Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetically lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell-derived IFN-γ to inhibit neuronal JAK/STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFN-γ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFN-γ/CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.

Mesenchymal stem cells (MSCs), an accessible and less ethically controversial class of adult stem cells, have demonstrated significant efficacy in treating a wide range of diseases in both the preclinical and clinical phases. However, we do not yet have a clear understanding of the mechanisms by which MSCs exert their therapeutic effects in vivo. We found that the transplanted MSCs go an apoptotic fate within 24 h in vivo irrespective of the route of administration. Still, the short-term survival of MSCs do not affect their long-term therapeutic efficacy. An increasing number of studies have demonstrated that transplantation of apoptotic MSCs (ApoMSCs) show similar or even better efficacy than viable MSCs, including a variety of preclinical disease models such as inflammatory diseases, skin damage, bone damage, organ damage, etc. Although the exact mechanism has yet to be explored, recent studies have shown that transplanted MSCs undergo apoptosis in vivo and are phagocytosed by phagocytes, thereby exerting immunomodulatory effects. The apoptotic extracellular vesicles secreted by ApoMSCs (MSC-ApoEVs) play a significant role in promoting immunomodulation, endogenous stem cell regeneration, and angiogenesis due to their apoptotic properties and inheritance of molecular characteristics from their parental MSCs. On this basis, this review aims to deeply explore the therapeutic applications and mechanisms of ApoMSCs and their secretion of MSC-ApoEVs, as well as the challenges they face.

Radiation enteritis is a common complication of radiation therapy in which the surrounding normal intestinal tissue is damaged by ionising radiation, and there is no standard pharmacological prophylaxis or treatment regimen available. Mesenchymal stem cell transplantation can be used for radiation protection and the treatment of acute radiation injury, but its therapeutic mechanism of action remains unclear.

To investigate the protective effects of autologous bone marrow-derived mesenchymal stem cell (ABMSC) transplantation on radiation-induced intestinal injury.

A model of acute radioactive enteritis was established in dogs by applying abdominal intensity-modulated radiation at a single X-ray dose of 12 Gy. ABMSCs were transplanted into the mesenteric artery with the technology of femoral artery puncture and DSA imaging two days after radiation. Visual and histopathological changes of the experimental dogs were observed. Different kinds of cytokines from intestinal samples were tested using Quantibody Canine Cytokine Array method. Enzyme-linked immunosorbent assay (ELISA) was also used to evaluate the cytokines changes in serum.

The ABMSCs group showed significant improvements in survival status compared with the blank and saline treatment groups. Histological observations revealed that the former had lower histological scores than the later after treatment (P < 0.05). Compared to the control groups, interleukin (IL)-10 and monocyte chemotactic protein (MCP)-1 from intestinal samples showed a remarkable increase and ELISA of serum samples proved higher secretion of the two target cytokines in the ABMSCs group (P < 0.05).

Our data suggest that transplantation of ABMSCs promotes intestinal recovery after acute radioactive injury in Beagle dogs. The cytokines of IL-10 and MCP-1 might play an important role in this process.

A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis.

Gastric cancer mesenchymal stem cells (GC-MSCs) are a crucial component of the gastric cancer microenvironment, exerting a pivotal influence on the formation of a suppressive immune microenvironment and the progression of gastric cancer. In this study, we utilized GC-MSCs to co-culture peripheral blood mononuclear cells (PBMCs) obtained from both gastric cancer patients and healthy individuals in a proportionate manner by direct cell-to-cell contact. Our findings reveal that co-culture of GC-MSCs with PBMCs led to a notable reduction in CD8+ T cells percentages and an increase in surface PD-1 expression levels on CD8+ T cells. However, flow cytometry analysis demonstrated no significant changes following pretreatment with GC-MSC-conditioned medium (GC-MSC-CM). Moreover, western blotting analysis demonstrated a notable reduction in phosphorylated AKT levels in co-cultured PBMCs. Collectively, our results suggest that GC-MSCs impair the anti-tumor immune response of PBMCs by elevating the PD-1 levels of CD8+ T cells and impairing the killing of CD8+ T cells. These findings provide new evidence that GC-MSCs contribute to immunosuppression within the tumor microenvironment (TME).

Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.

Rationale: Mesenchymal stem cells (MSCs) possess potent immunomodulatory capability, but occasionally, clinical application of MSCs is hindered by compromised cell functionality and insufficient therapeutic efficacy. Methods: Here, well-established mouse models of dextran sulfate sodium (DSS)-induced colitis and streptozotocin (STZ)-induced type 1 diabetes (T1D) were used to evaluate therapeutic immunomodulatory effects of human umbilical cord-derived MSCs. MSCs were examined at the fifth (P5) and the fifteenth (P15) passages, and three-dimensional (3D) culture was conducted by Matrigel incorporation. A series of biochemical, histopathological and cellular assays were performed to investigate the MSC function and therapeutic performance, and immunoregulation was evaluated by in vitro co-culture with T cells and in vivo analyses of T-cell infiltration into target tissues. RNA sequencing (RNA-seq) analysis followed by immunofluorescence staining, gene expression analyses and chemical regulation were used to investigate the molecular targets. Results: MSCs lose therapeutic immunomodulatory effects after extensive expansion to P15 when cell senescence occurs. Intriguingly, 3D preconditioning of MSCs in Matrigel promotes diminished immunoregulatory capability despite extensive passages, which benefits function of P15-MSCs to modulate T-cell subsets in co-culture, suppress infiltration of pro-inflammatory T cells in the colon and pancreas tissues after infusion, ameliorate systemic inflammation, and alleviate colitis and T1D in mice. Mechanistically, 3D culture provokes transcriptomic reprogramming of MSCs toward a Yes-associated protein 1 (YAP1)-marked, Hippo signaling pathway-upregulated state with promoted release of the anti-inflammatory cytokine, transforming growth factor-beta1 (TGF-β1). Moreover, chemical regulation of YAP1 by clinically relevant drugs, verteporfin (VP) and prostaglandin E2 (PGE2), affects TGF-β1 expression and the immunomodulatory capability of MSCs during dimensional culture. Conclusions: Taken together, these findings unravel YAP1-based dimensional and chemical coordination of expanded MSC immunoregulation, which will shed light on precisely controlled translational application.

Periodontal disease is a highly prevalent disease worldwide that seriously affects people's oral health, including gingivitis and periodontitis. Although the current treatment of periodontal disease can achieve good control of inflammation, it is difficult to regenerate the periodontal supporting tissues to achieve a satisfactory therapeutic effect. In recent years, due to the good tissue regeneration ability, the research on Mesenchymal stromal/stem cells (MSCs) and MSC-derived exosomes has been gradually deepened, especially its ability to interact with the microenvironment of the body in the complex immunoregulatory network, which has led to many new perspectives on the therapeutic strategies for many diseases. This paper systematically reviews the immunomodulatory (including bone immunomodulation) properties of MSCs and their role in the periodontal inflammatory microenvironment, summarizes the pathways and mechanisms by which MSCs and MSC-EVs have promoted periodontal regeneration in recent years, lists potential areas for future research, and describes the issues that should be considered in future basic research and the direction of development of "cell-free therapies" for periodontal regeneration.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

Immune imbalance is crucial in tuberculosis pathogenesis and may be modulated by mesenchymal stem cells (MSCs). However, how MSCs regulate the host's response to Mycobacterium tuberculosis (Mtb) is unclear.

Human umbilical cord-derived MSCs were co-cultured with Mtb-infected THP-1 macrophages. The intracellular release of ROS in macrophages was measured by DCFH-DA. Cytokine expression was measured by RT-qPCR, apoptosis by Annexin V/PI assay, and pyroptosis markers by Western blotting. Differentially expressed genes (DEGs) in Mtb-infected THP-1 co-cultured with or without MSCs were identified by RNA-seq and potential signaling pathways were analyzed through bioinformatics.

The fibroblastic morphology of MSCs exhibited 95 % positivity for CD73, CD90, and CD105, while the positivity rate for negative marker HLA-DR was less than 2 %. In Mtb-infected THP-1 macrophages, co-culturing with MSCs increased ROS release, cytokines expression (IL-1β, IL-6, TNF-α), apoptosis, and pyroptosis markers (NLRP3, Caspase-1, and GSDMD). Comparative transcriptome analysis identified 347 up-regulated and 291 down-regulated DEGs, primarily associated with receptor-ligand interactions and enriched in cytokine signaling pathways including JAK-STAT, TNF, ferroptosis, and autophagy.

MSCs could enhance the macrophages' immune response to Mtb by activating immune receptors and inflammatory signaling pathways.

Every 25th death worldwide is associated with liver pathology. The development of novel approaches to liver diseases therapy and protocols for maintaining the vital functions of patients on the liver transplant waiting list are urgently needed. Resident mesenchymal stem cells (MSCs) play a significant role in supporting liver tissue integrity and improve the liver condition after infusion. However, it remains unclear whether MSCs isolated from chronically inflamed livers are similar in their basic cellular properties to MSCs obtained from healthy livers. We applied a large array of tests to compare resident MSCs isolated from apparently normal liver tissue and from chronically inflamed livers of patients with fibrosis, cirrhosis, and viral hepatitis. Chronic inflammatory environment did not alter the major cellular characteristics of MSCs, including the expression of MSC markers, stem cell markers, adhesion molecules, and the hallmarks of senescence, as well as cell proliferation, migration, and secretome. Only the expression of some immune checkpoints and toll-like receptors was different. Evidently, MSCs with unchanged cellular properties are present in human liver even at late stages of inflammatory diseases. These cells can be isolated and used as starting material in the development of cell therapies of liver diseases.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) relieve lupus symptoms by inhibiting mainly T cells, whether MSCs also inhibit B cells has been controversial. Here, we found that naïve MSCs inhibited IFN-γ production by T cells, but not IgM production by B cells. We used a chemical approach to prime MSCs to inhibit B cells. We found that ingenol-3-angelate (I3A), a non-tumor-promoting phorbol ester, activated MSCs to inhibit B cells in a TGF-β1-dependent manner. We also showed that IL-1β induced MSCs to continuously secrete TGF-β1, which directly inhibited IgM production by B cells, whereas IL-1β did not. I3A-treated MSCs were better than naïve MSCs at ameliorating SLE symptoms in MRL.faslpr mice. In summary, our data provide information on how to generate MSCs that are effective for the treatment of SLE characterized by excessive B cell activation.

. 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.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited.

We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling.

Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons.

Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC.

Apoptotic vesicles (apoVs) play a vital role in various physiological and pathological conditions. However, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs). Here, we proved that systemic infusion of MSCs derived from wild-type (WT) mice rather than from ovariectomized (OVX) mice effectively improved the osteopenia phenotype and rescued the impaired recipient MSCs in osteoporotic mice. Meanwhile, apoVs derived from WT MSCs (WT apoVs) instead of OVX apoVs efficiently restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. The differential expression of miR-145a-5p is responsible for the distinct efficacy between the two types of apoVs. Overall, our findings unveil the remarkable potential of apoVs, as a novel nongenetic engineering approach, in rescuing the biological function and therapeutic capability of MSCs derived from patients. This discovery offers a new avenue for exploring apoVs-based stem cell engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.

Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes - the main cellular components in BMAC - interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes.

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction (n = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80+M1, CD206+M2 (anti-inflammatory macrophages), PDGFRα+MSC, and TNF-α+ cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm3 vs 0.02 mm3, p<.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p<.0001). Clodronate group showed significant reduction in mean number of CD80+, TNF-α+, PDGFRα+, and CD80+TNF-α+ cells on day 5 (306.5 vs 558.8, p<.0001; 280.5 vs 543.8, p<.0001; 365.0 vs 633.0, p<.0001, 29.0 vs 42.5, p<.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p=.0004; 479.3 vs 384.5, p=.0008; 593.0 vs 473.0, p=.0010, 41.0 vs 32.5, p=.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e, Gbp6, and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity.

Radiation enteritis is the most common complication of pelvic radiotherapy, but there is no effective prevention or treatment drug. Apoptotic T cells and their products play an important role in regulating inflammation and maintaining physiological immune homeostasis. Here it is shown that systemically infused T cell-derived apoptotic extracellular vesicles (ApoEVs) can target mice irradiated intestines and alleviate radiation enteritis. Mechanistically, radiation elevates the synthesis of intestinal 2'3' cyclic GMP-AMP (cGAMP) and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) proinflammatory pathway. After systemic infusion of ApoEVs, the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) enriches on the surface of ApoEVs hydrolyze extracellular cGAMP, resulting in inhibition of the cGAS-STING pathway activated by irradiation. Furthermore, after ApoEVs are phagocytosed by phagocytes, ENPP1 on ApoEVs hydrolyzed intracellular cGAMP, which serves as an intracellular cGAMP hydrolyzation mode, thereby alleviating radiation enteritis. The findings shed light on the intracellular and extracellular hydrolysis capacity of ApoEVs and their role in inflammation regulation.

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.

DNA methylation as intensively studied epigenetic regulatory mechanism exerts pleiotropic effects on dental-derived mesenchymal stem cells (DMSCs). DMSCs have self-renewal and multidifferentiation potential. Here, this review aims at summarizing the research status about application of DMSCs in tissue engineering and clarifying the roles of DNA methylation in influencing the functions of DMSCs, with expectation of paving the way for its in-depth exploration in tissue engineering.

The current research status about influence of DNA methylation in DMSCs was acquired by MEDLINE (through PubMed) and Web of Science using the keywords 'DNA methylation', 'dental-derived mesenchymal stem cells', 'dental pulp stem cells', 'periodontal ligament stem cells', 'dental follicle stem cells', 'stem cells from the apical papilla', 'stem cells from human exfoliated deciduous teeth', and 'gingival-derived mesenchymal stem cells'.

This review indicates DNA methylation affects DMSCs' differentiation and function through inhibiting or enhancing the expression of specific gene resulted by DNA methylation-related genes or relevant inhibitors.

DNA methylation can influence DMSCs in aspects of osteogenesis, adipogenesis, immunomodulatory function, and so on. Yet, the present studies about DNA methylation in DMSCs commonly focus on dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs). Little has been reported for other DMSCs.

Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.

The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.

Apoptotic vesicles (apoVs) play a vital role in various pathological conditions; however, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs) and regulating tissue homeostasis. Here, we proved that systemic infusion of bone marrow MSCs derived from wild-type (WT) mice effectively improved the osteopenia phenotype and hyperimmune state in ovariectomized (OVX) mice. Importantly, the WT MSCs rescued the impairment of OVX MSCs both in vivo and in vitro, whereas OVX MSCs did not show the same efficacy. Interestingly, treatment with apoVs derived from WT MSCs (WT apoVs) restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. This effect was not observed with OVX MSCs-derived apoVs (OVX apoVs) treatment. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. Conversely, treatment with OVX apoVs did not produce significant effects due to their limited expression of miR-145a-5p. Overall, our findings unveil the remarkable potential of apoVs in rescuing the biological function and therapeutic capability of MSCs derived from individuals with diseases. This discovery offers a new avenue for exploring apoVs-based MSC engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.

Psoriasis and rosacea are both chronic inflammatory skin disorders resulted from aberrant keratinocyte-immune cell crosstalk, but the common molecular foundations for these 2 conditions are poorly understood. In this study, we reveal that both patients with psoriasis and those with rosacea as well as their mouse models have significantly elevated expressions of SERPINB3/B4 (members of serine protease inhibitor) in the lesional skin. Skin inflammation in mice that resembles both psoriasis and rosacea is prevented by SERPINB3/B4 deficiency. Mechanistically, we demonstrate that SERPINB3/B4 positively induces NF-κB signaling activation, thereby stimulating disease-characteristic inflammatory chemokines and cytokines production in keratinocytes and promoting the chemotaxis of CD4+ T cells. Our results suggest that in keratinocytes, SERPINB3/B4 may be involved in the pathogenesis of both psoriasis and rosacea by stimulating NF-κB signaling, and they indicate a possible treatment overlap between these 2 diseases.

Myocardial infarction (MI) stands out as a highly lethal disease that poses a significant threat to global health. Worldwide, heart failure resulting from MI remains a leading cause of human mortality. Mesenchymal stem cell (MSC) therapy has emerged as a promising therapeutic approach, leveraging its intrinsic healing properties. Nevertheless, pervasive issues, including a low cell retention rate, suboptimal survival rate, and incomplete differentiation of MSCs, present formidable challenges for further research. The introduction and advancement of biomaterials have offered a novel avenue for the exploration of MSC therapy in MI, marking considerable progress thus far. Notably, hydrogels, among the representative biomaterials, have garnered extensive attention within the biomedical field. This review delves into recent advancements, specifically focusing on the application of hydrogels to augment MSC therapy for cardiac tissue regeneration in MI.

Breast cancer, the most prevalent malignancy in women, often progresses to bone metastases, especially in older individuals. Dormancy, a critical aspect of bone-metastasized breast cancer cells (BCCs), enables them to evade treatment and recur. This dormant state is regulated by bone marrow mesenchymal stem cells (BMMSCs) through the secretion of various factors, including those associated with senescence. However, the specific mechanisms by which BMMSCs induce dormancy in BCCs remain unclear. To address this gap, a bone-specific senescence-accelerated murine model, SAMP6, was utilized to minimize confounding systemic age-related factors. Confirming senescence-accelerated osteoporosis, distinct BMMSC phenotypes were observed in SAMP6 mice compared to SAMR1 counterparts. Notably, SAMP6-BMMSCs exhibited premature senescence primarily due to telomerase activity loss and activation of the p21 signaling pathway. Furthermore, the effects of conditioned medium (CM) derived from SAMP6-BMMSCs versus SAMR1-BMMSCs on BCC proliferation were examined. Intriguingly, only CM from SAMP6-BMMSCs inhibited BCC proliferation by upregulating p21 expression in both MCF-7 and MDA-MB-231 cells. These findings suggest that the senescence-associated secretory phenotype (SASP) of BMMSCs suppresses BCC viability by inducing p21, a pivotal cell cycle inhibitor and tumor suppressor. This highlights a heightened susceptibility of BCCs to dormancy in a senescent microenvironment, potentially contributing to the increased incidence of breast cancer bone metastasis and recurrence observed with aging.

Mesenchymal stem cells (MSCs) are widely distributed pluripotent stem cells with powerful immunomodulatory capacity. MSCs transplantation therapy (MSCT) is widely used in the fields of tissue regeneration and repair, and treatment of inflammatory diseases. Apoptosis is an important way for tissues to maintain cell renewal, but it also plays an important role in various diseases. And many studies have shown that MSCs improves the diseases by regulating cell apoptosis. The regulation of MSCs on apoptosis is double-sided. On the one hand, MSCs significantly inhibit the apoptosis of diseased cells. On the other hand, MSCs also promote the apoptosis of tumor cells and excessive immune cells. Furthermore, MSCs regulate apoptosis through multiple molecules and pathways, including three classical apoptotic signaling pathways and other pathways. In this review, we summarize the current evidence on the regulation of apoptosis by MSCs.

Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy.

A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors.

Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits.

The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a dysfunction of the immune system. Mesenchymal stromal cell (MSCs) derived extracellular vesicles (EVs) are nanometer-sized particles carrying a diverse range of bioactive molecules, such as proteins, miRNAs, and lipids. Despite the methodological disparities, recent works on MSC-EVs have highlighted their broad immunosuppressive effect, thus driving forwards the potential of MSC-EVs in the treatment of chronic diseases. Nonetheless, their mechanism of action is still unclear, and better understanding is needed for clinical application. Therefore, we describe in this review the diverse range of bioactive molecules mediating their immunomodulatory effect, the techniques and possibilities for enhancing their immune activity, and finally the potential application to SLE.

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

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.

Mesenchymal stem cells (MSCs) are a promising cell source for stem cell therapy of intractable diseases in veterinary medicine, but donor-dependent cellular heterogeneity is an issue that influences therapeutic efficacy. Thus, we previously established immortalized cells that maintain the fundamental properties of primary cells, but functional evaluation had not been performed. Therefore, we evaluated the immunomodulatory capacity of the immortalized canine adipose-derived MSCs (cADSCs) in vitro and in vivo to investigate whether they maintain primary cell functions. C57BL/6J mice were treated with dextran sulfate sodium (DSS) to induce colitis, injected intraperitoneally with immortalized or primary cADSCs on day 2 of DSS treatment, and observed for 10 days. Administration of immortalized cADSCs improved body weight loss and the disease activity index (DAI) in DSS-induced colitic mice by shifting peritoneal macrophage polarity from the M1 to M2 phenotype, suppressing T helper (Th) 1/Th17 cell responses and inducing regulatory T (Treg) cells. They also inhibited the proliferation of mouse and canine T cells in vitro. These immunomodulatory effects were comparable with primary cells. These results highlight the feasibility of our immortalized cADSCs as a cell source for stem cell therapy with stable therapeutic efficacy because they maintain the immunomodulatory capacity of primary cells.

Critical bone defects resulting in delayed and non-union are a major concern in the field of orthopedics. Over the past decade, mesenchymal stem cells (MSCs) have become a promising frontier for bone repair and regeneration owing to their high expansion rate and osteogenic differentiation potential ex vivo. MSCs have also long been associated with their ability to modulate immune response in the recipients. These can even skew the immune response towards pro-inflammatory or anti-inflammatory type by sensing their local microenvironment. MSCs adopt anti-inflammatory phenotype at bone injury site and secrete various immunomodulatory factors such as IDO, NO, TGFβ1 and PGE-2 which have redundant role in osteoblast differentiation and bone formation. As such, several studies have also sought to decipher the immunomodulatory effects of osteogenically differentiated MSCs. The present review discusses the immunomodulatory status of MSCs during their osteogenic differentiation and summarizes few mechanisms that cause immunosuppression by osteogenically differentiated MSCs and its implication during bone healing.

Dental pulp stem cells (DPSCs) have received a lot of attention as a regenerative medicine tool with strong immunomodulatory capabilities. The excessive inflammatory response involves a variety of immune cells, cytokines, and has a considerable impact on tissue regeneration. The use of DPSCs for controlling inflammation for the purpose of treating inflammation-related diseases and autoimmune disorders such as supraspinal nerve inflammation, inflammation of the pulmonary airways, systemic lupus erythematosus, and diabetes mellitus is likely to be safer and more regenerative than traditional medicines. The mechanism of the anti-inflammatory and immunomodulatory effects of DPSCs is relatively complex, and it may be that they themselves or some of the substances they secrete regulate a variety of immune cells through inflammatory immune-related signaling pathways. Most of the current studies are still at the laboratory cellular level and animal model level, and it is believed that through the efforts of more researchers, DPSCs/SHED are expected to be transformed into excellent drugs for the clinical treatment of related diseases.