MenSCs exhibit remarkable potential in the treatment of musculoskeletal disorders and the repair of soft tissue injuries. Through directed differentiation, these cells can be induced to transform into osteoblasts, chondrocytes, and adipocytes, offering new therapeutic avenues for the repair of bone injuries, degenerative diseases, and congenital defects.

In the context of bone and cartilage regeneration, MenSCs cultured in osteogenic induction medium for 21 days presented marked morphological changes, along with significantly upregulated expression of key osteogenic markers such as alkaline phosphatase (ALP), secreted phosphoprotein 1 (SPP1), and bone gamma-carboxyglutamic acid-containing protein (BGLAP) (Skliutė et al., 2021). During chondrogenic differentiation, increased expression of the collagen type II alpha 1 (COL2A1) gene further supports its regenerative potential in skeletal and cartilage tissues.

With respect to muscle regeneration and pelvic organ prolapse (POP), the ability of MenSCs to differentiate into smooth muscle cells provides new insights for POP repair. The pathological basis of POP involves degeneration of vaginal smooth muscle, leading to loss of pelvic floor support (Chen et al., 2016). In a study by Chen et al. (2016), MenSCs were successfully induced to differentiate into smooth muscle cells under TGF-β1 stimulation via the TGFBR2/ALK5/Smad2/3 signaling pathway, laying the groundwork for cell-based therapies. Furthermore, in a clinical study of Duchenne muscular dystrophy (DMD), a patient who received an intramuscular injection of 116 million MenSCs presented significantly improved muscle strength and restored dystrophin expression (Ichim et al., 2010), highlighting the therapeutic potential of MenSCs in muscle repair.

In the context of soft tissue regeneration, the adipogenic potential of MenSCs is critical. Under rosiglitazone induction, the mRNA expression of adipogenic markers—including leptin receptor (LEPR), peroxisome proliferator-activated receptor gamma (PPAR-γ), and lipoprotein lipase (LPL)—was significantly upregulated (Khanmohammadi et al., 2014). Compared with BM-MSCs, MenSCs offer advantages in terms of accessibility and ethical acceptability, making them ideal candidates for repairing soft tissue defects resulting from burns or tumor resection.

The application of MenSCs also extends to cutaneous wound healing. These cells can differentiate into mature keratinocytes and express epidermal-specific markers in vitro, including keratin 14 (K14), p63, and involucrin (IVL) (Fard et al., 2018; Akhavan-Tavakoli et al., 2017). This epithelial differentiation capacity positions MenSCs as promising cell sources for the treatment of skin injuries such as burns and ulcers.

MenSCs demonstrate significant potential for hepatocyte differentiation in the treatment of chronic liver diseases, suggesting a novel direction for regenerative medicine. Studies indicate that under the induction of factors such as hepatocyte growth factor (HGF) and Oncostatin M (OSM), MenSCs differentiate into hepatocyte-like cells, with the degree of differentiation showing a positive correlation with the concentrations of these factors (Malik et al., 2018). Differentiated cells express key hepatocyte markers—including albumin, tyrosine aminotransferase (TAT), and cytokeratin-18 (CK18)—at both the mRNA and protein levels and exhibit essential hepatocyte functions, such as albumin secretion, glycogen storage, and cytochrome P450 7A1 expression, thereby effectively mimicking the metabolic and detoxification functions of mature hepatocytes (Malik et al., 2018). Additionally, induced ERCs have been shown to differentiate into functional hepatocyte-like cells (Khademi et al., 2014). These findings suggest that menstrual blood-derived cells offer promising new avenues for cell-based therapies in chronic liver diseases, particularly in the regenerative treatment of hepatic fibrosis and cirrhosis.

Multilineage-differentiating stress-enduring (Muse) cells, derived from mesenchymal stem cells (MSCs), are pluripotent cells with the capacity to differentiate into all three germ layers and exhibit enhanced resistance to environmental stress (Heneidi et al., 2013). Muse cells can evade immunological barriers, such as the pulmonary capillary network (Li et al., 2013a), and preferentially home to sites of tissue injury (Kushida et al., 2018), thereby overcoming the limitations associated with conventional MSCs in clinical applications. Li et al. (2024) successfully isolated Muse cells from MenSCs via prolonged trypsin digestion and demonstrated their significant therapeutic efficacy in animal models of acute liver injury and intracerebral hemorrhage, with superior homing ability and treatment outcomes compared with those of conventional MSCs.

Induced pluripotent stem cells (iPSCs) are pluripotent cells reprogrammed from somatic cells without relying on embryonic sources (Li et al., 2013b). iPSCs exhibit gene expression, pluripotency, and epigenetic profiles highly similar to those of embryonic stem cells (Park et al., 2008a; Ratajczak et al., 2008; Ye et al., 2009; Lengerke and Daley, 2010), providing an ethically acceptable cell resource for disease modeling, drug development, and regenerative medicine. Although iPSCs can be generated from various somatic cell sources (Takahashi et al., 2007; Yu et al., 2007; Hockemeyer et al., 2008; Huangfu et al., 2008; Lowry et al., 2008; Park et al., 2008b; Aasen et al., 2008; Kim et al., 2009; Sun et al., 2009; Li et al., 2010; Zhao et al., 2010; Zhou et al., 2011), traditional sources such as human dermal fibroblasts (HDFs) require invasive skin biopsies and prolonged in vitro expansion, limiting their practical utility. In contrast, MenSCs, owing to their noninvasive sourcing, ease of acquisition, robust proliferation, and stem cell-like phenotype (Malik et al., 2018; Patel et al., 2008), represent ideal candidates for iPSC generation.

In the treatment of gynecological diseases, the paracrine activity of MenSCs has multiple therapeutic potential. The low success rate of in vitro fertilization (IVF) in older women is closely associated with abnormal reactive oxygen species (ROS) metabolism in oocytes (Mihalas et al., 2017). Studies have shown that EVs secreted by MenSCs can function as exogenous ROS scavengers, thereby reducing the dependence of embryos from aged female mice on endogenous antioxidant proteins such as superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPX1), ultimately improving IVF outcomes (Marinaro et al., 2018). Proteomic analyses further suggest that gene expression changes related to oxidative stress (GPX1, superoxide dismutase 1), metabolism (ACACA, GAPDH), placentation (PGF, VEGF-A), and stem cell differentiation (POU5F1, SOX2) may underlie the observed improvement in embryo quality (Marinaro et al., 2018; Marinaro et al., 2019).

In intrauterine adhesion (IUA) repair, MenSCs transplantation has been shown to accelerate endometrial regeneration. Zhang et al. (2016) reported that after being transplanted into a mouse model of endometrial injury, MenSCs activated the AKT and MAPK signaling pathways and upregulated angiogenesis-related proteins such as eNOS, VEGFA, VEGFR1, VEGFR2, and Tie2. These effects significantly shortened the repair time (complete regeneration within 7 days) and improved pregnancy rates and fetal counts (Huang et al., 2015; Lv et al., 2016). Additionally, fibroblast growth factor 2 secreted by MenSCs further promotes angiogenesis and cellular proliferation, thereby attenuating ovarian fibrosis and restoring sex hormone levels (Seo et al., 2013).

In the treatment of poor ovarian response (POR), paracrine factors from MenSCs modulate the local microenvironment to promote follicular development, as well as the differentiation of embryonic-like and ovarian stem cells. This leads to significant improvements in oocyte yield and quality, fertilization rates, embryo development rates, pregnancy rates, and live birth rates (Zafardoust et al., 2020; Rajabi et al., 2018; Bhartiya, 2018).

Moreover, the paracrine effects of MenSCs have shown their ability to inhibit epithelial ovarian cancer (EOC). Bu et al. (2016) demonstrated that MenSCs increased the proapoptotic Bax/Bcl-2 and Bad/Bcl-xL ratios, reduced the mitochondrial membrane potential, and activated the intrinsic apoptotic pathway to suppress EOC cell proliferation. Furthermore, they inhibited EOC cell cycle progression by blocking AKT phosphorylation. These findings suggest a promising strategy for the use of MenSCs in EOC therapy.

The paracrine effects of MenSCs have significant potential in the treatment of liver diseases. In nonalcoholic fatty liver disease, the progression of which is closely associated with metabolic dysregulation—such as insulin resistance and lipid accumulation (Zhao et al., 2017)—MenSCs have been shown to modulate the expression of the key gene Rnf186 by secreting HGF. Rnf186 interferes with insulin signaling and lipid synthesis, and its abnormal expression is suppressed by the paracrine action of MenSCs, thereby alleviating metabolic disturbances (Du et al., 2023).

In models of cholestatic liver injury, MenSCs repair tissue damage via paracrine mechanisms. Yang et al. (2022) demonstrated that MenSCs significantly enhanced survival in mice while reducing the serum levels of liver injury markers (AST, ALT, ALP, DBIL). This effect is attributed to the upregulation of hepatic β-catenin, which helps to restore the integrity of tight junctions and normalize the expression of bile transport proteins (OATP2, BSEP, and NTCP1), ultimately inhibiting intrahepatic bile duct dilation, cholestasis, and the progression of fibrosis.

With respect to liver fibrosis, MenSCs secrete an array of factors that collectively form a synergistic paracrine network. For example, monocyte chemoattractant protein-1 recruits immune cells to the injured area for targeted inflammation regulation (Chen et al., 2017a), whereas Interleukin (IL)-6 and IL-8 stimulate proliferative pathways in hepatic cells and promote the recruitment of neutrophils and macrophages, thereby enhancing tissue repair (Qiu et al., 2012; Cai et al., 2008). Moreover, HGF secreted by MenSCs inhibits the activation of hepatic stellate cells (e.g., the LX-2 cell line), directly impeding fibrogenesis (Chen et al., 2017a). In addition, angiopoietin stimulates cell proliferation and survival (Li and Hu, 2012) and, together with Axl, coregulates apoptotic and proliferative signaling (D’Ar et al., 2002). IGFBP-6 prevents fibroblast apoptosis (Qiu et al., 2012; Micutkova et al., 2011), further mitigating the chronic inflammation that drives fibrosis. Collectively, these paracrine factors contribute to a therapeutic network that counteracts the progression of liver fibrosis.

For hepatocellular carcinoma (HCC) treatment, MenSCs exert their therapeutic effects through epigenetic modulation. In a time-dependent manner, their paracrine secretions can restore the levels of 5-hydroxymethylcytosine (5-hmC) and TET1 in HCC cells (Wu et al., 2019). TET1 and TET2 regulate DNA demethylation to suppress aberrant demethylation in HCC cells (Chen Q. et al., 2017; Ko et al., 2010). Upon activation by MenSCs, increased enrichment of 5-hmC and 5-mC in key enhancer regions leads to downregulation of the PI3K/AKT and RAF/ERK pathways, thereby inhibiting HCC cell proliferation and promoting apoptosis. Moreover, MenSCs modulate the DNA modification of chemoresistance-related genes, such as ID4 and HMGA1, enhancing their therapeutic efficacy against HCC(96). These findings suggest that the paracrine mechanisms of MenSCs, which involve the targeting of oncogenic gene expression through epigenetic regulation, constitute a novel therapeutic strategy for HCC.

Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease characterized by excessive fibrosis of the lung tissue and is associated with high morbidity and mortality rates (Blackwell et al., 2014). Although lung transplantation remains the most effective treatment, its clinical application is limited by donor scarcity, and existing pharmacological interventions provide only modest antifibrotic efficacy. Chen et al. (2020a) demonstrated that MenSCs transplantation alleviated fibrosis in bleomycin-induced Idiopathic pulmonary fibrosis models by homing to injured sites, suppressing epithelial cell apoptosis and proinflammatory cytokine (e.g., IL-1β and TNF-α) secretion, and inhibiting myofibroblast activation and collagen deposition.

ERCs also exhibit multipotent therapeutic potential in Idiopathic pulmonary fibrosis treatment (Zhao et al., 2018a). On the one hand, ERCs suppress TGF-β signaling and downregulate the proinflammatory cytokines IL-1β and TNF-α by upregulating IL-10 (Sziksz et al., 2015). They also restore total superoxide dismutase (T-SOD) activity to reduce oxidative stress and modulate apoptotic signaling via downregulation of the Bax/Bcl-2 ratio, contributing to alveolar epithelial cell protection. On the other hand, ERCs upregulate antifibrotic genes such as HGF and matrix metalloproteinase-9 (MMP-9), further inhibiting fibrosis progression.

In acute lung injury animal models, MenSCs also exhibit therapeutic efficacy (Ren et al., 2018; Xiang et al., 2017). Through paracrine signaling, MenSCs increase proliferating cell nuclear antigen (PCNA) expression to promote cell proliferation, inhibit caspase-3-mediated apoptosis to reduce cell death, increase the secretion of anti-inflammatory factors such as IL-10 and keratinocyte growth factor (KGF), and simultaneously suppress proinflammatory cytokines such as IL-1β, neutrophil infiltration, and myeloperoxidase (MPO) activity, thereby attenuating pulmonary inflammation and restoring lung function.

Under diabetic conditions, wound healing is disrupted through multiple mechanisms, including persistent inflammation, hypoxia, cellular dysfunction, impaired angiogenesis, and neuropathy (Guo and Dipietro, 2010). The chronic nature of diabetic wounds is closely associated with dysregulated inflammatory phase transitions. While inflammation is essential for initiating tissue repair (Aller et al., 2004), excessive activation of proinflammatory macrophages (M1) and the resulting prolonged inflammatory state significantly impede healing (Landén et al., 2016). The phenotypic switch from M1 to reparative macrophages (M2) is critical for tissue regeneration (Finley et al., 2016; Zhang et al., 2010; Emin et al., 2007; Murray et al., 2014); however, in the diabetic microenvironment, downregulation of M2-associated genes (e.g., Arg-1) leads to impaired polarization (Finley et al., 2016; Schwab et al., 2007). MenSC-Exos promote M2 polarization by modulating inducible nitric oxide synthase activity and the ARG: inducible nitric oxide synthase ratio, with a sustained increase in the M2/M1 ratio observed between days 7–14 posttreatment (Dalirfardouei et al., 2019; Mirzadegan et al., 2022).

Macrophage function is also closely linked to neural regeneration. As the primary source of neuroprotectin D1 (NPD1), M2 macrophages may facilitate axonal regeneration and contribute to wound repair (C et al., 2013; Hong et al., 2014). Mirzadegan et al. (Mirzadegan et al., 2022) demonstrated that MenSC intervention significantly increased the density of protein-gene product 9.5 (PGP9.5)-positive nerve fibers in diabetic wounds, suggesting the potential for reversing cutaneous neuropathy. At the molecular level, MenSC-Exos activate the NF-κB signaling pathway to increase keratinocyte proliferation and differentiation (Dalirfardouei et al., 2019; Brantley et al., 2001). Additionally, through interactions with the Notch pathway (Na et al., 2017; Shi et al., 2015) and Jumonji domain-containing protein D3, they may regulate epigenetic remodeling in keratinocytes (Na et al., 2016), thereby promoting migration and re-epithelialization.

The balance of collagen metabolism is crucial for optimal wound healing. MenSC-Exos induce the expression of type I collagen and type III collagen mRNAs, initially promoting type III collagen synthesis to support granulation tissue formation (Volk et al., 2011). At later stages, they reduce the type I collagen/type III collagen ratio to suppress scar hyperplasia (Yates et al., 2012; Cuttle et al., 2005; Larson et al., 2010; Zhang et al., 2015).

In terms of angiogenesis, MenSC-Exos dose-dependently upregulated key angiogenic markers, including vascular endothelial growth factor A (VEGFA), CD31, and von Willebrand factor (vWF), with 10 μg of MenSC-Exos demonstrating tenfold greater efficacy than exosomes from other stem cell sources (Dalirfardouei et al., 2019; Mirzadegan et al., 2022; Hu et al., 2016; Liang et al., 2016).

Importantly, although MenSCs exhibit strong migratory capacity due to high CXCR4 expression (Luz-Crawford et al., 2016), dysfunctional fibroblasts in diabetic wounds often fail to produce stromal cell-derived factor-1, thereby compromising MenSC homing efficiency (Mirzadegan et al., 2022; Brem et al., 2007). This paradox underscores the critical role of the local microenvironment in modulating stem cell-based therapies.

Spinal cord injury (SCI), characterized by sensory and motor dysfunction, continues to pose major clinical challenges because of the limited therapeutic efficacy of current treatment paradigms (Kunte et al., 2015). Recent studies have demonstrated that MenSCs transplantation promotes neural repair via multiple mechanisms. Wu et al. (2018) confirmed that MenSCs increase the expression of brain-derived neurotrophic factor, thereby supporting neuronal survival and axonal regeneration (Uchida et al., 2016). Additionally, MenSCs upregulate mature neuronal markers such as neurofilament-200 (NF-200) and microtubule-associated protein-2 (MAP-2), facilitating structural reconstruction of neural tissue (Li et al., 2013a). MenSCs also contribute to neural repair by attenuating glial scar formation, as evidenced by the reduced expression of inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) (Anderson et al., 2016; Fan et al., 2017). Concurrently, MenSCs suppress the production of proinflammatory cytokines, including TNF-α and IL-1β, thereby alleviating neuroinflammation. In animal models, local injection of MenSCs significantly improved hindlimb motor function in rats with SCI(131).

Hjazi and colleagues (Hjazi et al., 2024) further advanced this therapeutic approach by combining MenSC-Exos with hyperbaric oxygen therapy (HBOT) in a model of traumatic SCI (TSCI). While MenSC-Exos exert anti-inflammatory and antiapoptotic effects (Dalirfardouei et al., 2019), HBOT reduces neuronal apoptosis by downregulating the expression of proinflammatory cytokines (e.g., IL-1β and TNF-α) (Ghaemi et al., 2023; Zhao et al., 2021). The combined therapy synergistically regulated apoptosis, oxidative stress, and inflammation, resulting in improved histopathological outcomes and functional recovery.

Alzheimer’s disease, the most common type of dementia, is pathologically defined by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs). Aβ originates from proteolytic cleavage of the transmembrane amyloid precursor protein (APP), whereas NFTs consist of hyperphosphorylated and misfolded tau proteins (Ballard et al., 2011). Zhao et al. (2018b) reported that MenSCs transplantation reduced Aβ deposition in the hippocampus and cortex, potentially by regulating aberrant APP processing, enhancing Aβ clearance by microglia, and suppressing tau hyperphosphorylation. Moreover, MenSCs promoted the transformation of microglia into a neuroprotective phenotype, facilitating anti-inflammatory cytokine secretion and markedly improving cognitive deficits in APP/PS1 transgenic mice.

Notably, Lopez-Verrilli et al. (2016) reported a biphasic effect of MenSCs on neurite outgrowth. While direct contact between MenSCs and neurons inhibited neurite elongation, their secreted factors—including VEGF, HGF, and brain-derived neurotrophic factor—promoted axonal extension. Further investigation revealed that the exosomal fractions of MenSC-EVs promoted neurite outgrowth, whereas the microvesicle fractions had inhibitory effects. This functional heterogeneity provides new insights into the application of MenSCs in treating neurodegenerative diseases.

Myocardial infarction (MI), an acute cardiovascular emergency, is primarily treated by curtailing the progression of myocardial necrosis and promoting functional recovery (Lu et al., 2015). Wang et al. (2017) reported that extracellular vesicles derived from MenSC-EVs regulate the PTEN/Akt pathway through high expression of miR-21. This mechanism both inhibits cardiomyocyte apoptosis and promotes angiogenesis, thereby significantly improving cardiac function in infarcted rat models. This discovery provides a novel strategy for myocardial regeneration therapy.

In the field of prostate cancer (PC) treatment, Alcayaga-Miranda et al. (2016) revealed that MenSC-Exos reduce tumor cell ROS levels and downregulate the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). This disrupts the tumor’s hypoxic adaptation, thereby inhibiting tumor hemoglobin biosynthesis and neovascularization, which contributes to an antitumor effect. Such microenvironmental modulation offers a new avenue for targeted therapy in solid tumors.

With respect to ulcerative colitis (UC), (Malik et al., 2018) demonstrated that ERCs exert anti-inflammatory effects by rebalancing cytokine profiles—reducing IL-2 and TNF-α while increasing IL-4 and IL-10 levels. Further research has shown that preconditioning with stromal cell-derived factor-1 enhances CXCR4 expression in ERCs, promoting M2 macrophage polarization and Treg cell generation (Li et al., 2019); prestimulation with IL-1β inhibits the DKK1 protein and activates the Wnt/β-catenin pathway, thereby strengthening their immunomodulatory function (Yu et al., 2021); and melatonin preconditioning enhances ERC efficacy via antioxidant protection, significantly lowering both the disease activity index and tissue damage scores (Hao et al., 2024).

In the treatment of type 1 diabetes mellitus (T1DM), (Malik et al., 2018) confirmed that intravenous infusion of MenSCs results in targeted migration to the injured pancreas. This migration activates Ngn3-positive endocrine progenitor cells, facilitating β-cell regeneration, effectively reversing hyperglycemia, increasing insulin secretion, and restoring islet architecture. This finding provides a potential solution to the shortage of islet donors.

In sepsis treatment research, (Alcayaga-Miranda et al., 2015a) reported that MenSCs enhance host defense by increasing the expression of antimicrobial peptides and hepcidin. When combined with antibiotics, this approach significantly improves bacterial clearance and survival. Notably, MenSC-Exos exert a protective effect against LPS-induced liver injury by modulating abnormal natural killer (NK) cell activation (Chen et al., 2017c), thereby reducing inflammatory organ damage and demonstrating multitarget therapeutic potential.

MenSCs exert reparative effects via the paracrine release of small extracellular vesicles (sEVs), which mediate multiple signaling pathways. miRNA profiling of exosomes has identified the enrichment of key microRNAs (miRNAs), such as miR-21 and miR-lethal-7 (let-7), in MenSC-derived sEVs. miR-21 enhances cell survival and improves cardiac function by targeting PTEN and activating the AKT/PKB signaling cascade (Wang et al., 2017). Let-7 modulates the NLRP3 pathway, enhancing the inhibition of ROS production and mitochondrial DNA damage via suppression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), thereby facilitating the repair of alveolar epithelial cells (Sun et al., 2019). In pancreatic regeneration, sEVs activate the PDX-1 signaling axis to promote β-cell regeneration and insulin secretion (Mahdipour et al., 2019).

In terms of immune regulation, MenSC-Exo induce phosphorylation of STAT3/STAT6, driving M2 macrophage polarization (Liu et al., 2017). Similarly, CD73 present in exosomes from endometrial regenerative cells promotes M2 polarization through a MAPK-dependent hydrolysis of ATP, thereby contributing to renal protection (Shao et al., 2025).

Regarding metabolic regulation, hepatocyte growth factor (HGF) secreted by MenSCs downregulates hepatic Rnf186 expression and modulates the AMPK-mTOR signaling pathway, improving glucose and lipid metabolism. In addition, HGF upregulates β-catenin, contributing to the repair of tight junctions and the expression of bile transporters (OATP2, BSEP, NTCP1), thereby attenuating the progression of hepatic fibrosis (Du et al., 2023; Yang et al., 2022).

At the epigenetic level, MenSCs restore the expression of TET1/2 and 5-hmC levels in hepatocellular carcinoma cells in a time-dependent manner. By modulating the 5-hmC/5-methylcytosine enrichment at enhancer regions of PI3K/AKT and RAF/ERK pathway target genes, MenSCs relieve repression of FOXO3, subsequently promoting downstream apoptotic processes (Wu et al., 2019).

ERCs demonstrate multifaceted immunomodulatory capabilities during tissue repair. Studies have shown that ERCs can induce the polarization of M2 macrophages, tolerogenic dendritic cells, and regulatory T and B cells both in vivo and in vitro. They also significantly suppress IgG and IgM antibody deposition and infiltration of CD4⁺ and CD8⁺ T cells. These immunoregulatory effects are closely associated with stromal cell-derived factor-1–mediated immunosuppressive mechanisms (Xu et al., 2017).

MenSCs exert notable regulatory effects on various immune cell populations. In reproductive immunology, uterine NK cells play essential roles in early pregnancy tolerance through killer cell immunoglobulin-like receptors (Male and Moffett, 2023). Shokri et al. reported that IFN-γ- and IL-1β-pretreated MenSCs inhibited NK cell cytotoxicity via the IL-6 and TGF-β pathways, thereby reducing perforin and granzyme production and promoting an immune-tolerant microenvironment conducive to pregnancy (de Pedro et al., 2021). Additionally, Hosseini et al. reported a significant decrease in TCRγδ cell proportions in the menstrual blood of patients with recurrent spontaneous abortion, suggesting a possible link to pregnancy-related immune dysregulation (Hosseini et al., 2016). With respect to dendritic cells, Bozorgmehr and colleagues demonstrated that MenSCs dose-dependently suppress monocyte differentiation into immature dendritic cells, possibly through high secretion levels of IL-6 and IL-10 (Bozorgmehr et al., 2014). In antitumor immunity, menstrual blood-derived immune cells also show substantial potential. Qin et al. isolated DC-CIK cells from the menstrual blood of ovarian cancer patients and reported that these cells inhibited ovarian cancer stem cells by activating the TNFR1–ASK1–AIP1–JNK signaling pathway (Qin et al., 2018).

Although MenSCs lack HLA-DR expression, limiting their antigen-presenting capacity, they exert immunoregulatory effects through the secretion of various paracrine molecules, including IL-6, TGF-β, COX-2, PGE2, indoleamine 2,3-dioxygenase, and programmed death ligand-1 (Malik et al., 2018; Luz-Crawford et al., 2016; Cuenca et al., 2018). Proteomic analysis revealed high expression levels of adhesion molecules such as activated leukocyte cell adhesion molecule and intercellular adhesion molecule-1 in MenSCs (Liu et al., 2018). These molecules interact with receptors such as LFA-1, directly participating in immune cell activation and regulation, and play critical roles in the immunomodulatory functions of MenSCs. Notably, MenSCs also secrete multiple angiogenic factors, including VEGF, HGF, angiogenin, and MMP-1, which contribute to both tissue regeneration and immune regulation.