Protection of neutrophils by bone marrow mesenchymal stromal cells is enhanced by tumor-associated inflammatory cytokines.

Mesenchymal stromal/stem cells (MSCs), which are distributed in many tissues including bone marrow, have been reported to play a critical role in tumor development. While bone marrow, the primary site for hematopoiesis, is important for establishing the immune system, whether MSCs in the bone marrow can promote tumor growth via influencing hematopoiesis remains unclear. We observed that the numbers of MSCs and neutrophils were increased in bone marrow in tumor-bearing mice. Moreover, co-culture assay showed that MSCs strongly protected neutrophils from apoptosis and induced their maturation. G-CSF and GM-CSF have been well-documented to be associated with neutrophil formation. We found a remarkably increased level of G-CSF, but not GM-CSF, in the supernatant of MSCs and the serum of tumor-bearing mice. The G-CSF expression can be enhanced with inflammatory cytokines (IFNγ and TNFα) stimulation. Furthermore, we found that IFNγ and TNFα-treated MSCs enhanced their capability of promoting neutrophil survival and maturation. Our results indicate that MSCs display robustly protective effects on neutrophils to contribute to tumor growth in bone niches.

Transition to a mesenchymal state in neuroblastoma may be characterized by a high expression of GD2 and by the acquisition of immune escape from NK cells.

Background: Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function. Methods: We studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays. Results: We identified mature (CD105+/CD133-) and undifferentiated (CD133+/CD105-) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2bright neuroblasts. Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic. Conclusions: NB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.

A comprehensive insight into the immunomodulatory role of MSCs-derived exosomes (MSC-Exos) through modulating pattern-recognition receptors (PRRs).

Mesenchymal stem cell-derived exosomes (MSC-Exos) are emerging as remarkable agents in the field of immunomodulation with vast potential for diagnosing and treating various diseases, including cancer and autoimmune disorders. These tiny vesicles are laden with a diverse cargo encompassing proteins, nucleic acids, lipids, and bioactive molecules, offering a wealth of biomarkers and therapeutic options. MSC-Exos exhibit their immunomodulatory prowess by skillfully regulating pattern-recognition receptors (PRRs). They conduct a symphony of immunological responses, modulating B-cell activities, polarizing macrophages toward anti-inflammatory phenotypes, and fine-tuning T-cell activity. These interactions have profound implications for precision medicine, cancer immunotherapy, autoimmune disease management, biomarker discovery, and regulatory approvals. MSC-Exos promises to usher in a new era of tailored therapies, personalized diagnostics, and more effective treatments for various medical conditions. As research advances, their transformative potential in healthcare becomes increasingly evident.

Mesenchymal stem cells-macrophages crosstalk and myeloid malignancy.

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.

Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.

Enhanced immunosuppressive capability of mesenchymal stem cell-derived small extracellular vesicles with high expression of CD73 in experimental autoimmune uveitis.

BACKGROUND: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. METHODS: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. RESULTS: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. CONCLUSION: Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Paracrine- and cell-contact-mediated immunomodulatory effects of human periodontal ligament-derived mesenchymal stromal cells on CD4+ T lymphocytes.

BACKGROUND: Mesenchymal stromal cells (MSCs) isolated from the periodontal ligament (hPDL-MSCs) have a high therapeutic potential, presumably due to their immunomodulatory properties. The interaction between hPDL-MSCs and immune cells is reciprocal and executed by diverse cytokine-triggered paracrine and direct cell-to-cell contact mechanisms. For the first time, this study aimed to directly compare the contribution of various mechanisms on this reciprocal interaction using different in vitro co-culture models at different inflammatory milieus. METHODS: Three co-culture models were used: indirect with 0.4 µm-pored insert, and direct with or without insert. After five days of co-culturing mitogen-activated CD4+ T lymphocytes with untreated, interleukin (IL)-1ß, or tumor necrosis factor (TNF)-α- treated hPDL-MSCs, the CD4+ T lymphocyte proliferation, viability, and cytokine secretion were investigated. The gene expression of soluble and membrane-bound immunomediators was investigated in the co-cultured hPDL-MSCs. RESULTS: Untreated hPDL-MSCs decreased the CD4+ T lymphocyte proliferation and viability more effectively in the direct co-culture models. The direct co-culture model without inserts showed a strikingly higher CD4+ T lymphocyte cell death rate. Adding IL-1ß to the co-culture models resulted in substantial CD4+ T lymphocyte response alterations, whereas adding TNF resulted in only moderate effects. The most changes in CD4+ T lymphocyte parameters upon the addition of IL-1ß or TNF-α in a direct co-culture model without insert were qualitatively different from those observed in two other models. Additionally, the co-culture models caused variability in the immunomediator gene expression in untreated and cytokine-triggered hPDL-MSCs. CONCLUSION: These results suggest that both paracrine and cell-to-cell contact mechanisms contribute to the reciprocal interaction between hPDL-MSCs and CD4+ T lymphocytes. The inflammatory environment affects each of these mechanisms, which depends on the type of cytokines used for the activation of MSCs' immunomodulatory activities. This fact should be considered by comparing the outcomes of the different models.

Immunomodulatory activity of argentatins A and B isolated from guayule.

Argentatins are secondary metabolites synthesized by guayule (Parthenium argentatum A. Gray) with numerous potential medical applications. In addition to inhibiting insect growth, they are endowed with several pharmacological properties including antimicrobial and antitumorigenic activity. However, their potential as immunomodulators remains unexplored. The aim of the present study was to investigate whether argentatins can modulate the function of the immune system. Human mesenchymal stem cells were treated with argentatins and the production of several anti- and proinflammatory cytokines was evaluated. The effect of argentatins on the polarization of CD4+ T-lymphocytes and macrophages was also assessed. Results demonstrated that argentatins can modulate the production of proinflammatory cytokines and the polarization of cellular phenotypes, including Th2 lymphocytes and M1 macrophages. These findings suggest that argentatins are promising therapeutic agents in autoimmune or allergic diseases, and open new perspectives for the investigation of argentatins in immune response and in the development of more targeted and effective immunomodulatory therapies.

Mesenchymal stem cell-derived exosomes for management of prostate cancer: An updated view.

Prostate cancer represents the second most prevalent form of cancer found in males, and stands as the fifth primary contributor to cancer-induced mortality on a global scale. Research has shown that transplanted mesenchymal stem cells (MSCs) can migrate by homing to tumor sites in the body. In prostate cancer, researchers have explored the fact that MSC-based therapies (including genetically modified delivery vehicles or vectors) and MSC-derived exosomes are emerging as attractive options to improve the efficacy and safety of traditional cancer therapies. In addition, researchers have reported new insights into the application of extracellular vesicle (EV)-MSC therapy as a novel treatment option that could provide a more effective and targeted approach to prostate cancer treatment. Moreover, the new generation of exosomes, which contain biologically functional molecules as signal transducers between cells, can simultaneously deliver different therapeutic agents and induce an anti-tumor phenotype in immune cells and their recruitment to the tumor site. The results of the current research on the use of MSCs in the treatment of prostate cancer may be helpful to researchers and clinicians working in this field. Nevertheless, it is crucial to emphasize that although dual-role MSCs show promise as a therapeutic modality for managing prostate cancer, further investigation is imperative to comprehensively grasp their safety and effectiveness. Ongoing clinical trials are being conducted to assess the viability of MSCs in the management of prostate cancer. The results of these trials will help determine the viability of this approach. Based on the current literature, engineered MSCs-EV offer great potential for application in targeted tumor therapy.

hUCMSC-derived exosomes protect against GVHD-induced endoplasmic reticulum stress in CD4+ T cells by targeting the miR-16-5p/ATF6/CHOP axis.

Exosomes generated from mesenchymal stem cells (MSCs) are thought to be a unique therapeutic strategy for several autoimmune deficiency illnesses. The purpose of this study was to elucidate the protective effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) on CD4+ T cells dysfunction during graft-versus-host disease (GVHD) and to identify the underlying processes involved. Here, we showed that hUCMSC-Exo treatment can effectively attenuate GVHD injury by alleviating redox metabolism disorders and inflammatory cytokine bursts in CD4+ T cells. Furthermore, hUCMSC-Exo ameliorate ER stress and ATF6/CHOP signaling-mediated apoptosis in CD4+ T cells and promote the development of CD4+IL-10+ T cells during GVHD. Moreover, downregulating miR-16-5p in hUCMSC-Exo impaired their ability to prevent CD4+ T cells apoptosis and weakened their ability to promote the differentiation of CD4+IL-10+ T cells. Collectively, the obtained data suggested that hUCMSC-Exo suppress ATF6/CHOP signaling-mediated ER stress and apoptosis in CD4+ T cells, enhance the differentiation of CD4+IL-10+ T cells, and reverse the imbalance of immune homeostasis in the GVHD process by transferring miR-16-5p. Our study provided further evidence that GVHD patients can benefit from hUCMSC-Exo-mediated therapy.

Mesenchymal stromal cells protect tissues from Th1 immune responses via IL-11 secretion.

Mesenchymal stromal cells (MSCs) have been shown to modulate the function of various subsets of T cells such as naïve CD4+ T cells and IFNγ+CD4+ Th1 cells; however, mechanisms underlying this regulation have not been fully deciphered. Our in vitro culture assays demonstrate that MSCs suppress the activation and function of CD4+ T cells by secreting interleukin 11, and neutralization of IL11 abrogates MSC-mediated suppression of CD4+ T cell function. Moreover, delayed-type, exogenous supplementation of IL11 significantly suppressed IFNγ+ expression by Th1 cells. Th1 and CD8+ cells play central roles in T cell-mediated tissue damage. Using a murine model of hypersensitivity response to study T cell-mediated tissue damage, we show that silencing IL11 in MSCs significantly abates the capacity of MSCs to suppress the generation of IFNγ-secreting CD4+ and CD8+ cells, failing to prevent T cell-mediated tissue inflammation and tissue damage.

Immunomodulatory effects of extracellular vesicles from mesenchymal stromal cells: Implication for therapeutic approach in autoimmune diseases.

Autoimmune disease is characterized by the proliferation of harmful immune cells, inducing tissue inflammation and ultimately causing organ damage. Current treatments often lack specificity, necessitating high doses, prolonged usage, and high recurrence rates. Therefore, the identification of innovative and safe therapeutic strategies is urgently required. Recent preclinical studies and clinical trials on inflammatory and autoimmune diseases have evidenced the immunosuppressive properties of mesenchymal stromal cells (MSCs). Studies have demonstrated that extracellular vesicles (EV) derived from MSCs can mitigate abnormal autoinflammation while maintaining safety within the diseased microenvironment. This study conducted a systematic review to elucidate the crucial role of MSC-EVs in alleviating autoimmune diseases, particularly focusing on their impact on the underlying mechanisms of autoimmune conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). By specifically examining the regulatory functions of microRNAs (miRNAs) derived from MSC-EVs, the comprehensive study aimed to enhance the understanding related to disease mechanisms and identify potential diagnostic markers and therapeutic targets for these diseases.

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation.

Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

High performance injectable Mg doped bioactive glass bone cement for the regulation of osteogenic immune microenvironment.

Although calcium phosphate has been extensively utilized in orthopedic applications such as spine, limbs, dentistry, and maxillofacial surgery, the lack of osteoinductive properties often hinders its effectiveness in treating bone defects resulting from pathological micro-environment such as tumor surgery, osteoporosis, osteomyelitis, and diabetic. Therefore, a novel bone cement based on magnesium-doped bioactive glass was developed in this study. The moderate release of magnesium ions improved the mechanical properties by controlling the crystal size of hydroxyapatite. Through detailed discussion of element content and heat treatment temperature, it was found that 2Mg-BG-800 was suitable for the construction of bone cement. 2Mg-BG-BC exhibited favorable initial (15 min) and final (30 min) setting time, compressive strength (29.45 MPa), compressive modulus (1851.49 MPa), injectability, and shape-adaptability. Furthermore, Mg-BG-BC demonstrated the ability to enhance the osteogenic differentiation of BMSCs, and induce macrophage polarization towards the M2 phenotype, suggesting its potential for osteoporotic fracture regeneration.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial.

Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 106 cells/kg, 1.0 × 106 cells/kg, and 2.0 × 106 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 106 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 106 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 106 cells/kg per week, and three received 2.0 × 106 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).

Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNß-HLA.

Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-ß (IFNß) by MSCs. IFNß reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.