Unexplained Recurrent Spontaneous Abortion (RSA) impacts the physical and psychological well-being of women of reproductive age. This study aimed to reveal the potential mechanisms behind unexplained RSA from the perspective of glucose and lipid metabolic profiles before conception and their relationship with immune, coagulation, and inflammatory markers.

A retrospective analysis was conducted on 100 patients with unexplained recurrent spontaneous abortion at our gynecology department from June 2022 to June 2023. According to whether abnormal glucose and lipid metabolism exist, patients were grouped into normal group and abnormal group. The study compared the glucose and lipid metabolic characteristics, immune status, coagulation, and inflammatory parameters between two groups.

The Abnormal Group exhibited higher fasting blood glucose, 2-hour oral glucose tolerance test, homeostatic model assessment of insulin resistance, total cholesterol, and LDL cholesterol, along with lower levels of HDL cholesterol. Additionally, alterations in immune profile parameters, including lower levels of CD4+ T cells, CD8+ T cells, B cells, NK cells, and elevated IL-6, were observed in the Abnormal Group. Regarding coagulation and inflammatory profile parameters, the Abnormal Group demonstrated prolonged prothrombin time, activated partial thromboplastin time, elevated fibrinogen and D-dimer levels, and increased platelet count, along with elevated C-reactive protein, TNF-α, and IL-1β levels. Correlation analysis revealed significant associations between the pre-pregnancy metabolic characteristics and immune, coagulation, and inflammatory profile parameters.

Abnormal glucose and lipid metabolism may lead to or exacerbate unexplained RSA in some patients, and therapeutic interventions targeting glucose and lipid metabolism hold promise for improving pregnancy outcomes in this population.

This study aims to investigate the biodistribution and persistence of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in NCG mice post-intravenous injection, utilizing 89Zr-PET/CT, bioluminescence imaging, multiplex immunohistochemistry (mIHC), and quantitative polymerase chain reaction (qPCR).

hUC-MSCs were labeled with 89Zr-oxine (89Zr-MSCs) or transduced with luciferase gene (Luc-MSCs). Real-time tracking of 89Zr-MSCs lasted for 14-days followed by mIHC staining of hCD73. Real-time tracking of Luc-MSCs lasted for 7-days, followed by mIHC staining of hCD73 and human Alu-based qPCR. All methods adhered to ICH and other regulatory guidelines for development of cell-based drugs.

A biodistribution and persistence pattern was observed in the order of lung > liver > kidney > >spleen, although discrepancies were noted for the liver and kidney.

Each method exhibited strengths and weaknesses: 89Zr-PET/CT enabled long-term tracking but encountered issues with 89Zr shedding and dead cells; bioluminescence provided specific detection but was hampered by a rapid decline in signal; mIHC identified cells but relied on antigen abundance; qPCR detected minimal cell quantities but was unable to differentiate between live and dead cells. These limitations may obscure the true fate of cells in vivo, highlighting the need for more accurate and reliable assessment techniques.

"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.

Insufficient invasion of extravillous trophoblasts (EVTs) is associated with adverse pregnancy outcomes, including recurrent miscarriage (RM). Dysregulated expression of growth differentiation factor 15 (GDF15) has been implicated in RM, but the underlying mechanism remains unclear. This study investigated the role of GDF15 in EVTs function and pregnancy outcomes. Spearman correlation analysis revealed a positive correlation between GDF15 and both BMPR1A and BMPR2 in EVTs. Furthermore, GDF15, BMPR1A, BMPR2, and phosphorylated SMAD1 (p-SMAD1) expression were significantly reduced in placental tissue from RM patients compared to Normal controls. Mechanistically, GDF15 activated the p-SMAD1 signaling pathway, inducing expression of its downstream targets, ID1 and Snail, and enhancing migratory and invasive activity in HTR-8/SVneo cells through interaction with the BMPR1A-BMPR2 receptor complex. Eriodictyol, a small molecule activator of BMPR2, was identified and shown to improve pregnancy outcomes in a mouse model of lipopolysaccharide (LPS)-induced early pregnancy loss (EPL). Eriodictyol can also enhance EVTs migration and invasion as well as activated the p-SMAD1 pathway by activating BMPR2. In conclusion, this study identifies BMPR1A as a receptor for GDF15 in EVTs and demonstrates that GDF15 promotes EVTs invasion and improves pregnancy outcomes via the BMPR1A/BMPR2/p-SMAD1 signaling axis. Eriodictyol, acting as a BMPR2 agonist, may offer a novel therapeutic strategy for preventing early pregnancy loss.

Umbilical Cord-derived Mesenchymal Stromal Cells (UC-MSCs) display high immunoregulatory properties, offering new perspectives to treat severe immune and inflammatory diseases. However, the heterogeneity of their biological properties remains a challenge to predict clinical response. The aim of our study is to evaluate a strategy based on the constitution of a pool of several pre-selected donors to reduce the biological variability of UC-MSCs and improve their immunomodulatory properties.

Umbilical cords were collected from 10 healthy donors. Isolated UC-MSCs were characterized in the basal state and after a pro-inflammatory priming in vitro by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, the expression of activation markers and the inhibition of T cell proliferation in vitro were assessed in UC-MSCs from selected single donors and from pools.

Our study highlights the donor-dependent heterogeneity of UC-MSCs immunomodulatory functions. Based on their ability to suppress T-cell proliferation in vitro, we classified donors into three profiles: high, medium and low. Preparation of pools containing UC-MSCs derived from each profile in a 1:1:1 ratio reduced the donor-dependent variability and, most importantly, improved the lowest immunomodulatory functions. After priming with pro-inflammatory cytokines, the inhibition of T-cell expansion by the pooled UC-MSCs was significantly higher than the low donor and the theoretical mean of individual donors, and was associated with increased expression of the key immunoregulatory proteins. Interestingly, the pool did not induce a cumulative immunogenic effect: expression of HLA or costimulatory molecules between the high donor and the pool were similar. Finally, pooling UC-MSCs derived from high and low donors in a 1:2 ratio was sufficient to enhance the lowest immunomodulatory properties.

Overall, our results demonstrate that pooled UC-MSCs with selected high donor offers a new strategy to optimize the immunomodulatory functions of allogeneic UC-MSC-based medicinal products.

Bovine embryo resorption is one of the key factors restricting the reproductive efficiency in dairy cattle, which mainly occurs in the early stage of maternal recognition of pregnancy, causing substantial economic losses to the dairy industry. Macrophages, the most numerous endometrial immune cells in cows during early pregnancy, are critical in developing maternal-fetal immune tolerance. However, the mechanism of their action on the maternal-fetal interface of dairy cows remains unknown. MicroRNAs have important roles in immune tolerance and macrophage polarization, but the underlying mechanisms still need further investigation. In previous laboratory studies, RNA-sequencing revealed that bta-miR-93 was dramatically reduced in bovine endometrial luminal epithelial cells (bEECs) upon IFN-tau stimulation. In the current study, it is revealed that the expression of bta-miR-93 was decreased substantially in the endometrium of pregnant cows and negatively correlated with that of Programmed Cell Death Ligand 1 (PD-L1). In vitro experiments displayed that suppression of bta-miR-93 promoted M2 polarization via promoting PD-L1/PD-1/AKT/mTOR signaling pathway in bEECs and bovine macrophage co-culture model, and vice versa. The 3'-untranslated region of PD-L1 is directly regulated by bta-miR-93. Furthermore, our in vivo studies revealed that overexpression of bta-miR-93 efficiently leads to embryo resorption and suppression of M2 polarization in mice.

Bone defects result in substantial medical expenses and a diminished quality of life for patients. Macrophage polarization is crucial in the bone regeneration process mediated by bone marrow-derived mesenchymal stem cells (BMSCs). macrophage-derived sulfur dioxide (SO2), the fourth endogenous gas signaling molecule, following hydrogen sulfide (H2S), has been shown to regulate macrophage chemotaxis and inflammatory responses. Nevertheless, the specific regulatory effects and mechanisms of macrophage-derived SO2 on bone regeneration are not yet fully understood. This study reveals for the first time that the absence of macrophage-derived SO2 promotes M1 macrophage polarization, whereas the administration of exogenous SO2 donors inhibits M1 polarization. The deficiency of macrophage-derived SO2 results in impaired osteogenic differentiation of BMSCs, whereas the administration of SO2 donors enhances this differentiation process. Further investigations have elucidated that p38α MAPK (p38) is crucial in mediating SO2's effects on M1 macrophage polarization and BMSCs osteogenic differentiation. Mechanistically, SO2 induces S-sulfenylation of p38 in macrophages, an effect that can be reversed by the thiol reductant dithiothreitol. Additionally, the C211S mutation in p38 abrogates the SO2-induced S-sulfenylation of p38, thereby preventing the inhibition of p38 activation and subsequently disrupting the regulation of M1 macrophage polarization and BMSCs osteogenic differentiation. In a model of mouse calvarial bone defects, we consistently observed that inhibiting SO2 production using the SO2-generating enzyme inhibitor HDX impaired bone regeneration capacity in mice, whereas the administration of an SO2 donor enhanced this capacity. In summary, macrophage-derived SO2 S-sulfenylates p38 at cysteine 211, thereby suppressing p38 activation, which inhibits M1 polarization and subsequently maintains the osteogenic differentiation of BMSCs. This study is the first to elucidate the role and mechanism of SO2 in sustaining osteogenesis, offering a novel strategy for addressing bone defect-related disorders.

Mesenchymal stem cells (MSCs) have therapeutic potential due to their immunomodulatory and anti-inflammatory properties. In veterinary medicine, adipose tissue is the most common source of MSCs to treat canine disease, but the collection process is invasive, and the cells are influenced by the age and health conditions of the donor. These problems enhance interest in seeking alternative MSC sources, such as perinatal tissues. In this study, we developed and validated an optimized protocol for isolating canine umbilical cord MSCs for application in veterinary therapies. Umbilical cords obtained from cesarean sections were processed using three different protocols, involving combinations of mechanical and enzymatic tissue dissociation. The cells were cultured and evaluated for membrane receptors by flow cytometry to identify MSCs and assessed for their differentiation capacity. The number of cells obtained did not differ significantly between the combined protocol with trypsin and collagenase (TRIP + COL) and the collagenase protocol (COL). In in vitro culture, the combined TRIP + COL and COL yielded 12 to 14 times more cells, respectively, in the first passage than the explant (EXP) group, within fewer days of culture. Additionally, the cells obtained from these protocols showed a greater capacity for expansion over passages, and cells from both protocols showed fibroblast-like morphology and proliferation capacity up to the sixth passage. The cells obtained from these protocols were characterized by phenotype: CD45-, CD34-, CD14-, HLA-DR-, CD29+, CD44+, and CD90+, consistent with MSC identity. However, CD90 expression in the cells decreased significantly at sixth passage. Regarding differentiation, cells obtained from the COL protocol showed a capacity for commitment to the chondrogenic and osteogenic lineages. In conclusion, the COL and TRIP + COL protocols were more effective than the EXP protocol in terms of both the number and quality of isolated cells. However, due to its less-aggressive enzymatic nature, we considered the COL protocol to be the best method to obtain canine MSCs.

Recurrent pregnancy loss (RPL) is one of obstetrical diseases with no effective therapy methods. Trophoblast cell dysfunction and inflammation induce embryo implantation insufficiency, thereby resulting in RPL. OTU deubiquitinase with linear linkage specificity (OTULIN) plays a role in regulating the immune response and cell death. However, the role of OTULIN in RPL remains unclear. Spontaneous abortion mouse model and lipopolysaccharide-treated HTR-8/SVneo cells were used to investigate the role of OTULIN in RPL. OTULIN expression was downregulated in the labyrinth trophoblast of RPL mice and LPS-treated trophoblast cells. The embryonic reabsorption rate was decreased in OTULIN-overexpressed spontaneous abortion mice, accompanied with the increase in placental/fetus weight ratio. OTULIN overexpression significantly inhibited apoptosis in vivo and in vitro, as evidenced by the decrease in the activity of caspase 3. The expression of pro-inflammatory cytokines was decreased with OTULIN overexpression. Moreover, OTULIN overexpression decreased p-IκBα/IκBα and p-p65/p65 ratio. The nuclear translocation of NF-κB was suppressed via OTULIN overexpression both in vivo and in vitro. Our study suggested that OTULIN deficiency might cause inflammation and trophoblast abnormalities in RPL. The supplementation with OTULIN might alleviate the development of RPL via inhibiting NF-κB mediated inflammation response.

Subclinical hypothyroidism (SCH) is associated with multiple adverse outcomes in early pregnancy. This study aims to explore the regulatory mechanisms underlying histone lactylation modification in early pregnancy with SCH. Peripheral blood mononuclear cells were collected from early pregnant women with or without SCH. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses were performed to identify the transcriptional pattern and histone lactylation modification in early pregnancy with SCH. RNA-seq analysis revealed that the differentially expressed genes associated with the extracellular matrix exhibited a significant downregulation in early pregnancy with SCH (EP_SCH) compared to early pregnancy without SCH (EP), while those involved in apoptosis were significantly upregulated. In the ChIP-seq analysis, 1660 hypomodified and 766 hypermodified H3K18la-binding peaks were identified in the EP_SCH group compared to the EP group. The hypomodified genes in early pregnancy with SCH compared to its control were enriched in GO terms of apoptotic process and differentiation of immune cells. The genes with increased H3K18 lactylation in early pregnancy with SCH compared to its control were associated with the nervous system, female pregnancy, and the OXT signaling pathway. When RNA-seq data was integrated with ChIP-seq data, we found that the expression and H3K18la enrichment of KCTD7, SIPA1L2, HDAC9, BCL2L14, TXNRD1, and SGK1 were increased in early pregnancy with SCH compared to its control, which was further confirmed by RT-qPCR and ChIP-PCR analyses. This study identifies the changes in histone lactylation modification in early pregnancy with SCH. These findings provide novel insights into the regulatory mechanisms of SCH during early pregnancy.

Allergic rhinitis (AR) affects 10-40% of the global population, yet current therapies (drugs, immunotherapy) face limitations in efficacy and safety. Mesenchymal stem cells (MSCs) have emerged as a promising alternative due to their immunomodulatory properties.

Preclinical studies demonstrate that MSCs from adipose, bone marrow, umbilical cord, and tonsils reduce AR symptoms (sneezing, nasal inflammation) and serum IgE (Immunoglobulin E) levels by restoring Th1/Th2 immune equilibrium and enhancing Treg (Regulatory T cells) activity. MSC-derived exosomes and hydrogel-encapsulated formulations further improve targeting and safety. However, clinical translation is hindered by heterogeneous protocols and unresolved long-term risks (e.g., tumorigenicity).

MSC-based therapies offer potential for durable AR remission by addressing immune dysregulation at its root. Future efforts must prioritize standardized production, phase I safety trials, and combination strategies (e.g., exosomes + hydrogels) to accelerate clinical adoption.

Acute respiratory distress syndrome is characterized by the dysregulation and activation of several inflammatory pathways which lead to widespread inflammation in the lungs. Presently, direct therapy is unavailable and the use of mesenchymal stromal cells as a direct therapy has been proposed, as early-phase studies have shown promise.

MSCs exert various therapeutic effects on the inflammatory microenvironment, such as anti-microbial effects, restoration of the alveolar-capillary barrier, and exuding various anti-inflammatory effects. However, to exert these effects MSCs need to be submitted to specific external stimuli which can affect their immunomodulation, survival, migration and metabolic state. This review references several articles found through targeted searches in PubMed [Accessed between November 2024 and March 2025], for key terms such as 'mesenchymal stromal cells', 'inflammatory microenvironment', anti-inflammatory', 'metabolism', and 'immunomodulation'.

The advancement of MSCs therapy in the treatment of ARDS has not progressed as effectively as one might have anticipated. Several clinical findings have established patient subgroups based on inflammatory cytokine profiles and severity of ARDS. This variation in patients may influence the clinical efficacy of MSCs and instead of concluding that MSCs therapy is not worth pursuing, more research is needed to develop an appropriate therapy.

Spontaneous abortion (SA) remains a clinical challenge in early pregnancy. It has been reported that endoplasmic reticulum stress (ERS) is implicated in pregnancy-related complications. However, the precise mechanistic role of ERS in SA pathogenesis remains elusive. This study aims to explore the therapeutic potential of targeting ERS-related decidual dysfunction in SA.

An ERS model was established in both decidualized stromal cells (DSCs) and pregnant mice through tunicamycin (Tu) administration. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to determine the interaction between XBP1s and the transcription factor binding site (TFBS) of tumor necrosis factor receptor-associated factor 6 (TRAF6). Mitochondrial membrane potential (MMP) and mitochondrial function were assessed using JC-1 and TMRM staining following ERS induction in DSCs. The effects of XBP1s inhibitors on mitochondrial metabolism and autophagy were evaluated through RT-qPCR, Western blotting, RNA-Seq, TUNEL assays, ROS and MitoSOX detection, and histological analyses in Tu-treated DSCs and SA patients. STF-083010 (STF) or shXBP1 was utilized to assess the inhibitory effects of X-box binding protein 1 (XBP1s) on DSC function both in vitro and in vivo.

We observed significant upregulation of XBP1s in decidual tissues from SA patients and Tu-exposed DSCs. Tu exposure significantly increased the proportion of TUNEL-positive cells and upregulated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-18) in DSCs. XBP1s inhibition via shXBP1 or pharmacological inhibitor STF attenuated Tu-induced apoptosis and inflammatory cytokine expression. Notably, STF or shXBP1 treatment enhanced MMP and upregulated LC3-II expression in Tu-treated DSCs, indicating autophagy activation.Intriguingly, chloroquine (CQ)-mediated autophagy suppression exacerbated apoptosis in STF/Tu-co-treated DSCs, suggesting that XBP1s inhibition confers cytoprotection through autophagy induction. Mechanistically, XBP1s directly bound to the TFBS of TRAF6, a ubiquitin E3 ligase. TRAF6 overexpression exacerbated mitochondrial dysfunction and apoptosis while suppressing autophagy via inhibition of mTORC2/Akt pathway in Tu-treated DSCs.

XBP1s inhibition restored mitochondrial homeostasis and promoted autophagy by modulating the TRAF6/mTORC2 axis under ERS conditions, providing novel mechanistic insights into SA pathogenesis and potential therapeutic targets.

Advancements in regenerative medicine have led to the applicability of stem cell technology in various diseases. Stem cells that have self-renewable abilities may differentiate into several cell types to provide therapeutic potential. Among different stem cells, adult stem cells are considered as the safest with remarkable potential for therapeutic application. In this review, we provide current available evidence regarding the application of adult stem cells in medicine, especially in the field of obstetrics and gynecology.

This scoping review aims to map and describe the current research on adult stem cell application in obstetrics and gynecology.

We performed a systematic search on PubMed, Google Scholar, and Cochrane Library in August 2024 to identify research articles involving adult stem cells in the field of obstetrics and gynecology. We used the Deduplicate website to filter articles based on keywords that met our inclusion and exclusion criteria. The results were presented based on recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.

We found 42 articles that met the inclusion criteria. Some studies were clinical studies, whereas the majority were preclinical studies. We categorized the articles into clinical and preclinical studies to understand their applicability in human subjects.

Adult stem cell therapy is a candidate treatment for several pathologies in obstetrics and gynecology. The promising results of adult stem cell therapy, especially in degenerative gynecologic diseases, may lead to further application of the technology in the near future.

The establishment of placentation and maternal-fetal tolerance are important determinants of a successful pregnancy. Tacrolimus, also known as FK506, is a calcineurin inhibitor that has often been used for pregnant women after solid organ transplantation. Previous therapeutic interventions have shown the benefits of using the immuno-suppressive agent FK506 in improving clinical pregnancy and live birth rates and reducing the risk of spontaneous miscarriage. However, the mechanism(s) by which FK506 is involved in these processes have not been fully elucidated. To further characterize its function in early pregnancy, we explored the effect of FK506 on the human-derived first trimester extravillous trophoblast cells (HTR8/SVneo cells) and found that FK506 promoted invasion, tube formation and proliferation, but inhibited apoptosis of HTR8/SVneo cells. Based on the integrated metabolomics and transcriptomics analyses, the present study provided the cellular and molecular cues evidently showing that FK506 had positive effects on the placentation and maternal-fetal tolerance through modulating FASN-CEACAM1 pathway. The spontaneous-abortion-prone model gave further evidence that FK506 exerted a protective effect on pregnancy by regulating the FASN-CEACAM1 axis. These findings might provide a new fundamental mechanism and promising potential of low-dose FK506 in preventing pregnancy loss.

MSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore, strategies to improve their therapeutic potential, such as preconditioning with proinflammatory factors, have been proposed. Several priming approaches have provided non-conclusive results, and the duration of priming effects on MSC properties or their response to a second inflammatory stimulus have not been fully addressed.

We have investigated the impact of triple cytokine priming in MSCs on their characterization and viability, their transcriptomic profile, the functionality of innate and acquired immune cells, as well as the maintenance of the response to priming over time, their subsequent responsiveness to a second inflammatory stimulus.

Priming MSCs with proinflammatory cytokines (CK-MSCs) do not modify the differentiation capacity of MSCs, nor their immunophenotype and viability. Moreover, cytokine priming enhances the anti-inflammatory and immunomodulatory properties of MSCs against NK and dendritic cells, while maintaining the same T cell immunomodulatory capacity as unstimulated MSCs. Thus, they decrease T-lymphocytes and NK cell proliferation, inhibit the differentiation and allostimulatory capacity of dendritic cells and promote the differentiation of monocytes with an immunosuppressive profile. In addition, we have shown for the first time that proinflammatory priming reduces the variability between different donors and MSC origins. Finally, the effect on CK-MSC is maintained over time and even after a secondary inflammatory stimulus.

Cytokine-priming improves the therapeutic potential of MSCs and reduces inter-donor variability.

Mesenchymal stem cells (MSCs) are the most widely used stem cells in regenerative medicine. They can be isolated from multiple sources, most commonly bone marrow and adipose tissue. MSCs derived from different sources show similar molecular and biological characteristics, but there is ongoing debate regarding the best source of MSCs and the potential biological differences between MSCs from different origins. Bone marrow derived-MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) share many molecular and immunomodulatory properties. In this study, we compared the levels of major immunomodulatory, adhesive, and migratory factors in human BM-MSCs and AD-MSCs under normal conditions, which will help determine the suitability and specificity of each type for certain therapeutic applications. WST1 assay and fluorescent assay SUC-LLVY-AMC were used to measure MSC proliferation and 26S proteasome activity, respectively. Western blotting, ELISA Assays, and bright field live imaging were also used. AD-MSCs and BM-MSCs exhibited similar morphology and proliferation rate. A significantly higher 26S proteasome activity was detected in AD-MSCs than in BM-MSCs. Levels of ICAM-1, integrin α5 and integrin α6 were significantly higher in AD-MSCs compared to BM-MSCs, while no significant difference in CXCR4 levels was observed. Expression of IDO and factor H was significantly higher in AD-MSCs, while CTLA-4 and IL-10 levels were higher in BM-MSCs. This indicates that AD-MSCs and BM-MSCs have different immunomodulatory and adhesion profiles. MSCs isolated from different sources may show differences in their biological and immunomodulatory properties, suggesting a potential suitability of certain MSCs type for specific conditions. Also, combination of different MSCs types could help optimize therapeutic outcomes.

The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.

Immunosuppression is one key feature of mesenchymal stromal cells (MSCs) that has high expectations for therapeutic use. The influence of pro-inflammatory stimuli can modify the characteristics of MSCs and enhance immunosuppressive properties. The local postoperative environment contains cytokines, MSCs, and immune cells in high quantities, and their mutual influence is still unclear. Knowledge of in vivo processes is pivotal for potential therapeutic applications, and therefore, the aim of this study was to investigate the influence of wound fluid (WF) on the immunomodulatory potential of MSCs. CD4+ cells were co-cultured with native or WF-preconditioned MSCs for 5 days. CFSE staining revealed significant suppression of T cell proliferation after co-culture that was even more distinct in co-culture with WF-MSCs. The concentration of IDO-1, TGF-β1 and IFN-γ was higher while TNF-α was reduced in co-culture supernatants, indicating a transition to an anti-inflammatory milieu. In summary, the results provide evidence that the influence of WF alters the immunomodulatory potential of MSCs. These findings should serve as the basis for further investigations with a focus on T cell subpopulations.

Mesenchymal stem cells (MSCs), recognized for their self-renewal and multi-lineage differentiation capabilities, have garnered considerable wide attention since their discovery in bone marrow. Recent studies have underscored the potential of MSCs in immune regulation, particularly in the context of autoimmune diseases, which arise from immune system imbalances and necessitate long-term treatment. Traditional immunosuppressive drugs, while effective, can lead to drug tolerance and adverse effects, including a heightened risk of infections and malignancies. Consequently, adjuvant therapy incorporating MSCs has emerged as a promising new treatment strategy, leveraging their immunomodulatory properties. This paper reviews the immunomodulatory mechanisms of MSCs and their application in autoimmune diseases, highlighting their potential to regulate immune responses and reduce inflammation. The immunomodulatory mechanisms of MSCs are primarily mediated through direct cell contact and paracrine activity with immune cells. This review lays the groundwork for the broader clinical application of MSCs in the future and underscores their significant scientific value and application prospects. Further research is expected to enhance the efficacy and safety of MSCs-based treatments for autoimmune diseases.

Endometrial decidualization is critical for successful embryo implantation. Dysregulation of the immune microenvironment can disrupt normal decidualization processes, potentially resulting in early pregnancy loss. Ferroptosis, a form of cell death dependent on iron and lipid hydroperoxides, is closely associated with inflammation. In this study, we developed an inflammatory early pregnancy loss model to elucidate the mechanisms of decidual damage induced by lipopolysaccharide (LPS) and to assess whether ferroptosis contributes to LPS-induced early pregnancy loss. Through in vivo experiments, we observed that embryo implantation was significantly inhibited and endometrial decidualization was impaired during LPS-induced early pregnancy loss. LPS exposure resulted in abnormal mitochondrial morphology, reduced antioxidant capacity, accumulation of reactive oxygen species (ROS) and disruptions in iron metabolism during decidualization in mouse endometrial stromal cells (mESCs). The administration of ferroptosis inhibitors, specifically ferrostatin-1 (Fer-1) and deferoxamine (DFO), effectively reversed embryo loss and mitigated the decidual damage associated with LPS-induced early pregnancy loss. Fer-1 and DFO exhibited resistance to ferroptosis during decidualization by modulating the antioxidant system and iron metabolism in mESCs, respectively. Our findings indicate that the inhibition of ferroptosis can confer protective effects against decidual damage during LPS-induced early pregnancy loss in mice.

Skin injuries and infections are an inevitable part of daily human life, particularly with chronic wounds, becoming an increasing socioeconomic burden. In treating skin infections and promoting wound healing, bioactive peptides may hold significant potential, particularly those possessing antimicrobial and anti-inflammatory properties. However, obtaining these peptides solely through traditional wet laboratory experiments is costly and time-consuming, and peptides identified by current computer-assisted predictive models largely lack validation of their effects via wet laboratory experiments. Consequently, this study aimed to integrate computer-assisted methods and traditional wet laboratory experiments to identify anti-inflammatory and antimicrobial peptides.

We developed a computer-assisted mining pipeline to screen potential peptides from the epitopes of the major histocompatibility complex class II.

The peptide AIMP1 was identified, with the ability to physically damage Escherichia coli by increasing bacterial cell membrane permeability, and with the ability to inhibit inflammation by binding to endotoxin-lipopolysaccharide. Additionally, in an LPS-induced inflammation animal model, AIMP1 slightly increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and in a skin wound infection animal model, AIMP1 effectively accelerated healing, reduced levels of these pro-inflammatory cytokines, and showed no acute hepatotoxicity or nephrotoxicity.

In conclusion, this study not only developed a computer-assisted mining pipeline for identifying anti-inflammatory and antimicrobial peptides but also successfully pinpointed the peptide AIMP1, demonstrating its therapeutic potential for skin injury treatment.

We aimed to determine the peripheral blood mononuclear cell (PBMC) immune profiles of mid- and late-stage pregnant women to establish a foundation for studying pregnancy-related diseases. Peripheral blood samples were collected from three women each during mid- and late-stage pregnancy, and PBMCs were extracted for single-cell RNA sequencing (scRNA-seq). Peripheral blood samples were also collected for flow cytometry analysis to validate the analytical results. HOPX+ CD4+ T cells, ZNF683+CD8+ T cells, and KLRB1+CD8+ T cells significantly differed in quantitative ratio and gene transcript level between women at mid- and late-stage pregnancy. In late pregnancy, cell-to-cell communication was enhanced and effector CD8+ T cells highly expressed infection-related pathways. A rare T cell subtype, "XIST+ T cells," exhibited high XIST expression, a gene that may be involved in the regulation of immune-related gene transcription and translation, and insulin signaling pathway, during pregnancy. Monocytes exhibited significant proinflammatory and metabolic properties in mid- and late-stage pregnancy, respectively. Natural killer (NK) cells were mainly involved in T- and B-cell-mediated signaling pathways, and in T cell differentiation, in mid-pregnancy. Enhanced innate immunity of NK cells was observed. Moreover, NK cells expressed genes associated with diabetes-related pathways in late-stage pregnancy. To conclude, we present detailed changes in the immune response occurring in pregnant women from mid- to late-stage gestation, revealing significant differences in PBMC subtypes and molecular properties. These findings provide insights into the physiopathological mechanisms of chronic hepatitis B infection, systemic lupus erythematosus, and gestational diabetes mellitus underlying systemic immune responses during mid- and late-stage pregnancy.NEW & NOTEWORTHY There are significant differences in three subtypes of memory/effector T cells (HOPX+ CD4+ T cells, ZNF683+CD8+ T cells, and KLRB1+CD8+ T cells) between mid- and late pregnancy. In late pregnancy, intercellular interaction was enhanced and effector CD8+ T cells highly expressed infection-related pathways. A rare T cell subtype, "XIST+ T cells," may be involved in the regulation of immune-related gene transcription and translation with a strong female bias.

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients.

Sustained or chronic inflammation in the placenta can result in placental insufficiency, leading to adverse reproductive outcomes such as pregnancy loss. Branched-chain amino acid transaminase 1 (BCAT1) expresses in the placenta and is involved in the pathological inflammatory response, but its role in recurrent miscarriage (RM) has not been fully investigated. In the present study, we delved into the effects of BCAT1 on trophoblast inflammation induced by lipopolysaccharide (LPS) and a mouse model of pregnancy loss induced by LPS. In vitro, after the HTR-8/SVneo cells were treated with LPS and BCATc inhibitor 2 (a selective BCAT inhibitor), the cell apoptosis was verified by TUNEL assay, and the activity of caspase-3 and caspase-9 was detected. Real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF) were used to determine the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammasomes (NLRP3 and ASC) in LPS-treated trophoblast cells. Western blot analysis was performed to verify the expression of phospho-IκBα (p-IκBα) in cells and NF-κB p65 in the nuclei. IF staining was used to detect the nuclear translocation of NF-κB p65. The DNA binding activity of NF-κB was detected by an electrophoretic mobility shift assay (EMSA). The results demonstrated that inhibition of BCAT1 reduced trophoblast apoptosis, suppressed the release of proinflammatory cytokines, and prevented NLRP3 inflammasome activation in response to LPS. Additionally, BCAT1 inhibition blocked the activation of the NF-κB pathway in trophoblasts. This study highlights the potential therapeutic role of targeting BCAT1 in preventing adverse reproductive outcomes associated with chronic placental inflammation.

Embryo implantation and decidualization are crucial for a successful pregnancy. How the inflammatory response is regulated during these processes is undefined. Pyroptosis is an inflammatory form of cell death mediated by gasdermin D (GSDMD). Through in vivo, cultured epithelial cells and organoids, it is shown that pyroptosis occurs in epithelial cells at the implantation site. Compared with those on day 4 of pseudopregnancy and delayed implantation, pyroptosis-related protein levels are significantly increased on day 4 of pregnancy and activated implantation, suggesting that blastocysts are involved in regulating pyroptosis. Blastocyst-derived cathepsin B (CTSB) is stimulated by preimplantation estradiol-17β and induces pyroptosis in epithelial cells. Pyroptosis-induced IL-18 secretion from epithelial cells activates a disintegrin and metalloprotease 12 (ADAM12) to process the epiregulin precursor into mature epiregulin. Epiregulin (EREG) enhances in vitro decidualization in mice. Pyroptosis-related proteins are detected in the mid-secretory human endometrium and are elevated in the recurrent implantation failure endometrium. Lipopolysaccharide treatment in pregnant mice causes implantation failure and increases pyroptosis-related protein levels. Therefore, the data suggest that modest pyroptosis is beneficial for embryo implantation and decidualization. Excessive pyroptosis can be harmful and lead to pregnancy failure.

Traditional treatment strategies for recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) often result in limited success, placing significant emotional and financial burdens on couples. However, novel approaches such as diagnostic gene profiling, cell therapy, stem cell-derived exosome therapy, and pharmacogenomics offer promising, personalized treatments. Combining traditional treatments with precision and regenerative medicine may enhance the efficacy of these approaches and improve pregnancy outcomes. This review explores how integrating these strategies can potentially transform the lives of couples experiencing repeated pregnancy loss or implantation failure, providing hope for improved treatment success. Precision and regenerative medicine represent a new frontier for managing RPL and RIF, offering promising solutions.

Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.

Despite promise in preclinical models of acute respiratory distress syndrome (ARDS), mesenchymal stem cells (MSC) have failed to translate to therapeutic benefit in clinical trials. The MSC is a live cell medicine and interacts with the patient's disease state. Here, we explored this interaction, seeking to devise strategies to enhance MSC therapeutic function.

Human bone-marrow-derived MSCs were exposed to lung homogenate from healthy and E. coli-induced ARDS rat models. Apoptosis and functional assays of the MSCs were performed.

The ARDS model showed reduced arterial oxygenation, decreased lung compliance and an inflammatory microenvironment compared to controls. MSCs underwent more apoptosis after stimulation by lung homogenate from controls compared to E. coli, which may explain why MSCs persist longer in ARDS subjects after administration. Changes in expression of cell surface markers and cytokines were associated with lung homogenate from different groups. The anti-microbial effects of MSCs did not change with the stimulation. Moreover, the conditioned media from lung-homogenate-stimulated MSCs inhibited T-cell proliferation.

These findings suggest that the ARDS microenvironment plays an important role in the MSC's therapeutic mechanism of action, and changes can inform strategies to modulate MSC-based cell therapy for ARDS.

Ischemic preconditioning (PC) induced by a sub-lethal cerebral insult triggers brain tolerance against a subsequent severe injury through diverse mechanisms, including the modulation of the immune system. Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, has recently been involved in the regulation of the neuroimmune response following ischemic stroke. Thus, we aimed at assessing whether the neuroprotective effects of ischemic PC involve the modulation of TSG-6 in a murine model of transient middle cerebral artery occlusion (MCAo). The expression of TSG-6 was significantly elevated in the ischemic cortex of mice subjected to 1 h MCAo followed by 24 h reperfusion, while this effect was further potentiated (p < 0.05 vs. MCAo) by pre-exposure to ischemic PC (i.e., 15 min MCAo) 72 h before. By immunofluorescence analysis, we detected TSG-6 expression mainly in astrocytes and myeloid cells populating the lesioned cerebral cortex, with a more intense signal in tissue from mice pre-exposed to ischemic PC. By contrast, levels of TSG-6 were reduced after 24 h of reperfusion in plasma (p < 0.05 vs. SHAM), but were dramatically elevated when severe ischemia (1 h MCAo) was preceded by ischemic PC (p < 0.001 vs. MCAo) that also resulted in significant neuroprotection. In conclusion, our data demonstrate that neuroprotection exerted by ischemic PC is associated with the elevation of TSG-6 protein levels both in the brain and in plasma, further underscoring the beneficial effects of this endogenous modulator of the immune system.

Recurrent spontaneous abortion is thought to be mostly triggered by immune-related causes. Mesenchymal stem cells, which exhibit the traits of multi-directional differentiation capacity and low immunogenicity, have recently been recommended as a viable treatment for spontaneous abortion-prone mice to increase the success of pregnancy. Amniotic membrane tissue is a byproduct of pregnancy and delivery that has a wide range of potential uses due to its easy access to raw materials and little ethical constraints. To construct an abortion-prone mouse model for this investigation, CBA/J female mice were coupled with male DBA/2 mice, while CBA/J female mice were paired with male BALB/c mice as a control. The identical volume of human amniotic mesenchymal stem cells or phosphate buffer was injected intraperitoneally on the 4.5th day of pregnancy. CBA/J female mice were sacrificed by cervical dislocation on the 13.5th day of pregnancy, the embryo absorption rate was calculated, and the uterus, decidua tissues and placenta were gathered for examination. Through detection, it was discovered that human amniotic mesenchymal stem cells significantly increased the expression of interleukin 10 and transforming growth factor beta, while they significantly decreased the expression of interleukin 1 beta and interleukin 6, improved vascular formation and angiogenesis, and minimized the embryo absorption rate and inflammatory cell infiltration in the recurrent spontaneous abortion + human amniotic mesenchymal stem cells group. In any case, human amniotic mesenchymal stem cells regulate inflammatory factors and cell balance at the maternal-fetal interface, which result in a reduction in the rate of embryo absorption and inflammatory infiltration and provide an innovative perspective to the clinical therapy of recurrent spontaneous abortion.

Spontaneous abortion is the most common complication in early pregnancy, the exact etiology of most cases cannot be determined. Emerging studies suggest that mutations in ciliary genes may be associated with progression of pregnancy loss. However, the involvement of primary cilia on spontaneous abortion and the underlying molecular mechanisms remains poorly understood. We observed the number and length of primary cilia were significantly decreased in decidua of spontaneous abortion in human and lipopolysaccharide (LPS)-induced abortion mice model, accompanied with increased expression of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The length of primary cilia in human endometrial stromal cell (hESC) was significantly shortened after TNF-α treatment. Knocking down intraflagellar transport 88 (IFT88), involved in cilia formation and maintenance, promoted the expression of TNF-α. There was a reverse regulatory relationship between cilia shortening and TNF-α expression. Further research found that shortened cilia impair decidualization in hESC through transforming growth factor (TGF)-β/SMAD2/3 signaling. Primary cilia were impaired in decidua tissue of spontaneous abortion, which might be mainly caused by inflammatory injury. Primary cilia abnormalities resulted in dysregulation of TGF-β/SMAD2/3 signaling transduction and decidualization impairment, which led to spontaneous abortion.

Pain is a very common and complex medical problem that has a serious impact on individuals' physical and mental health as well as society. Non-steroidal anti-inflammatory drugs and opioids are currently the main drugs used for pain management, but they are not effective in controlling all types of pain, and their long-term use can cause adverse effects that significantly impair patients' quality of life. Mesenchymal stem cells (MSCs) have shown great potential in pain treatment. However, limitations such as the low proliferation rate of MSCs in vitro and low survival rate in vivo restrict their analgesic efficacy and clinical translation. In recent years, researchers have explored various innovative approaches to improve the therapeutic effectiveness of MSCs in pain treatment. This article reviews the latest research progress of MSCs in pain treatment, with a focus on methods to enhance the analgesic efficacy of MSCs, including engineering strategies to optimize the in vitro culture environment of MSCs and to improve the in vivo delivery efficiency of MSCs. We also discuss the unresolved issues to be explored in future MSCs and pain research and the challenges faced by the clinical translation of MSC therapy, aiming to promote the optimization and clinical translation of MSC-based analgesia therapy.

As major components of the tumor microenvironment, both mesenchymal stem cells (MSCs) and macrophages can be remodelled and exhibit different phenotypes and functions during tumor initiation and progression. In recent years, increasing evidence has shown that tumor-associated macrophages (TAMs) play a crucial role in the growth, metastasis, and chemotherapy resistance of hematological malignancies, and are associated with poor prognosis. Consequently, TAMs have emerged as promising therapeutic targets. Notably, MSCs exert a profound influence on modulating immune cell functions such as macrophages and granulocytes, thereby playing a crucial role in shaping the immunosuppressive microenvironment surrounding tumors. However, in hematological malignancies, the cellular and molecular mechanisms underlying the interaction between MSCs and macrophages have not been clearly elucidated. In this review, we provide an overview of the role of TAMs in various common hematological malignancies, and discuss the latest advances in understanding the interaction between MSCs and macrophages in disease progression. Additionally, potential therapeutic approaches targeting this relationship are outlined.

The tolerance of the semi-allogeneic fetus by the maternal immune system is an eternal topic of reproductive immunology for ensuring a satisfactory outcome. The maternal-fetal interface serves as a direct portal for communication between the fetus and the mother. It is composed of placental villi trophoblast cells, decidual immune cells, and stromal cells. Decidual immune cells engage in maintaining the homeostasis of the maternal-fetal interface microenvironment. Furthermore, growing evidence has shown that decidual macrophages play a crucial role in maternal-fetal tolerance during pregnancy. As the second largest cell population among decidual immune cells, decidual macrophages are divided into two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 polarization is critical for placentation and embryonic development. Cytokines, exosomes, and metabolites regulate the polarization of decidual macrophages, and thereby modulate maternal-fetal immunotolerance. Explore the initial relationship between decidual macrophages polarization and maternal-fetal immunotolerance will help diagnose and treat the relevant pregnancy diseases, reverse the undesirable outcomes of mothers and infants.

Intrauterine adhesion (IUA) is characterized by the formation of fibrous scar tissue within the uterine cavity, which significantly impacts female reproductive health and even leads to infertility. Unfortunately, severe cases of IUA currently lack effective treatments. This study presents a novel approach that utilizes tumor necrosis factor-(TNF) stimulated gene 6 (TSG6)-modified exosomes (Exos) in conjunction with an injectable thermosensitive hydrogel (CS/GP) to mitigate the occurrence of IUA by reducing endometrium fibrosis in a mouse IUA model. This study demonstrate that TSG6-modified Exos effectively inhibits the activation of inflammatory M1-like macrophages during the initial stages of inflammation and maintains the balance of macrophage phenotypes (M1/M2) during the repair phase. Moreover, TSG6 inhibits the interaction between macrophages and endometrial stromal fibroblasts, thereby preventing the activation of stromal fibroblasts into myofibroblasts. Furthermore, this research indicates that CS/GP facilitates the sustained release of TSG6-modified Exos, leading to a significant reduction in both the manifestations of IUA and the extent of endometrium fibrosis. Collectively, through the successful construction of CS/GP loaded with TSG6-modified Exos, a reduction in the occurrence and progression of IUA is achieved by mitigating endometrium fibrosis. Consequently, this approach holds promise for the treatment of IUA.

The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.

Mesenchymal stem cells (MSCs) display unique homing and immunosuppression features which make them promising candidates for cell therapy in inflammatory disorders. It is known that C-X-C chemokine receptor type 4 (CXCR4, also known as CD184) is a critical receptor implicated in MSCs migration, and the protein programmed death ligand-1 (PD-L1) is involved in MSC's immunosuppression. However, it remains unclear how the molecular mechanisms regulate PD-L1 expression for migration and immunosuppression of MSCs under the inflammatory microenvironment. In this article, we used the human adipose-derived mesenchymal stem cells (hADMSCs) treated with lipopolysaccharide (LPS) as an in vitro inflammatory model to explore the roles of PD-L1 on the migration and immunosuppression of MSC. Our results demonstrate that in hADMSCs, LPS significantly increased PD-L1 expression, which mediated the migration of the LPS-treated hADMSCs via CXCR4. In addition, we found that the increased PD-L1 expression in the LPS-treated hADMSCs inhibited B cell proliferation and immunoglobulin G secretion through nuclear factor-κB. Our study suggests that the PD-L1 plays critical roles in the homing and immunosuppression of MSCs which are a promising cell therapy to treat inflammatory diseases.