PDLSCs are key components in the periodontal tissue engineering of seed cells. Compared to other stem cells in the jaw, PDLSCs appear to be the most effective stem cell-based therapy for repairing the alveolar bone and PDL (LI Q. et al., 2020). In particular, PDLSCs activity is regulated by mechanical stimulation (MEN et al., 2020).

The osteoblastic potential of PDLSCs has always been a hot topic. Various types of periodontal ligament stem cells have been identified, including Gli1⁺ cells, Prx1⁺ cells, Axin2⁺, and LepR⁺ cells. Gli1⁺ cells contribute to alveolar bone regeneration, and the activity of Gli1⁺ PDLSCs is regulated by physiological occlusal force (MEN et al., 2020). Gli1 is also a transcription factor required for Hedgehog (Hh) signaling, which helps regulate bone formation (SHALEHIN et al., 2022). Axin2⁺ cells help maintain periodontal tissue homeostasis and facilitate bone healing (LI Q. et al., 2020). Bone morphogenetic protein (BMP) signaling regulates the role of Axin2⁺ cells in periodontal tissue development. The conditional knockout of BMP1A damages Axin2⁺ cells, leading to periodontal defects and alveolar bone loss (XIE et al., 2022). Prx1⁺ cells are also important PDLSC isotypes associated with osteogenesis. An experimental study showed that Prx1⁺ cells are indispensable during PDL reconstruction of transplanted teeth (GONG et al., 2022). Finally, LepR⁺ cells are activated after tooth extraction and contribute to newly formed bone in the extraction socket (ZHANG D. et al., 2020). And LepR⁺ cells can contribute to periodontal homeostasis via Piezo1-mediated mechanosensing (ZHANG D. et al., 2023).

Moreover, MSCs derived from gingiva (GMSCs) have characteristics similar to those of PDLSCs in periodontal tissues, both of which exhibit high potential for osteogenic differentiation (SHEN et al., 2023). When GMSCs were implanted into an animal model of mandibular defects, they repaired the mandible and promoted new bone formation (WANG et al., 2011). GMSCs-derived exosomes can reduce the inflammatory response of PDLSCs (SUN et al., 2022).

DPSCs exhibit superior proliferative capabilities and display enhanced senescence resistance (MA et al., 2019). In addition, opportunely differentiated DPSCs showed an osteoblastic phenotype with the expression of the osteogenic marker genes ALP, RUNX2, and OCN during this process (LEE et al., 2019).

Following pulp trauma, DPSCs increase osteogenic potential through NF-kB pathway or Wnt/β-catenin signaling pathway activation (WANG et al., 2013; ZHANG et al., 2019). Extracellular vesicles (EVs) are secreted by cells. When DPSC-EVs were injected into a mandible defect model, bone formation was observed, which was comparable to the effect of BMP-2 on inducing bone formation (IMANISHI et al., 2021; LEE et al., 2023). Therefore, DPSC-EVs can provide a safe and effective cell-free treatment for jawbone regeneration.

JBMSCs originating from the jawbone demonstrate superior proliferative ability compared to marrow mesenchymal stem cells (BMSCs) (HUANG et al., 2020). Two types of cells were implanted into the periodontal tissue defect models. BMSCs only show osteogenic potential, whereas JBMSCs show cementoid, periodontal ligament-like tissue, and alveolar bone regeneration (NAKAJIMA et al., 2014). Consequently, JBMSCs are particularly well-suited for repairing jaw defects when compared to BMSCs. Implantation of autologous JBMSCs into bone defects can effectively treat jaw defects caused by maxillary cysts (REDONDO et al., 2018). JBMSCs also promote implant osseointegration by inducing osteogenic differentiation (YAN et al., 2023).

A recent study identified a distinct osteogenic progenitor derived from JBMSCs that highly expressed protocadhern Fat4 (Fat4 cells) (JIN et al., 2023). They have significant osteogenic abilities and promote osteogenic differentiation of JBMSCs. Above, we mentioned the DPSC-EVs. Under the action of DPSC-EVs, the osteogenic differentiation potential of JBMSCs is enhanced, thereby aiding jaw regeneration (LEE et al., 2023).

The interaction between the nerve and bone tissue has been demonstrated during bone repair (CARR et al., 2019). Schwann cells derived from neural crest cells or mesenchymal cells are glial cells of the peripheral nervous system that have important potential for repair and regeneration (LOPEZ-LEAL and COURT, 2016).

Schwann cells play an crucial role in regulating the bone microenvironment and that the repair of jaw defects is dependent on the repair potential of Schwann cells (SALHOTRA et al., 2020; WANG et al., 2023). The lack of Schwann cells directly leads to impaired mandibular healing (JONES et al., 2019). Schwann cells accumulate in damaged alveolar bone and promote bone healing, which is related to jaw stem cell proliferation acceleration (ITOYAMA et al., 2020; ZHANG X. et al., 2023). In addition, Schwann cell-derived extracellular vesicles can enhance the osteogenic potential of DPSCs (WANG et al., 2022). Therefore, the application of Schwann cells in jaw defects is expected to provide a new method for promoting bone regeneration by regulating the nervous system.

Stem cells derived from human exfoliated deciduous teeth (SHED), suture-derived mesenchymal stem cells (SuSC), and synovial mesenchymal stem cells (SMSC) from temporomandibular joint also exist in jaw. SHED has the potential of osteogenic differentiation and has superior proliferative (KUNIMATSU et al., 2018). SuSC can quickly migrate to the injured site and promote bone repair when the craniofacial bone is injured (MARUYAMA, 2019). SMSC has the potential of multidirectional differentiation and can differentiate into osteoblasts, chondrocytes, neurons, which is conducive to the repair of mandibular tissue (KOYAMA et al., 2011).

Undoubtedly, there are many more stem cells in the jaw than those mentioned above. Stem cells from different sources in the jaw play their own roles in maintaining the balance of jaw.

Macrophages can recruit and regulate MSC differentiation, which plays a key role in bone regeneration (PAJARINEN et al., 2019). Compared to long bones, the jaw exhibits a higher proportion of activated macrophage subpopulations, with these macrophages displaying an enhanced capacity to induce MSC proliferation and migration (LIN et al., 2021). The macrophage in the jaw is an important reason for its unique immune microenvironment.

Macrophages are the most important group of immune cells that interact with MSCs (PAJARINEN et al., 2019). The different effects of macrophages on the jawbone depend on the cytokines they secrete and their polarization. Macrophages express BMP-2, oncostatin M (OSM) and Wnt10b, which mediate osteogenic differentiation of MSCs through paracrine signaling (ZHANG et al., 2022).

There are two main types of macrophages. M1-type macrophages cause bone tissue damage by releasing TNF-α, IL-12, and IL-23, while M2-type macrophages promote sustained bone regeneration by secrete IL-10 and TGF-β (SHAPOURI-MOGHADDAM et al., 2018). Stem cells in the jaw can influence the polarization of macrophages. DPSCs and GMSCs can induce the polarization of M2-type macrophages (ZHANG et al., 2010; YANG et al., 2023). PDLSCs can downregulate the TNF-α expression and upregulate IL-10 and CD163 to promote the polarization of M2-type macrophages (LIU et al., 2019).

T cell-mediated adaptive immune responses can recruit MSCs and thus promote tissue regeneration (ZHAO et al., 2020). Regulatory T cells (Treg cells) and T cell-derived cytokines have also been demonstrated to play a positive role in bone regeneration (LI et al., 2018; YU et al., 2022).

The jawbone exhibits a higher proportion of Treg cells than the long bones (KWACK et al., 2021). Many studies have shown that PDLSCs, GMSCs, and DPSCs promote the polarization of Tregs and inhibit the polarization of Th17 cells (YANG et al., 2018; ZHENG et al., 2019; MATSUMURA-KAWASHIMA et al., 2021). And enhancement of the Treg/Th17 ratio can effectively improve bone loss (YANG et al., 2021). In a study on palatal expansion (LI J. et al., 2020), Treg cells were observed to maintain high levels in the later stages, downregulating osteoclast numbers by inhibiting Th1 and Th17 cells and participating in forming a new maxilla. In addition, T Cell-Derived IL-22 and IL-17A can promote bone regeneration by accelerating BMSC osteogenesis (ONO et al., 2016; YU et al., 2022).

B cells participate in the bone repair process and play important regulatory roles in the later bone repair stages (KöNNECKE et al., 2014). Studies have shown that jawbone marrow-derived cells have a higher B cell proportion than long bone (KWACK et al., 2021).

In periodontal inflammation states, B cells produce higher TGF-β1 levels, inhibiting osteoblast activity (CHEN et al., 2023). Switched memory B cells produce more RANKL (HAN et al., 2018), leading eventually to alveolar bone loss. Conversely, B cells help regenerate the bone. Zeng et al. discovered that a lack of B cells exacerbats alveolar bone loss (ZENG et al., 2021). Moreover, IL-10-secreting B cells reduce the expression of IL-17 and RANKL genes and inhibit Th17 cell proliferation, thereby reducing alveolar bone uptake (SHI et al., 2020). Consequently, the role of B cells in promoting or inhibiting bone loss remains unclear and warrants further research to elucidate their divergent effects on jaw stem cells.

Many neutrophils are present in the jaw. GMSCs increase the proportion of neutrophils in the immune environment (GAO et al., 2023). Neutrophils are widely believed to have anti-inflammatory, antibacterial, and tissue-repair properties (LIEW and KUBES, 2019; LIN et al., 2021). However, limited research has been conducted on bone tissue repair.

Neutrophils indirectly influence bone regeneration by recruiting important immune cells (ABARICIA et al., 2021). A recent study has shed light on the direct role of neutrophils in bone regeneration, which is required during the initial stages of bone regeneration (CAI et al., 2021). At specific IL-8 thresholds, neutrophils are recruited and undergo to acquire the anti-inflammatory N2 phenotype. N2- programmed neutrophils secrete SDF-1α to induce chemotaxis of BMSCs (WANG et al., 2021). The recruited BMSCs then trigger a regenerative cascade. In addition, BMSCs effectively inhibit neutrophil apoptosis by producing IL-6, IFN-β and granulocyte macrophage colony-stimulating factor (GM-CSF) (CASSATELLA et al., 2011). Neutrophils can also promote the expression of M2-type macrophages and Tregs, thereby indirectly contributing to regeneration (WANG et al., 2021).

The jawbone’s prolonged exposure to an oral microbiota-rich environment renders dendritic cells (DCs) more susceptible to microbial invasion (EL-AWADY et al., 2022). These cells are essential in maintaining the integrity of both the oral mucosa and the mandible (HOVAV, 2014).

DCs are indispensable for immune responses in the jawbone. PDLSCs cause DCs to skew towards a more immature phenotype, which is more conducive to he osteogenic differentiation of MSCs and jaw regeneration (YANG et al., 2019; ASHOUR et al., 2020). Moreover, Immune-regulatory exosome derived from tolerant dendritic cells (regDC Exo), which is abundant in TGF-β/IL-10, exhibits the ability to suppress alveolar bone loss and jaw inflammation (ELASHIRY et al., 2020). DCs also promoted BMSCs recruitment (ZHAO et al., 2023). Ranya et al. discovered that DCs deficiency leads to bone necrosis in the jaw after tooth extraction (ELSAYED et al., 2020).

Cells produce and release various populations of EVs that contain bioactive molecules. Serving as key messengers in intercellular communication, EVs can deliver bioactive substances to recipient cells and induce their corresponding effects.

EVs from immune cells affect jaw stem cell function. Macrophage-derived EVs increase the expression of osteoblast differentiation markers and promote MSC osteogenesis via the BMP2/Smad5 pathway (LIU et al., 2020). EVs can recruit MSCs. One study showed that DC-derived EVs facilitate MSC recruitment by enriching molecules, such as osteopontin and MMP-9, which are involved in cell recruitment (SILVA et al., 2017). Exosomes are nanovesicular structures in extracellular vesicles released by cells. Studies have demonstrated that Immune cell-derived exosomes regulate the proliferation, differentiation, and migration of jaw stem cells. M0-type, M1-type, and M2-type macrophage-derived exosomes exert different effects on bone repair (KANG et al., 2020). Exosomes derived from M2 macrophages (M2D-Exos) promote osteogenic differentiation and reduce lipogenic differentiation of BMSCs by upregulating miR-690, IRS-1, and TAZ (LI Z. et al., 2021). M2D-Exos contains high IL-10 mRNA levels, which ultimately upregulate IL-10 expression in BMSCs (CHEN et al., 2022). As mentioned previously, IL-10 aids in the osteogenic differentiation of BMSCs. Treatment with DC-derived exosomes increases Runx2 expression and APL activity (WANG et al., 2014). Therefore, DC-derived exosomes can induce the osteogenic differentiation of BMSCs.

EVs are important mediators of these interactions. BMSC-derived small extracellular components secrete exosomes that possess anti-inflammatory and regulatory functions (HA et al., 2020). MSC-EVs can impede DC maturation, and immature DC can promote the osteogenic differentiation of MSCs (REIS et al., 2018; YANG et al., 2019). Liu et al. reported that BMSC-EVs modulate TGF-β1 expression and macrophage polarization to regulate inflammatory immune responses (LIU et al., 2021). These studies have demonstrated that MSC-EVs ultimately lead to bone regeneration by regulating immune cells. Zheng et al. reported that PDLSC-EVs participate in the regulation of the Th17/Treg balance by targeting SIRT1 (ZHENG et al., 2019). Jana et al. reported that GMSC-EVs can reduce the secretion of pro-inflammatory factors by mononuclear macrophages and T cells, and inhibit T cell activation while inducing Treg formation (ZARUBOVA et al., 2022). DPSC-EVs promote M2-type macrophage polarization by inhibiting TLR and NFκΒ signaling (ZHENG et al., 2020). Additionally, exosomes derived from JBMSCs promoted M2-type macrophage polarization by targeting pknox1 with miR-233 (HE et al., 2019).

Overall, EVs can promote jaw tissue regeneration and repair, regulate the immune response, and may lead to jaw resorption. Consequently, EVs have various potential applications in treating jaw defects and are expected to become important therapeutic tools.

Jaw development is inseparable from the immune and stem cells, and damage to either side leads to abnormal jaw development. During jaw development, immune and bone cells share a microenvironment (OKAMOTO et al., 2017). Jaw development is closely associated with the immune system. Immune cells play a role in tissue remodeling and repair of damaged tissues during development (MEZU-NDUBUISI and MAHESHWARI, 2021). BMSCs support the differentiation of immune cells (CALVI et al., 2003). For example, BMSCs can maintain T cell generation by producing Notch ligands (YU et al., 2015). Previously, we also mentioned that MSCs can affect the polarization of macrophages (ZHANG et al., 2010; YANG et al., 2023). The interaction between jaw immune and stem cells is the cornerstone of normal jaw development.

Autosomal recessive osteopetrosis is a disease of abnormal bone development involving the mandible (GARCíA et al., 2013; SAĞLAM et al., 2017). Osteoclast dysfunction in patients with this disease (PENNA et al., 2021). Osteoclasts are derive from monocyte/macrophage-lineage cells, which is conducive to the catabolism of jawbone (MCDONALD et al., 2021). Jacome-Galarza et al. found that timely infusion of monocytes into neonatal mice can save bone dysplasia caused by early autosomal bone hyperplasia (JACOME-GALARZA et al., 2019). It may also be possible to treat the disease by modifying the existing immune environment. One study has found that T cell subsets like Th1 and Th17 help promote osteoclast production (LI J. et al., 2020). TNF-α, IL-1β and IL-6 produced by immune cells also increase osteoclast production (RANA et al., 2018).

Gaucher disease (GD) is an autosomal recessive disease associated with jaw bone involvement (MOHAMED et al., 2020). Patients with GD, mainly macrophages, have impaired immune cell functions, resulting in unbalanced bone formation and breakdown (STIRNEMANN et al., 2017). The damaged macrophages produced numerous pro-inflammatory factors, including IL-1β, TNF-α, and IL-6, which act on MSCs through paracrine, resulting in the inhibition of osteogenic differentiation of MSCs (MUCCI and ROZENFELD, 2015; YAO et al., 2021). The severity of the disease in GD have a positive correlation with the levels of pro-inflammatory cytokines such as IL-1β, TNF-α, and M-CSF (CHEN et al., 2018). Therefore, a new treatment scheme for bone dysplasia caused by GD can be provided by down-regulating the level of proinflammatory factors.

Normal bone homeostasis is necessary to maintain jaw health. Bone homeostasis is maintained through a balance between osteoblasts and osteoclasts, and the immune system has an important influence on bone homeostasis (SALHOTRA et al., 2020). The uniqueness of jaw immune environment is also an important factor to help maintain jaw homeostasis, such as higher proportion of macrophages (LIN et al., 2021). Dysregulated jaw homeostasis generally leads to bone disease.

Periodontitis is a disease in which jaw homeostasis is disrupted, often resulting in bone loss. Modulation of M1/M2 macrophage phenotypes can slow inflammation and reduce bone loss in periodontitis (HUANG et al., 2022). Macrophage macrophages promote osteogenic differentiation of MSCs by secreting OSM and BMP-2 (ZHANG Y. et al., 2017). OSM also can increasing the number of M2-type macrophages to help relieve bone loss from periodontitis (YUAN et al., 2023). Tregs inhibit the absorption of alveolar bone by secreting TGF-β and IL-10 (CAFFERATA et al., 2020). The interaction between Tregs and CD8+T cells increases Wnt10b secretion, thereby regulating bone anabolism (TYAGI et al., 2018). Maintenance of jaw homeostasis in periodontitis is also related to other immune cells, such as B cells, neutrophils, and mast cells. Rational use of immune response is a common method in clinical treatment of periodontitis.

Heterotopic ossification (HO) refers to the formation of extraskeletal bone in none-osseous tissues. Macrophages are key cells involved in HO (AGARWAL et al., 2016). Macrophages express high levels of osteogenic factors, including OSM and BMP, resulting in excessive osteogenic differentiation of BMSCs (HUANG et al., 2021). TGF-β produced by immune cells in HO exacerbates the disease, by inducing MSC migration and osteogenic differentiation (MAO et al., 2020). Recent studies have shown that neutrophils are involved in HO injury and that toll-like receptor signaling is highly expressed in cells at the site of injury (NUNEZ et al., 2023). Toll-like receptor signaling regulates BMSC function (NEMETH et al., 2010). Inhibiting the effection of immune cells on MSC osteogenic differentiation can be an effective means to inhibit HO.

During the healing process of jaw injury, different immune cell compositions and activation energies in the immune cell environment have favorable effects on jaw injury repair (MUIRE et al., 2020). The repair function of MSCs in inflammatory diseases depends on their immune microenvironment (XIONG et al., 2022). Here, we list several clinical jaw injury diseases and review the correlation between the immune microenvironment and jaw stem cells, from a pathological perspective, to promote jaw defect repair.

Jaw fractures are common traumatic jaw diseases. Fracture healing begins with an inflammatory response and the immune system is involved in the healing process (CLAES et al., 2012). Early in a fracture, neutrophils are recruited to the injury site (BASTIAN et al., 2011). Under inflammatory conditions, neutrophils produce chemokines that recruit BMSCs (CAI et al., 2021). The recruited MSCs can induce the production of Tregs, which can promote fracture healing by reducing the levels of IFN-γ and TNF-α (LIU et al., 2011). Macrophages also play a key role in wound healing. In the early stage of fracture, M1 macrophages can stimulate inflammation, and in the later stage, M2 macrophages help fracture healing by producing OSM, PGE2 and BMP-2 (PAJARINEN et al., 2019). Moreover, Macrophages directly promotes the MSC osteogenic differentiation to aid fracture healing (ZHANG et al., 2022).

Alveolar bone regeneration is a key step in restoring healthy jaw function after tooth extraction. Immediately after tooth extraction, neutrophils are recruited to activate other immune cells (COSKUN BENLIDAYI and GUZEL, 2013). Subsequently, macrophages are recruited and mature. When the aggregation of macrophages is inhibited, the healing of alveolar bone slows down (AOYAGI et al., 2018). Reducing the number of lymphocytes and eosinophils in tooth extraction patients is significantly associated with delayed wound healing (HAYASHI et al., 2018). Therefore, a suitable immune environment is necessary for alveolar bone healing after tooth extraction.

In conclusion, the interaction between jaw stem cells and immune cells is very complex and runs through the process of jaw development, maintenance and injury repair. However, the current research is limited, additional studies are warranted to elucidate the potential mechanisms of interaction.