (EVs), which induce coagulation. In fact, clot formation can be exacerbated because of the expression of these two elements that trigger a thrombotic reaction. Some research has demonstrated that Annexin V is on the surface of MSCs. It indicates that phosphatidylserine is present, which is what makes clots form (Guillamat-Prats, 2021).

MSCs begin to have immunosuppressive effects once they arrive at injury sites (Hu et al., 2018). MSCs immediately reduce the inflammatory response. In addition, MSCs regulate it by lowering the quantity of neutrophils, macrophages, and activated T cells (Maxson et al., 2012; Mahjoor et al., 2023b). Pro-inflammatory cytokines, including IL-1, TNF-α, and IFN-γ, are reduced in MSC-treated wounds, while anti-inflammatory cytokines such as IL-10 and IL-4 are increased. The immunosuppressive phenotype of MSCs is activated with exposure to pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1α, and IL-1β, leading to the expression of chemokines and inducible nitric oxide synthase (iNOS), all of which inhibit T-cell responsiveness to inflammation (Maxson et al., 2012; Hu et al., 2018).

The presence of TNF-α and IFN-γ may increase the production of cytokines such as cyclooxygenase 2 (COX2), hepatocyte growth factor (HGF), and prostaglandin E2 (PGE2) for inhibiting T-cell proliferation. Furthermore, they aid in the synthesis of chemokines such as CCR5, CCR10, and CXCL9, which prevent the growth of immunological effector cells (Huang et al., 2022). T cells emit less IFN-γ and more IL-4 to respond to MSC activity. Thus, the number of regulatory T cells rises. In addition, MSCs control the growth, development, and activity of B cells and natural killer cells (NK cells), leading to reduced IFN-γ secretion by NK cells (Maxson et al., 2012; Hu et al., 2018). MSCs can cause a switch from the pro-inflammatory M1 state to the anti-inflammatory M2 state of macrophage polarization (Ulivi et al., 2014).

Fibroblasts and myofibroblasts are crucial during the third phase of wound healing. Proliferation and restoration of epithelial cells, as well as the synthesis of collagen and ECM proteins, occur during this phase (Andalib et al., 2023). A vast array of growth factors, including PDGF, VEGF, FGF, and tumor necrosis factor-induced Dutch gene-6 (TSG-6), are also produced by MSCs and can promote the reparative abilities of fibroblasts, endothelial cells, and tissue precursor cells. MSCs, by acting on PDGF-BB, promote the migration, secretion, and proliferation of fibroblasts (Liu et al., 2022).

In the latter phases of wound healing, MSCs effectively manage matrix remodeling and scar reduction (Magne et al., 2018). MSCs play a role by secreting MMPs to induce matrix deposition and TIMPs to prevent ECM deposition. It is thought that MSCs can reduce hypertrophic scarring by secreting HGF, FGF, adrenomedullin, and TGF-3 (Riedl et al., 2021). Stoff et al. (2009) found that after transplanting human MSCs into rabbit wounds, the wounds’ tensile strength rose and scar formation was greatly reduced. These results show that future MSC therapy may result in less scarring (Li et al., 2015).