Clinical trials have demonstrated the safety and potential efficacy of ex vivo expanded regulatory T cells (Tregs) for immune-mediated diseases. Nonetheless, achieving consistent and timely Treg yield and purity remains challenging. We aimed to evaluate the potential to enhance culture expansion of primary human total Treg (CD4+/CD25+/CD127lo) and Treg subpopulations through coculture with human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs). In 14- to 21-day anti-CD3/anti-CD28-, interleukin-2-, and rapamycin-containing cultures, fluorescence-activated cell sorting (FACS)-purified total Treg underwent 4-fold greater expansion following hUC-MSC coculture. Potency to suppress T effector cell (Teff) proliferation was equivalent for hUC-MSC-cocultured and control Tregs and correlated with the expression of HLA-DR, CD39, and inducible costimulator (ICOS). The impact of hUC-MSC coculture on ex vivo expansion of 3 FACS-purified Treg subpopulations [CD45RA+ (Subtype I), CD45RA-HLA-DR+ (Subtype II), and CD45RA-HLA-DR- (Subtype III)] was then investigated. Both initial and continuous hUC-MSC coculture yielded significantly higher fold expansion of each Treg subpopulation compared to control. However, the magnitude of enhancement was substantially greater for non-naive (Subtypes II and III) than for naive (Subtype I) Treg. Coculture with hUC-MSC increased HLA-DR expression of all 3 expanded Treg subpopulations while maintaining comparable Teff suppressive potency. For non-naive Treg (Subtypes II and III), both initial and continuous hUC-MSC coculture also increased the final %Foxp3+ and %Helios+. Thus, coculture with clinical-grade hUC-MSC substantially enhances the ex vivo yield, preserves the suppressive potency, and modulates HLA-DR expression of FACS-purified Treg subpopulations with greatest effect on non-naive (CD45RA-) Treg. The findings have potential to facilitate identification, functional characterization, and manufacturing of Treg subpopulations with distinct therapeutic benefits.

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.

Islet transplantation offers a promising treatment for type 1 diabetes (T1D), by aiming to restore insulin production and improve glycemic control. However, T1D is compounded by impaired angiogenesis and immune dysregulation, which hinder the therapeutic potential of cell replacement strategies. To address this, this work evaluates the proangiogenic and immunomodulatory properties of mesenchymal stem cells (MSCs) to enhance vascularization and modulate early-stage immune rejection pathways in the context of islet allotransplantation. This work employs the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) platform, a subcutaneous vascularized implant with localized immunomodulation developed by the group. This study assesses vascularization and immune regulation provided by MSCs, aiming to improve islet survival and integration in diabetic rats while considering sex as a biological variable. These findings demonstrate that MSCs significantly enhance vascularization and modulate the local microenvironment during the peri-transplant period. Importantly, this work discovers sex-specific differences in both processes, which influence islet engraftment and long-term function.

Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.

Immune-mediated disorders are a broad range of diseases, arising as consequence of immune defects, exaggerated/misguided immune response or a mixture of both conditions. Their frequency is on a rise in the developed societies and they pose a significant challenge for diagnosis and treatment. Traditional pharmacological, monoclonal antibody-based or polyclonal antibody replacement-based therapies aiming at modulation of the immune responses give very often dissatisfactory results and/or are burdened with unacceptable adverse effects. In recent years, a new group of treatment modalities has emerged, utilizing cells as living drugs, especially with the use of the up-to-date genetic engineering. These modern cellular therapies are designed to offer a high potential for more targeted, safe, durable, and personalized treatment options. This work briefly reviews the latest advances in the treatment of immune-mediated disorders, mainly those related to exaggeration of the immune response, with such cellular therapies as hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), regulatory T cells (Tregs), chimeric antigen receptor (CAR) T cells and others. We highlight the main features of these therapies as new treatment options for taming the dysregulated immune system. Undoubtfully, in near future such therapies can provide lasting remissions in a range of immune-mediated disorders with reduced treatment burden and improved quality of life for the patients.

Tissue repair following skin injury is a complex process that encompasses hemostasis, inflammation, tissue cell proliferation, and structural remodeling. Mesenchymal stem cells (MSCs) are derived from the mesodermal layer of tissues and possess multidirectional differentiation potential and self-renewal capabilities. MSCs from various sources, including the bone marrow, adipose tissue, dental pulp, umbilical cord, and amniotic membrane, have demonstrated effectiveness in promoting skin injury repair. They aid in this process by fostering the formation of new blood vessels in damaged tissues, self-renewal, or transdifferentiation into skin or sweat gland cells. Moreover, MSCs promote the proliferation and migration of skin cells, reduce wound inflammation, and restore the extracellular matrix through paracrine secretion. In this paper, we review recent findings regarding MSCs and their role in burn wound repair. Additionally, we explore the potential of combining MSCs with various biomaterials for treating burn wounds and analyze clinical cases wherein MSCs were administered to patients, offering insights into ongoing research on MSC-based therapies for skin injuries.

Affecting a large proportion of the population worldwide, corneal disorders constitute a concerning health hazard associated to compromised eyesight or blindness for most severe cases. In the last decades, mesenchymal stem/stromal cells (MSCs) demonstrated promising abilities in improving symptoms associated to corneal diseases or alleviating these affections, especially through their anti-inflammatory, immunomodulatory and pro-regenerative properties. More recently, MSC therapeutic potential was shown to be mediated by the molecules they release, and particularly by their extracellular vesicles (EVs; MSC-EVs). Consequently, using MSC-EVs emerged as a pioneering strategy to mitigate the risks related to cell therapy while providing MSC therapeutic benefits. Despite the promises given by MSC- and MSC-EV-based approaches, many improvements are considered to optimize the therapeutic significance of these therapies. This review aspires to provide a comprehensive and detailed overview of current knowledge on corneal therapies involving MSCs and MSC-EVs, the strategies currently under evaluation, and the gaps remaining to be addressed for clinical implementation. From encapsulating MSCs or their EVs into biomaterials to enhance the ocular retention time to loading MSC-EVs with therapeutic drugs, a wide range of ground-breaking strategies are currently contemplated to lead to the safest and most effective treatments. Promising research initiatives also include diverse gene therapies and the targeting of specific cell types through the modification of the EV surface, paving the way for future therapeutic innovations. As one of the most important challenges, MSC-EV large-scale production strategies are extensively investigated and offer a wide array of possibilities to meet the needs of clinical applications.

Multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS), is characterized by inflammation, demyelination, and neurodegeneration, leading to diverse clinical manifestations such as fatigue, sensory impairment, and cognitive dysfunction. Current pharmacological treatments primarily target immune modulation but fail to arrest disease progression or entirely reverse CNS damage. Mesenchymal stem cell (MSC) therapy offers a promising alternative, leveraging its immunomodulatory, neuroprotective, and regenerative capabilities. This review provides an in-depth analysis of MSC mechanisms of action, including immune system regulation, promotion of remyelination, and neuroregeneration. It examines preclinical studies and clinical trials evaluating the efficacy, safety, and limitations of MSC therapy in various MS phenotypes. Special attention is given to challenges such as delivery routes, dosing regimens, and integrating MSCs with conventional therapies. By highlighting advancements and ongoing challenges, this review underscores the potential of MSCs to revolutionize MS treatment, paving the way for personalized and combinatory therapeutic approaches.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins.

This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions.

This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.

Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.

Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression.

The immunomodulatory function of mesenchymal stem cells (MSCs) is plastic and susceptible to resident microenvironment in vivo or inflammatory factors in vitro. We propose a unique method to enhance the immunoregulatory functions of mesenchymal stem cells (MSCs) through an artificially controllable in vivo inflammatory microenvironment generated by biomaterials loaded with BMP-2 that induce bone development. MSCs activated through this method effectively induce M1 macrophage polarization toward the M2 phenotype, promote differentiation of naïve T cells into regulatory T cells, and inhibit the proliferation of activated T cells via prostaglandin E2 (PGE2) secretion. This in vivo licensing not only preserves the immunogenicity of MSCs but also alters DNA methylation patterns, enabling MSCs to exhibit immunoregulatory effects with epigenetic memory. Validation in a mouse colitis model demonstrated their therapeutic efficacy and long-term viability. Furthermore, we found that the material composition influences the inflammatory response during development, with polysaccharide-based biomaterials proving advantageous over protein-based materials in establishing an inflammatory niche conducive to MSC activity. These findings underscore the potential of tissue engineering to create in vivo environments that license MSCs, offering a strategic avenue to enhance MSC-based therapies for addressing significant immune disorders.

. CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown.

. We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells.

. In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells.

Glioma is a disease with a poor prognosis despite the availability of multimodality treatments, and the development of novel therapies is urgently needed. Challenges in glioma treatment include the difficulty for drugs to cross the blood-brain barrier when administered systemically and poor drug diffusion when administered locally. Mesenchymal stem cells exhibit advantages for glioma therapy because of their ability to pass through the blood-brain barrier and migrate to tumor cells and their tolerance to the immune system. Therefore, mesenchymal stem cells have been explored as vehicles for various therapeutic agents for glioma treatment. Mesenchymal stem cells loaded with chemotherapeutic drugs show improved penetration and tumor accumulation. For gene therapy, mesenchymal stem cells can be used as vehicles for suicide genes, the so-called gene-directed enzyme prodrug therapy. Mesenchymal stem cell-based oncolytic viral therapies have been attempted in recent years to enhance the efficacy of infection against the tumor, viral replication, and distribution of viral particles. Many uncertainties remain regarding the function and behavior of mesenchymal stem cells in gliomas. However, strategies to increase mesenchymal stem cell migration to gliomas may improve the delivery of therapeutic agents and enhance their anti-tumor effects, representing promising potential for patient treatment.

Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.

Stem cell therapy has become a hot research topic in the medical field in recent years, with enormous potential for treating a variety of diseases. In particular, bone marrow mesenchymal stem cells (BMSCs) have wide-ranging applications in the treatment of ischemic stroke, autoimmune diseases, tissue repair, and difficult-to-treat diseases. BMSCs can differentiate into multiple cell types and exhibit strong immunomodulatory properties. Although BMSCs can regulate the inflammatory response activated after stroke, the mechanism by which BMSCs regulate inflammation remains unclear and requires further study. Recently, stem cell therapy has emerged as a potentially effective approach for enhancing the recovery process following an ischemic stroke. For example, by regulating post-stroke inflammation and by transferring mitochondria to exert therapeutic effects. Therefore, this article reviews the therapeutic effects of intracranial BMSCs in regulating post-stroke inflammation and mitochondrial transfer in the treatment of stroke, providing a basis for further research.

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting.

Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field.

The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers.

Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.

Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. At present, the treatment of OA includes drug therapy to relieve symptoms and joint replacement therapy for advanced OA. However, these palliatives cannot truly block the progression of the disease from the immunological pathogenesis of OA. In recent years, bone marrow mesenchymal stem cell (BMSC) transplantation has shown great potential in tissue engineering repair. In addition, many studies have shown that BMSC paracrine signals play an important role in the treatment of OA through immune regulation and suppressing inflammation. At present, the mechanism of inflammation-induced OA and the use of BMSC transplantation in joint repair have been reviewed, but the mechanism and significance of BMSC paracrine signals in the treatment of OA have not been fully reviewed. Therefore, this article focused on the latest research progress on the paracrine effects of BMSCs in the treatment of OA and the related mechanisms by which BMSCs secrete cytokines to inhibit the inflammatory response, regulate immune balance, and promote cell proliferation and differentiation. In addition, the application potential of BMSC-Exos as a new type of cell-free therapy for OA is described. This review aimed to provide systematic theoretical support for the clinical application of BMSC transplantation in the treatment of OA.

Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD.

Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA.

MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls.

MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.

The T-helper 17 (Th17) cell and regulatory T cell (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines and the maintenance of immune tolerance. Mesenchymal stem cell (MSC)-mediated therapies have received increasing attention in MS research. In MS and its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter the differentiation of CD4+T cells. This alteration occurred by inducing anergy and reduction in the number of Th17 cells, stimulating the polarization of antigen-specific Treg to reverse the imbalance of the Th17/Treg axis, reducing the inflammatory cascade response and demyelination, and restoring an overall state of immune tolerance. In this review, we summarize the mechanisms by which MSCs regulate the balance between Th17 cells and Tregs, including extracellular vesicles, mitochondrial transfer, metabolic reprogramming, and autophagy. We aimed to identify new targets for MS treatment using cellular therapy by analyzing MSC-mediated Th17-to-Treg polarization.

Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects.

First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD.

The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis.

MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.

Immunomodulation is the predominant mechanism via which Mesenchymal stromal cells (MSCs) mediate their therapeutic benefits. However, inconsistent success in numerous clinical trials warrants a better understating of the molecular mechanisms regulating their immunomodulatory properties. CD73, an ecto-5'-nucleotidase is abundantly expressed by MSCs, however its precise role in regulating their immunomodulatory properties is still elusive. The present study explored the role of CD73 in Interferon-gamma (IFNγ) sensing and in turn their ability to suppress "inflammatory" M1 macrophages.

CD73 knockdown MSCs (CD73-KDN) were initially assessed for expression of immunoregulatory molecules and IFNγ sensing ability by analysing expression of IFNγ signalling downstream targets such as pSTAT-1, Interferon-Stimulated Genes (ISG) and Indoleamine 2,3-dioxygnease (IDO), a prototypic IFNγ-induced immunomodulator. Next CD73-KDN MSCs were co-cultured with inflammatory M1 macrophages and evaluated for their ability to suppress them. To delineate the contributory role of CD73 and IFNγ signalling downstream target IDO, they were overexpressed independently in CD73-KDN MSCs and re-evaluated for their ability to suppress M1 macrophages.

CD73-KDN MSCs exhibited reduced expression of immunoregulatory molecules and were refractory to IFNγ signalling as indicated by attenuated expression of pSTAT-1, Interferon-Stimulated Genes (ISG) and Indoleamine 2,3-dioxygnease (IDO) upon IFNγ exposure. Since sensing of inflammation is critical for MSC mediated immunomodulation, CD73-KDN MSCs were functionally evaluated for their ability to immune-modulate "inflammatory" M1 macrophages wherein they failed to suppress M1 macrophages. Interestingly, ectopic expression of either CD73 or IFNγ signalling target IDO1 in CD73-KDN MSCs restored their ability to suppress M1 macrophages, establishing the importance of CD73-IFNγ signalling axis in MSC-mediated inflammatory macrophage suppression.

The present study uncovers the unexplored role of CD73-IFNγ axis in MSC-mediated M1 macrophage suppression. MSC-educated macrophages are the actual immune-modulators at MSC transplant sites, thus CD73 can serve as a key immune-potency marker for benchmarking therapeutically relevant MSCs.

In the dynamic landscape of tissue engineering, the integration of tissue-engineered constructs (TECs) faces a dual challenge-initiating beneficial inflammation for regeneration while avoiding the perils of prolonged immune activation. As TECs encounter the immediate reaction of the immune system upon implantation, the unique immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) emerge as key navigators. Harnessing the paracrine effects of MSCs, researchers aim to craft a localized microenvironment that not only enhances TEC integration but also holds therapeutic promise for inflammatory-driven pathologies. This review unravels the latest advancements, applications, obstacles, and future prospects surrounding the strategic alliance between MSCs and TECs, shedding light on the immunological symphony that guides the course of regenerative medicine.

Multiple Sclerosis (MS) is an immune-mediated condition that persistently harms the central nervous system. While existing treatments can slow its course, a cure remains elusive. Stem cell therapy has gained attention as a promising approach, offering new perspectives with its regenerative and immunomodulatory properties. This article reviews the application of stem cells in MS, encompassing various stem cell types, therapeutic potential mechanisms, preclinical explorations, clinical research advancements, safety profiles of clinical applications, as well as limitations and challenges, aiming to provide new insights into the treatment research for MS.

Canine mesenchymal stromal cells (MSCs) possess the capacity to differentiate into a variety of cell types and secrete a wide range of bioactive molecules in the form of soluble and membrane-bound exosomes. Extracellular vesicles/exosomes are nano-sized vesicles that carry proteins, lipids, and nucleic acids and can modulate recipient cell response in various ways. The process of exosome formation is a physiological interaction between cells. With a significant increase in basic research over the last two decades, there has been a tremendous expansion in research in MSC exosomes and their potential applications in canine disease models. The characterization of exosomes has demonstrated considerable variations in terms of source, culture conditions of MSCs, and the inclusion of fetal bovine serum or platelet lysate in the cell cultures. Furthermore, the amalgamation of exosomes with various nano-materials has become a novel approach to the fabrication of nano-exosomes. The fabrication of exosomes necessitates the elimination of extrinsic proteins, thus enhancing their potential therapeutic uses in a variety of disease models, including spinal cord injury, osteoarthritis, and inflammatory bowel disease. This review summarizes current knowledge on the characteristics, biological functions, and clinical relevance of canine MSC exosomes and their potential use in human and canine research. As discussed, exosomes have the ability to control lethal vertebrate diseases by administration directly at the injury site or through specific drug delivery mechanisms.

Multipotent mesenchymal stromal cells (MSC) play an increasing role in the treatment of immune-mediated diseases and inflammatory processes. They regulate immune cells via cell-cell contacts and by secreting various anti-inflammatory molecules but are in turn influenced by many factors such as cytokines. For MSC culture, platelet lysate (PL), which contains a variety of cytokines, is a promising alternative to fetal bovine serum (FBS). We aimed to analyze if PL with its cytokines improves MSC immunoregulatory characteristics, with the perspective that PL could be useful for priming the MSC prior to therapeutic application. MSC, activated peripheral blood mononuclear cells (PBMC) and indirect co-cultures of both were cultivated in media supplemented with either PL, FBS, FBS+INF-γ or FBS+IL-10. After incubation, cytokine concentrations were measured in supernatants and control media. MSC were analyzed regarding their expression of immunoregulatory genes and PBMC regarding their proliferation and percentage of FoxP3+ cells. Cytokines, particularly IFN-γ and IL-10, remained at high levels in PL control medium without cells but decreased in cytokine-supplemented control FBS media without cells during incubation. PBMC released IFN-γ and IL-10 in various culture conditions. MSC alone only released IFN-γ and overall, cytokine levels in media were lowest when MSC were cultured alone. Stimulation of MSC either by PBMC or by PL resulted in an altered expression of immunoregulatory genes. In co-culture with PBMC, the MSC gene expression of COX2, TNFAIP6, IDO1, CXCR4 and MHC2 was upregulated and VCAM1 was downregulated. In the presence of PL, COX2, TNFAIP6, VCAM1, CXCR4 and HIF1A were upregulated. Functionally, while no consistent changes were found regarding the percentage of FoxP3+ cells, MSC decreased PBMC proliferation in all media, with the strongest effect in FBS media supplemented with IL-10 or IFN-γ. This study provides further evidence that PL supports MSC functionality, including their immunoregulatory mechanisms. The results justify to investigate functional effects of MSC cultured in PL-supplemented medium on different types of immune cells in more detail.

Immunomodulatory properties of mesenchymal stem cells are widely studied, supporting the use of MSCs as cell-based therapy in immunological diseases. This study aims to generate cell-free MSC extract and improves their immunomodulatory potential. Intracellular extracts were prepared from adipose-derived stem cells (ADSC) spheroid via a freeze-thawing method. The immunomodulatory capacities of ADSC spheroid extracts were investigated in vitro, including lymphocyte proliferation, T regulatory cell expansion, and macrophage assays. A comparative study was conducted with ADSC monolayer extract. The key immunomodulatory mediators presented in ADSC extract were identified. The results revealed that ADSC spheroid extract could suppress lymphocyte activation while enhancing T regulatory cell expansion. Immunomodulatory molecules such as COX-2, TSG-6, and TGF-β1 were upregulated in ADSC priming via spheroid culture. Selective inhibition of COX-2 abrogates the effect of ADSC extract on inducing T regulatory cell expansion. Thus, ADSC spheroid extract gains high efficacy in regulating the immune responses which are associated in part by COX-2 generation. Furthermore, ADSC spheroid extract possessed a potent anti-inflammation by manipulation of TNF-α production from LPS-activated macrophage. Our current study has highlighted the opportunity of using cell-free extracts from adipose tissue-derived mesenchymal stem cells spheroid as novel immunomodulators for the treatment of immunological-associated diseases.

Bone marrow mesenchymal stem cells (BMSCs) mediated immunomodulation by secreting certain bioactive cytokines has been recognized as a promising approach for disease treatment. However, microenvironmental oxygen tension affect immunomodulatory functions and activate autophagy in BMSCs. The mechanism governing BMSCs immunomodulation in hypoxia hasn't been expounded clearly. The aim of this study is to investigate the function of pathological hypoxia on immunomodulatory properties of bone marrow mesenchymal stem cells and its possible mechanism.

BMSCs were cultured in either normoxia (21 % oxygen) or hypoxia (0.1 % oxygen) for 24 h, then electron microscopy (EM) and immunofluorescence staining were used to detect the activation of autophagy. Besides autophagy-related markers were monitored by Western blotting. Atg5 siRNA induced autophagic inhibition. Additional, gene expression levels of Real-time fluorescence quantitative PCR and Western blot were used to detect BMSCs related cytokines. Both the proliferation and apoptosis of CD4+ T cell in co-culture were detected by flow cytometry. Exogenous anti-IL-10 antibody and anti-TGF-β1 antibody were used in co-cultured BMSCs-CM and CD4+ T cells, which enabled us to assess how autophagy affected BMSCs-mediated CD4+ T cell proliferation in low oxygen tension.

Compared with normal BMSCs, Hypo-BMSCs enhanced the immunosuppressive effect of BMSCs on CD4+ T cell proliferation, while si-atg5 weakened the inhibition of Hypo-BMSCs. Furthermore, exogenous anti-TGF-β1 antibody and the addition of anti-TGF-β1 antibody reversed the immunosuppressive ability of Hypo-BMSCs.

Our findings reveal that BMSCs possess significant immunosuppression on CD4+T cell through IL-10 and TGF-β1 dependent of autophagy in hypoxic microenvironment.

Mesenchymal stromal/stem cells (MSCs) are used in many studies due to their therapeutic potential, including their differentiative ability and immunomodulatory properties. These cells perform their therapeutic functions by using various mechanisms, such as the production of anti-inflammatory cytokines, growth factors, direct cell-to-cell contact, extracellular vesicles (EVs) production, and mitochondrial transfer. However, mechanisms related to immune checkpoints (ICPs) and their effect on the immunomodulatory ability of MSCs are less discussed. The main function of ICPs is to prevent the initiation of unwanted responses and to regulate the immune system responses to maintain the homeostasis of these responses. ICPs are produced by various types of immune system regulatory cells, and defects in their expression and function may be associated with excessive responses that can ultimately lead to autoimmunity. Also, by expressing different types of ICPs and their ligands (ICPLs), tumor cells prevent the formation and durability of immune responses, which leads to tumors' immune escape. ICPs and ICPLs can be produced by MSCs and affect immune cell responses both through their secretion into the microenvironment or direct cell-to-cell interaction. Pre-treatment of MSCs in inflammatory conditions leads to an increase in their therapeutic potential. In addition to the effect that inflammatory environments have on the production of anti-inflammatory cytokines by MSCs, they can increase the expression of various types of ICPLs. In this review, we discuss different types of ICPLs and ICPs expressed by MSCs and their effect on their immunomodulatory and therapeutic potential.

Systemic sclerosis (SSc) and sclerodermatous graft-versus-host disease (Scl-GVHD)-characterized by similar developmental fibrosis, vascular abnormalities, and innate and adaptive immune response, resulting in severe skin fibrosis at the late stage-are chronic autoimmune diseases of connective tissue. The significant immune system dysfunction, distinguishing autoimmune-related fibrosis from mere skin fibrosis, should be a particular focus of treating autoimmune-related fibrosis. Recent research shows that innovative mesenchymal stem cell (MSC)-based therapy, with the capacities of immune regulation, inflammation suppression, oxidation inhibition, and fibrosis restraint, shows great promise in overcoming the disease.

This review of recent studies aims to summarize the therapeutic effect and theoretical mechanisms of MSC-based therapy in treating autoimmune-related fibrotic skin diseases, SSc and Scl-GVHD, providing novel insights and references for further clinical applications. It is noteworthy that the efficacy of MSCs is not reliant on their migration into the skin. Working on the immune system, MSCs can inhibit the chemotaxis and infiltration of immune cells to the skin by down-regulating the expression of skin chemokines and chemokine receptors and reducing the inflammatory and pro-fibrotic mediators. ​Furthermore, to reduce levels of oxidative stress, MSCs may improve vascular abnormalities, and enhance the antioxidant defenses through inducible nitric oxide synthase, thioredoxin 1, as well as other mediators. The oxidative stress environment does not weaken MSCs and may even strengthen certain functions. Regarding fibrosis, MSCs primarily target the transforming growth factor-β signaling pathway to inhibit fibroblast activation. Here, miRNAs may play a critical role in ECM remodeling. Clinical studies have demonstrated the safety of these approaches, though outcomes have varied, possibly owing to the heterogeneity of MSCs, the disorders themselves, and other factors. Nevertheless, the research clearly reveals the immense potential of MSCs in treating autoimmune-related fibrotic skin diseases.

The application of MSCs presents a promising approach for treating autoimmune-related fibrotic skin diseases: SSc and Scl-GVHD. Therapies involving MSCs and MSC extracellular vesicles have been found to operate through three primary mechanisms: rebalancing the immune and inflammatory disorders, resisting oxidant stress, and inhibiting overactivated fibrosis (including fibroblast activation and ECM remodeling). However, the effectiveness of these interventions requires further validation through extensive clinical investigations, particularly randomized control trials and phase III/IV clinical trials. Additionally, the hypothetical mechanism underlying these therapies could be elucidated through further research.

Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed.

Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed.

From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias.

This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.

Red blood cells are the predominant cellular component in human body, and their numbers increase significantly during pregnancy due to heightened erythropoiesis. CD71+ erythroid cells (CECs) are immature red blood cells, encompassing erythroblasts and reticulocytes, constitute a rare cell population primarily found in the bone marrow, although they are physiologically enriched in the neonatal mouse spleen and human cord blood. Presently, the mechanisms underlying the CECs expansion during pregnancy remain largely unexplored. Additionally, the mechanisms and roles associated with extramedullary hematopoiesis (EMH) of erythroid cells during pregnancy have yet to be fully elucidated. In this study, our objective was to examine the underlying mechanisms of erythroid-biased hematopoiesis during pregnancy. Our findings revealed heightened erythropoiesis and elevated CECs in both human and mouse pregnancies. The increased presence of transforming growth factor (TGF)-β during pregnancy facilitated the differentiation of CD34+ hematopoietic stem and progenitor cells (HSPCs) into CECs, without impacting HSPCs proliferation, ultimately leading to enhanced erythropoiesis. The observed increase in CECs during pregnancy was primarily attributed to EMH occurring in the spleen. During mouse pregnancy, splenic stromal cells were found to have a significant impact on splenic erythropoiesis through the activation of TGF-β signaling. Conversely, splenic macrophages were observed to contribute to extramedullary erythropoiesis in a TGF-β-independent manner. Our results suggest that splenic stromal cells play a crucial role in promoting extramedullary erythropoiesis and the production of CECs during pregnancy, primarily through TGF-β-dependent mechanisms.

Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.

Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death.

In this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined.

We observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range.

Our results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy.

Immune-related applications of mesenchymal stromal cells (MSCs) in cell therapy seek to exploit immunomodulatory paracrine signaling pathways to reduce inflammation. A key MSC therapeutic challenge is reducing patient outcome variabilities attributed to insufficient engraftment/retention of injected heterogenous MSCs. To address this, we propose directly transplantable human single-cell-derived clonal bone marrow MSC (hcBMSC) sheets. Cell sheet technology is a scaffold-free tissue engineering strategy enabling scalable production of highly engraftable cell constructs retaining endogenous cell-cell and cell-matrix interactions, important to cell function. cBMSCs, as unique MSC subset populations, facilitate rational selection of therapeutically relevant MSC clones from donors. Here, we combine human cBMSCs with cell sheet technology, demonstrating cell sheet fabrication as a method to significantly upregulate expression of immunomodulatory molecules interleukin (IL)-10, indoleamine 2,3-dioxygenase (IDO-1), and prostaglandin E synthase 2 (PTGES2) across GMP-grade hcBMSC lines and whole human bone marrow-derived MSCs compared to respective conventional cell suspensions. When treated with carbenoxolone, a gap junction inhibitor, cell sheets downregulate IL-10 and IDO-1 expression, implicating functional roles for intercellular sheet interactions. Beyond producing directly transferable multicellular hcBMSC constructs, cell sheet technology amplifies hcBMSC expression of immunomodulatory factors important to therapeutic action. In addition, this work demonstrates the importance of cell-cell interactions as a tissue engineering design criterion to enhance consistent MSC functions.

Mesenchymal stem cells (MSCs) are a heterogeneous group of progenitor cells that play a multifunctional role including tissue regeneration, self-renewal properties, and differentiate into cells of mesodermal lineage such as adipocytes, osteoblasts, and chondrocytes. MSCs come into contact with tumor microenvironment (TME) and differentiate into tumor-associated MSCs (TA-MSCs). Various substances such as chemokines, cytokines, growth factors, and others are released by tumor cells to recruit MSCs. TA-MSCs induced epithelial-mesenchymal transition (EMT) program which mediates tumor growth progression, migration, and invasion. Role of MSCs in the tumor progression, stemness, malignancy, and treatment resistance in the breast cancer TME. Immunomodulation by MSCs is mediated by a combination of cell contact-dependent mechanisms and soluble substances. Monocytes/macrophages, dendritic cells, T cells, B cells, and NK cells all show signs of MSCs' immunomodulatory capability. In a complicated interplay initiated by MSCs, anti-inflammatory monocytes/macrophages and regulatory T cells (Tregs) play a key role, as they unveil their full immunomodulatory potential. MSC- secreted cytokines are commonly blamed for the interaction between MSCs, monocytes, and Tregs. Here, we review the current knowledge of cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the role MSCs play in breast cancer progression and its TME.Abbreviation MSC: Mesenchymal Stem Cells; TME: Tumor Microenvironment; TAMS; Tumour-associated Macrophages; ECM: Extracellular matrix; CAFs: Cancer-associated Fibroblasts; CFUs: Colony-forming unit Fibroblasts; Tregs: T regulatory cells; Bregs; Regulatory B cells; IFN-γ: Interferon-gamma; TNF-α: Tumour Necrosis Factor-alpha; IL: Interleukin; TGF-β: transforming growth factorβ; PGE2: Prostaglandin E2; CXCR: Chemokine Receptor; Blimp-1; B lymphocyte-induced maturation protein-1; CCL: Chemokine motif ligand; EMT: Epithelial-mesenchymal transition.