SS is one of the autoimmune diseases most associated with SGH, with a prevalence of about 60 patients/100,000 inhabitants, primarily affecting the exocrine glands and causing dry mouth and dry eyes (Qin et al., 2015; Brito-Zerón et al., 2016). Similar to most autoimmune diseases, the pathogenesis of SS is not completely understood. Various cells and cytokines are involved in the pathogenic process of SS, including salivary gland epithelial cells, T cells, B cells, dendritic cells, interferon (IFN), interleukins, tumor necrosis factor (TNF), and chemokines (Tian et al., 2021; Verstappen et al., 2021; Negrini et al., 2022). In addition, some signaling pathways are involved in the damage and fibrosis of salivary glands in patients with SS, including the JAK/STAT pathway activated by the binding of IFN to its receptor, Toll-like receptor (TLR) pathway, cGAS-STING signaling pathway, and TGF-β1/SMAD signaling pathway (Sisto et al., 2021; Tian et al., 2021; Zhu et al., 2023). Targeting these cells (such as B cells and T cells), cytokines (such as IL-6, IL-1 and TNF), and signaling pathways (such as JAK signaling pathway) may help regulate the immune response and improve SS (Seror et al., 2021; Zhan et al., 2023).

IgG4-related disease is a newly recognized fibroinflammatory disorder characterized by elevated serum IgG4 levels, which is usually accompanied by massive inflammatory infiltration, swelling, fibrosis of the major salivary glands (Li et al., 2015; Avincsal and Zen, 2017). It was reported that dry mouth could be observed in 30% of patients with IgG4-related disease (Puxeddu et al., 2018). In addition to these, several other autoimmune diseases have also been reported that may be associated with an increased risk of SGH, including rheumatoid arthritis (Aliko et al., 2010; Silvestre-Rangil et al., 2017), juvenile idiopathic arthritis (Kobus et al., 2017), systemic lupus erythematosus (Ben-Aryeh et al., 1993), diffuse systemic scleroderma (Parat et al., 2020), and primary biliary cirrhosis (Mang et al., 1997).

Diabetes mellitus is one of the most common endocrine diseases and is expected to affect 693 million adults worldwide by 2045 (Cole and Florez, 2020). About 12.5%–53.5% of diabetic patients (both type I and type II diabetes) usually suffer from dry mouth and insufficient salivation (Moore et al., 2001; López-Pintor et al., 2016; Manjushree et al., 2022). This may be related to diabetic neuropathy the use of drugs for diabetes treatment, and salivary gland parenchymal injuries (including oxidative stress injury) (Chen et al., 2020; Genco and Borgnakke, 2020; Fouani et al., 2021). Furthermore, an increasing number of studies have reported changes in the expression of various proteins in the saliva and glands of diabetes patients, including salivary amylase, sodium-glucose cotransporter 1 (SGLT1), nitric oxide synthase and tetrahydrobiopterin protein (NOS-BH4), bone morphogenetic protein 7 (BMP7), common salivary protein 1 (CSP1), aquaporins (AQP), muscarinic receptors, and heat shock protein 60 (Hsp60) (Fouani et al., 2021).

Thyroid disorders are another common group of endocrine disorders that manifest as abnormal production of thyroid hormones, including hyperthyroidism, hypothyroidism, thyroiditis, and Hashimoto’s thyroiditis. More than half of dry mouth sufferers are living with thyroid disease (Jung et al., 2017). In addition, some common treatments for thyroid disease, such as radioiodine therapy and thyroid hormone replacement therapy, may also exacerbate dry mouth symptoms (Bergdahl and Bergdahl, 2001; Smidt et al., 2011; Hesselink et al., 2016).

Salivary gland function is controlled by the autonomic nervous system and regulated by the central nervous system (Proctor, 2016; Sørensen et al., 2018). When affected by neurodegenerative diseases, salivary gland function may be altered accordingly (Proctor, 2016; Sørensen et al., 2018). Studies have shown that patients with neurodegenerative diseases such as Alzheimer’s disease, age-related cognitive decline, and Parkinson’s disease suffer from lower salivary flow rates and a higher risk of dry mouth compared to healthy individuals (Sørensen et al., 2018; Zalewska et al., 2021; Verhoeff et al., 2023). Furthermore, Zalewska and colleagues (Zalewska et al., 2021) have also identified oxidative stress imbalance and downregulation of total proteins in the saliva of Alzheimer’s disease patients. Although some studies have reported salivation problems in people with Parkinson’s disease, it may be related to a lack of control of their masticatory muscles (Verhoeff et al., 2023). The impact of mental disorders on salivary gland function remains controversial. Although some studies have found that anxiety and depression reduce the salivary flow rate and increase the risk of dry mouth (Milin et al., 2016; Proctor, 2016; Gholami et al., 2017), this may be an effect of antidepressant drugs rather than the disorder (Hunter and Wilson, 1995; de Almeida Pdel et al., 2008).

Burning mouth syndrome (BMS) is a condition often associated with the development of mental disorders such as anxiety and depression (Abetz and Savage, 2009). Despite the lack of clinical signs of neuropathy, several more accurate diagnostic methods have suggested the involvement of the small nerve fibers, the trigeminal nerve, the brainstem, and the central nervous system in patients with BMS (Jääskeläinen, 2018). The results of several randomized controlled studies have shown reduced unstimulated salivary flow rate (USFR) and stimulated salivary flow rate (SSFR) in patients with BMS (Poon et al., 2014; Spadari et al., 2015), but multiple others did not find differences in USFR and SSFR between patients suffering from BMS and healthy individuals (Aitken-Saavedra et al., 2022).

As of August 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 59 million Coronavirus disease 2019 (COVID-19) cases and more than 6 million COVID-19-related deaths, and has become the greatest global public health threat of the century (Yuan et al., 2023). SARS-CoV-2 proliferates actively in the salivary glands, which directly affects the salivary glands and triggers SGH (Xu et al., 2020; Atukorallaya and Ratnayake, 2021). This was demonstrated in several clinical studies of COVID-19 patients with ongoing infection or treatment completion (Freni et al., 2020; Lechien et al., 2020; Omezli and Torul, 2021). According to data reported by the Joint United Nations Program on HIV/AIDS (UNAIDS, 2023), as of 2022 approximately 39 million people are living with acquired immune deficiency syndrome (AIDS) worldwide. Studies have shown that patients with AIDS have decreased salivary flow in the parotid, submandibular and sublingual glands in both the early and late stages of infection (Lin et al., 2003; Navazesh et al., 2003; Meer, 2019). Development of benign lymphoepithelial lesions of the salivary glands (including epimyoepithelial islands and an extensive lymphoid infiltrate) caused by long-term infection with human immunodeficiency virus (HIV) may play an important role in AIDS-associated dry mouth or SGH (Shanti and Aziz, 2009; Nizamuddin et al., 2018). In addition, several other sources of infection have been shown to induce a similar disease manifestation as SS (Maslinska and Kostyra-Grabczak, 2022), such as Epstein-Barr virus (Nakamura et al., 2020), coxsackievirus (Triantafyllopoulou et al., 2004), human T-lymphotropic virus type 1 (Nakamura et al., 2020), hepatitis C virus (Ramos-Casals et al., 2005), hepatitis D virus (Weller et al., 2016), and Helicobacter pylori (Wang et al., 2022).

Patients with salivary gland hypoplasia and ectodermal dysplasia are often characterized by underdevelopment or complete absence of large and small salivary glands, which in turn directly affects the formation and secretion of saliva (Nordgarden et al., 2003; Pham Dang et al., 2010; Seymen et al., 2017). Prader-Willi syndrome is a complex multisystem genetic disorder characterized by hyperphagia, hypotonia, growth hormone deficiency, and growth retardation (Vasconcelos et al., 2022). Although low salivary flow is a consistent manifestation in patients with Prader-Willi syndrome, the total amount of protein in saliva is not altered (Saeves et al., 2012a; Saeves et al., 2012b).

Down syndrome is a condition caused by a chromosomal abnormality (the presence of a supernumerary chromosome 21), with common symptoms of intellectual backwardness, peculiar facial features, growth disorders, and multiple malformations. The results of several studies suggest that individuals with Down syndrome have significantly lower salivary flow than healthy individuals (Yarat et al., 1999; Domingues et al., 2017). Saliva flow in children with Down syndrome is 36% lower than in healthy sibling pairs (Areias et al., 2012). In addition to these, a number of other genetic disorders have been reported to be associated with SGH or insufficient salivation, including cystic fibrosis (da Silva Modesto et al., 2015), familial amyloid polyneuropathy (Johansson et al., 1992), Fanconi anemia (Mattioli et al., 2010), Gosher’s disease (Dayan et al., 2003), Papillon-Lefèvre syndrome (Lundgren et al., 1996), hemochromatosis (Rao et al., 2021), mucopolysaccharides (Nunes et al., 2022), and neurofibromatosis type 1 (Cunha et al., 2015).

Dry mouth and SGH are also commonly associated with hypertension. The cross-sectional study by Ramírez et al. (2023) included 221 hypertensive patients, who were assessed for dry mouth by asking questions and the Xerostomia Inventory and had their USFR recorded. The results of the study found that 51.13% and 37.56% of hypertensive patients were accompanied by dry mouth and reduced USSF, respectively (Ramírez et al., 2023). In another epidemiologic study that included 1,933 hypertensive patients, dry mouth was present in about 8% of hypertensive patients, which may be related to the reductions in the number of salivary gland acinar cells, enhanced fatty infiltration, and arterial stenosis (Kawamoto et al., 2021). Sarcoidosis, a chronic multisystem inflammatory granulomatous disease with an unknown origin that affects the salivary glands, exhibits mean salivary flow rates and total salivary protein similar to those in patients with SS (Mansour et al., 2013; Drent et al., 2021).

Medications are the most common cause of dry mouth (Mese and Matsuo, 2007). A large number of drugs can trigger SGH, most commonly those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and digestive systems, which act with receptors on the central nervous system and/or at the neuroglandular junctions, including muscarinic, α- and β-adrenergic, and certain peptidergic receptors (Femiano et al., 2008; Villa et al., 2016; Einhorn et al., 2020). For example, some anticholinergic drugs, including amitriptyline, hyoscine butylbromide, chlorpromazine, oxybutynin, and others, may potentially block the binding of acetylcholine to muscarinic receptors in the salivary glands, thereby inhibiting saliva secretion (Arany et al., 2021). An in vivo study also found that muscarinic receptor antagonists can induce histological and ultrastructural changes in the salivary glands of rats, leading to atrophy of glandular tissue (Aboulhoda and Ali, 2018).

In addition, the cytotoxic effects of different drugs on acinar and ductal cells and the inhibition of ion transport pathways in acinar cells may also be the causative factors of SGH (Hattori and Wang, 2007; Jensen et al., 2008). Chemotherapy is a well-established treatment for tumors (Weingart et al., 2018). The cytotoxicity of chemotherapy drugs varies depending on the type of chemotherapy drug and the type of cells, such as specific phases of the cell cycle, structures or functions of cell membrane (Jensen et al., 2008; Weingart et al., 2018). Some chemotherapy drugs, such as cyclophosphamide, epirubicin, methotrexate, and 5-fluorouracil, may lead to damage and impaired function of acinar cells and ductal cells in salivary gland tissues (Jensen et al., 2008).

Unfortunately, most of the data in these studies originated from patients’ chief complaints of dry mouth rather than from clinical examination of salivary flow rate, which may have contributed to the bias in the final results (Saleh et al., 2015). In most cases, drug-induced SGH can be resolved by discontinuing and replacing related drugs, and combined with symptomatic treatment (Einhorn et al., 2020).

Radiotherapy is a common treatment for head and neck tumors and hyperthyroidism, including conventional radiotherapy, three-dimensional conformal radiotherapy, intensity-modulated conformal radiotherapy, proton beam radiotherapy, and radioiodine therapy (Jensen et al., 2010; Kim et al., 2018; Wiersinga et al., 2023). The physiological location of the salivary glands is more superficial than that of most head and neck tumors, and the radiation used for treatment usually needs to penetrate the salivary glands in order to effectively act on the deeper tumor tissues, which inevitably adversely affects the function of the salivary glands. For patients with head and neck cancer treated with conventional radiation therapy, three-dimensional conformal radiation therapy, and intensity-modulated conformal radiation therapy, 93% were reported to present with xerostomia or salivary gland hypofunction at the time of treatment, and 73.6%–85.3% at the post-treatment period (Jensen et al., 2010; Rigert et al., 2022). Also, after 1–2 years of treatment of thyroid cancer with radioactive iodine, 33.6%–37.8% of the patients also developed dry mouth symptoms (Jensen et al., 2010).

Notably, a dramatic loss of salivary gland function occurs within a week of radiation treatment and continues to downregulate salivary flow rates to unmeasurable levels throughout the course of treatment (Jensen et al., 2019). Progressive, irreversible changes in the salivary gland may be accompanied by the second stage of salivary gland hypofunction in the months following the completion of treatment (Jensen et al., 2010; Jensen et al., 2019). In this process, high doses of radiation may induce, on the one hand, selective damage to the cytoplasmic membrane of salivary gland acinar cells at an early stage, interfering with aqueous secretion after muscarinic receptor stimulation, and on the other hand, causing salivary gland acinar cells death, lack of cellular renewal, and impairment of ductal function at a later period (Konings et al., 2005). In addition, damage to vascular structures (increased capillary permeability, loss of capillary beds and arteriovenous fibrosis, interstitial edema, and inflammatory infiltration) may also be involved in radiotherapy-associated SGH (Cotrim et al., 2007; Jensen et al., 2019).

Cell-based therapies aim to utilize living cells to restore, enhance or replace organ function (Chibly et al., 2022). Transplantation of PSC-derived cells, paracrine products, and engineered salivary gland organoids are several potential methods for PSCs in the treatment of SGH (Figure 2). SGSCs/SGPCs are the potential cell sources for treating salivary gland diseases, which can be obtained by in vivo isolation (by two-dimensional culture or suspension culture to form salispheres) and PSCs-induced differentiation (Lombaert et al., 2008; Sui et al., 2020; Chansaenroj et al., 2021; Zhang et al., 2023) (Figures 3, 4).

In 2008, Lombaert et al. (2008) successfully formed and maintained salispheres containing c-Kit⁺ SGPCs by suspension culture of mice submandibular gland cells (Figure 4A). In this study, intraglandular injection of only a few c-Kit⁺ cells (300–1,000 cells/gland) rescued salivary secretion in most mice (69%, 9/13) with radiation-induced salivary gland injury (Lombaert et al., 2008). In further studies, c-Kit⁺CD24⁺Sca1⁺ and c-Kit⁺CD24⁺CD49f⁺ mice SGSCs/SGPCs transplants also proved to be able to contribute to the restoration of salivary gland function and tissue homeostasis in mice with radiotherapy-induced SGH (Nanduri et al., 2013; Xiao et al., 2014). Notably, c-Kit⁺ SGPCs also exist in human salivary glands and can be isolated and cultured in vitro (Feng et al., 2009; Lombaert et al., 2013). A groundbreaking study using human salivary gland-derived c-Kit⁺ SGSCs/SGPCs successfully rescued radiotherapy-induced salivary insufficiency in the mice model (Pringle et al., 2016). This may be related to self-renewal and differentiation of transplanted SGSCs/SGPCs (Pringle et al., 2016).

With the increasing understanding of repairing salivary gland damage and SGSCs/SGPCs, it is becoming clear that SGSCs/SGPCs transplantation may have the potential to regenerate salivary glands. Although still controversial, in addition to c-Kit, proteins such as KRT5, KRT14, Axin2, SOX2, SOX9, SOX10, LGR5, CD90, and others have been recognized as markers of SGSCs/SGPCs (Yi et al., 2016; Chibly et al., 2022). Treating SGH by transplanting SGSCs/SGPCs with different markers is worthy of further exploration.

In addition to isolation from the salivary gland, SGSCs/SGPCs can also be obtained by PSCs differentiation (Figure 4C). In 2022, the protocol proposed by Zhang et al. (2023) successfully differentiated hESCs and hiPSCs into human salivary epithelial progenitor cells expressing SOX9, CD24, α-SMA, KRT5, and KRT19. In this scheme, ESCs and iPSCs need to be first formed into embryoid bodies (EBs) under suspension conditions, and then sequentially treated with BMP4, retinoic acid, and CHIR99021 in adherent culture, and ultimately differentiated into salivary epithelial progenitor cells with a similar transcriptome profile to that of human submandibular glands through the oral ectoderm (Zhang et al., 2023). In another of their studies, BMP4, retinoic acid, and FGF10 were used to promote ESC differentiation into salivary gland substrates in vitro (Zhang et al., 2022). Notably, in addition to the formation of invaginated epithelium and the development of initial budding, the expression of salivary gland progenitor cell markers such as KRT5, KRT19, SOX9, and E-cadherin was found in the ESC-derived salivary gland placodes, suggesting the differentiation ability of PSCs to salivary gland epithelial progenitor cells (Zhang et al., 2022).

In addition, the differentiation of PSCs into salivary gland cells, including acinar and ductal cells, also has the potential for therapeutic applications. In recent years, the induction of ESCs and iPSCs into salivary gland cells by co-culture with salivary gland cells, the use of salivary gland cell-conditioned medium, and direct salivary gland transplantation has been successively reported (Kawakami et al., 2013; Ono et al., 2015; Meng et al., 2022). In 2013, Kawakami et al. (2013) co-cultured mouse early embryonic stem cells (mEES-6) with human salivary gland-derived fibroblasts and found that mEES-6 expressed salivary gland-associated markers, such as amylase, AQP-5, bFGF, and NGF, and possessed similar characteristics to salivary gland cells. After transplantation of salivary gland cells obtained by co-culture into normal submandibular glands of mice, the submandibular glands of mice in the transplanted group were significantly enlarged compared with those in the non-transplanted group without any obvious abnormality in the histological examination, suggesting the formation of functional salivary gland tissues (Kawakami et al., 2013). Meng et al. (2022) found the formation of salivary gland acinar-like and duct-like structures and amylase expression after treatment of iPSCs and IRF6-overexpressing iPSCs using the conditioned medium from human parotid cells. However, this study did not compare the difference in salivary gland cell formation between normal iPSCs and IRF6-overexpressing iPSCs (Meng et al., 2022). In another study, mouse iPSCs were directly transplanted into the submandibular gland of SCID mice to observe the effect of the submandibular gland microenvironment on the differentiation of iPSCs (Ono et al., 2015). It was found that transplanted iPSCs could partially form salivary gland-like tissues and express salivary gland markers such as parotid secretory protein (PSP), amylase, E-cadherin, but the issue of tumorigenicity of iPSCs was not addressed in this study (Ono et al., 2015).

To date, most tissue regeneration strategies have focused on direct transplantation using specific cell populations, but this is changing with the advent of organoid culture systems (Lancaster and Knoblich, 2014). Salivary gland organoids can be generated from SGSCs/SGPCs or non-saliva gland stem cells (such as dental follicle stem cells or PSCs) embedded in reconstituted extracellular matrix-like materials (such as matrigel, fibrin gel, and collagen gel) (Maimets et al., 2016; Srinivasan et al., 2017; Xu et al., 2017; Tanaka et al., 2018). Due to differences in cell sources and culture methods, these reported salivary gland organoids often do not have consistent cell composition, structure, and gene expression patterns with normal salivary gland tissues. For the purpose of salivary gland organoids to produce saliva and transport it to the oral cavity, salivary gland organoids should have acinar-like structures (to produce saliva), duct-like structures (to transport saliva), myoepithelial cells (to assist saliva secretion) and corresponding neuromodulatory system for saliva secretory (Zhao et al., 2021; Yoon et al., 2022).

The first evidence for transplantation therapy using engineered salivary gland organoids was provided by Tanaka and colleagues (Tanaka et al., 2018). Several small molecules (BMP4, SB-431542, LDN-193189, and FGF2) were firstly applied to induce differentiation of mouse ESCs-derived EBs into oral ectoderm in vitro, followed by overexpression of Sox9 and Foxc1 and FGF signaling (FGF7 and FGF10) activating, finally generated salivary gland organoids composed of AQP5⁺ acinar-like cells, CK18⁺ duct-like cells and α-SMA⁺ myoepithelial-like cells were (Tanaka et al., 2018). After orthotopic transplantation of collagen gel-encapsulated salivary gland organoids into mice with defective parotid glands, mouse ESCs-derived salivary gland organoids connect with surrounding tissues and mature (Tanaka et al., 2018). Notably, saliva production was significantly increased after gustatory stimulation of salivary gland organoids transplanted mice with citrate, suggesting that orthotopically transplanted salivary gland organoids reconstitute the afferent and efferent neural pathways required for the regulation of salivary gland function (Tanaka et al., 2018). Another study by Tanaka and colleagues (Tanaka et al., 2022) succeeded in inducing human iPSCs to generate salivary gland organoids with similar gene expression patterns to human embryonic salivary glands after changing partial culture conditions (applying SB431542, FGF7, and FGF10). After co-transplantation of the formed organoid combined with embryonic mouse salivary gland mesenchymal tissue into parotid gland deficient mice in situ, further development and maturation of salivary gland organoids were observed, and CD31⁺ endothelial cells and TUBB3⁺ neuronal fibers were detected close to the acinar cells (Tanaka et al., 2022).

In addition to orthotopic transplantation of salivary glands, renal capsule transplantation in nude mice was also used to assess the continued development and function of salivary gland organoids. Sui et al. (2020) combined human submandibular gland stem/progenitor cells to generate salivary gland organoids and embryonic mouse salivary gland mesenchyme heterogeneously transplanted into the renal capsules of nude mice, showing mature salivary gland characteristics, including histological structure (the presence of ducts-like and acinar-like structures with the myoepithelial cells surrounding them) and salivary secretion. In another study from the research group, ESCs were treated with BMP4, retinoic acid, and FGF10 to obtain salivary gland placodes in vitro (Zhang et al., 2022). One month after implantation into the renal capsule of nude mice, the salivary gland placodes continued to develop and formed duct-like structures with continuous lumen, but unfortunately, acinar structures were not observed (Zhang et al., 2022).

In addition, SGSCs/SGPSCs or other salivary gland cells combined with different extracellular matrix-like materials to directly generate salivary gland organoids in vitro have been reported by several studies (Joraku et al., 2007; Maria et al., 2011; Shin et al., 2016; Srinivasan et al., 2017; Sui et al., 2020). This also provides a new strategy for PSC-derived engineered salivary gland organoid transplantation therapy, that is, PSCs can be differentiated into salivary gland cells first, and then the salivary gland organoids generated from these cells can be used for the treatment of salivary gland diseases (Figure 2). At present, there are no reports of salivary gland organoids for the treatment of SGH disease models, but based on the rapid progress in the research on this field, engineered salivary gland organoids derived from PSCs are expected to play a therapeutic role by replacing hypo-function salivary glands.

MSCs originate from the embryonic mesoderm and are widely found in various tissues, such as the umbilical cord, bone marrow, and adipose, with self-renewal ability and multidirectional differentiation potentials (Pittenger et al., 1999). As mentioned above, the results of several clinical studies have demonstrated the favorable therapeutic effects of stem cell therapy for SS and radiotherapy-induced SGH (Xu et al., 2012; Lynggaard et al., 2022a; Lynggaard et al., 2022b). However, the mechanism of MSCs for the treatment of SGH has not yet been fully clarified. On the one hand, MSCs are able to differentiate directly into salivary gland acinar cells, which holds promise for alleviating SGH by regenerating salivary glands (Lim et al., 2013; Adine et al., 2018; Mona et al., 2020; Yan et al., 2020; Tran et al., 2022). On the other hand, transplantation of MSCs can upregulate the release of anti-inflammatory cytokines and downregulate the release of pro-inflammatory cytokines, while regulating T cells, B cells, dendritic cells, and natural killer cells to perform anti-inflammatory and immune regulation effects (Chihaby et al., 2021). In addition, MSCs can release soluble factors through paracrine effects, which promote cell proliferation and angiogenesis, activate endogenous progenitor cells, and inhibit epithelial cell apoptosis (Lee et al., 2011; Guan et al., 2023).

MSCs are a common source of cells for cell therapy. Still, several factors limit their widespread application in the clinic, such as the need for invasive manipulation for cell isolation, the limited number of isolated cells and expansion capacity, heterogeneity depending on the source and donor (Zhou et al., 2021), Differentiation from homogeneous and well-characterized iPSC cell lines into iMSCs would effectively address these biological and technical limitations. Dozens of studies have reported differentiation strategies for iMSCs, which can be categorized into MSC switch, EBs, specific differentiation, pathway inhibitor, and platelet lysate according to the differentiation procedures (Dupuis and Oltra, 2021). Hai et al. (2018) found that tail vein injection of iMSCs prevented salivary gland lymphocyte infiltration and inhibited further progression of SS in mice through immunomodulatory effects. Unfortunately, this study did not evaluate salivary gland function indicators such as saliva flow rate in experimental animals (Hai et al., 2018). Nevertheless, iMSCs, as an emerging source of stem cells, are expected to play an effective role in the treatment of SGH based on the available animal and clinical evidence.

Utilizing the salivary gland differentiation potential of iMSCs to construct engineered salivary gland organoids may become another option for the treatment of SGH. In 2018, an in vitro study by Adine et al. (2018) successfully generated innervated secretory salivary gland epithelial organoids, including secretory epithelium, ducts, myoepithelium, and neuronal structures using DPSCs and magnetic 3D bioprinting technology, were able to produce α-amylase in response to FGF10 stimulation. In another study, co-culture of BMSCs with homogenates of decellularized salivary glands extracellular matrix successfully formed cell aggregates expressing salivary gland epithelial cell markers that were morphologically and ultrastructurally similar to submandibular gland tissues (Tran et al., 2022). In further experiments, cell aggregates continued to develop and enlarge after renal capsule transplantation, and generated salivary gland-like organoids (Tran et al., 2022). Whether iMSCs possess salivary gland organoid formation ability similar to that of DPSCs and BMSCs still needs to be verified by more in vivo and in vitro experiments.

Although various MSCs have been extensively explored in tissue engineering or regenerative medicine, the safety of allogeneic MSCs transplantation is still controversial (El-Naseery et al., 2018; Kim et al., 2022) In addition to direct transplantation of MSCs, transplantation of paracrine products derived from MSCs (including EVs and conditioned medium), which are more stable and suitable for long-term storage, has also been reported to help the recovery of SGH without causing pulmonary embolism and the risk of processing tumor formation (Jung et al., 2013; Chansaenroj et al., 2021). EVs are cell-derived membranous structures, enriched with proteins, nucleic acids, and lipids, which can be categorized into exosomes, microvesicles, and apoptotic vesicles based on their diameter (Zhao et al., 2022). Similar to direct stem cell transplantation, the mechanisms of extracellular vesicle-based therapy include immune modulation and tissue regeneration promotion (Harrell et al., 2019; Fujii and Miura, 2022).

Exosomes are currently the most widely studied and used EVs, and have also been tried to be used in the treatment of SGH (Willms et al., 2018). The study by Hu et al. (Hu et al., 2023) found that intravenous injection of exosomes derived from DPSCs could alleviate SS, reduce the level of salivary gland inflammation and increase saliva flow in animal models. SS may cause the death of salivary gland epithelial cells and the decrease of AQP5 expression, which could be reversed by DPSC-derived exosomes through the cAMP/PKA/CREB pathway (Hu et al., 2023). Human UCMSC-derived exosomes could effectively inhibit the over proliferation and apoptosis of CD4⁺ cells and restore the Th17/Treg balance through the autophagy pathway in patients with SS (Ma et al., 2023).

Several studies have reported the improvement of SS in mice treated with intravenous injection of exosomes derived from olfactory ecto- and labial gland-derived mesenchymal stem cells (Li et al., 2021; Rui et al., 2021; Xing et al., 2022). In addition, it was also reported the preventive effect of exosomes derived from tonsil MSCs on submandibular gland dysfunction caused by ovariectomy (Kim et al., 2022). In this study, local injection of tonsillar MSC-derived exosomes in the submandibular gland reversed ovariectomy-induced pro-inflammatory cytokine release, decreased expression of salivary gland secretion-associated proteins (AQP3, AQP5, and α-amylase) (Kim et al., 2022).

Two animal studies found that intravenous injection of iMSC-derived exosomes in the early stage of SS can control the progression of the disease before the onset of salivary gland inflammation (Hai et al., 2018; Zhao et al., 2023). Although the salivary gland function of mice was not further explored in the two studies, based on the injured effect of immune abnormalities in SS on salivary gland function, iMSC-derived exosomes are expected to alleviate SGH caused by SS through immunomodulation. In addition to anti-inflammatory effects, exosomes derived from MSCs have also been reported to promote tissue regeneration, such as regulation of angiogenesis, anti-apoptosis, and improvement of cell aging, through their contained cytokines and microRNA components (Hade et al., 2021). This also makes it possible for iMSC-derived exosomes to be applied to the therapeutic exploration of SGH caused by salivary gland tissue damage.

Conditioned medium of MSCs is another cell-free therapeutic modality that utilizes the paracrine effects of MSCs. Direct support for the application of stem cell conditioned medium is provided by the research of Bi et al. (2007) who found that the use of stem cell conditioned medium can mimic the beneficial effects of stem cell therapy. Matsumura-Kawashima and colleagues (Matsumura-Kawashima et al., 2021) observed a significant reduction in inflammation and a significant increase in the salivary secretion of submandibular glands in mice with SS after intravenously injecting DPSC-derived conditioned medium. However, this therapeutic effect was not found in the BMSC-derived conditioned medium group, which may be related to the fact that the DPSC-derived conditioned medium contains more cytokines that regulate cell proliferation, anti-inflammatory and immunomodulatory effects than the BMSC-derived conditioned medium. Another subsequent study used conditioned medium of human SHEDs for prophylactic treatment of radiotherapy-injured mice (Kano et al., 2023). SHED-derived conditioned medium was found to effectively upregulate the expression of antioxidant genes in mouse salivary glands and human acinar cells damaged by radiotherapy and strongly inhibit the radiotherapy-induced oxidative stress, thereby maintaining the salivary gland function (Kano et al., 2023). There are still few reports of conditioned medium of iMSCs origin for disease treatment. A study in 2021 found that conditioned media derived from iMSCs had a better effect on promoting skin wound healing in mice than that derived from UCMSCs (Liang et al., 2021). Nevertheless, based on the effectiveness of the two kinds of adult MSC-derived conditioned medium for the treatment of SGH and the safety of MSC-derived exosomes, the iMSC-derived conditioned medium has good clinical application potential for SGH.

Salivary gland development begins with the migration of neural crest-derived cells and their mediated formation of ectodermal mesenchymal tissue, making NCCs an attractive cell source for the study of salivary gland development and regeneration (Chibly et al., 2022). On the one hand, the paracrine effect of neural crest-derived mesenchyme can help the development and maturation of salivary gland and engineered salivary gland organoids (Patel and Hoffman, 2014; Hosseini et al., 2018; Sui et al., 2020; Zhao et al., 2021). On the other hand, compared with BMSCs, DPSCs derived from neural crest contain more cytokines with tissue regeneration mechanisms (regulating cell proliferation, anti-inflammatory, and immunomodulatory), which can more effectively restore salivary gland function in vivo (Matsumura-Kawashima et al., 2021). Therefore, PNMSCs may be a more promising cell source for the treatment of SGH than mesoderm-derived MSCs. Currently, two studies have successfully induced the differentiation of iPSCs and ESCs into PNMSCs in vitro (Fukuta et al., 2014; Ouchi et al., 2016; Mitsuzawa et al., 2019). In the future, further research on PNMSCs is still needed to compare their characteristics and the differences in their therapeutic effects on SGH with other MSCs.