• CD4+ T lymphocytes
• Glycolysis
• Mesenchymal stem cells
• Metabolic reprogramming
• Systemic lupus erythematosus
• mRNA

• Humans
• Lupus Erythematosus, Systemic/therapy
• Lupus Erythematosus, Systemic/metabolism
• Lupus Erythematosus, Systemic/pathology
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• CD4-Positive T-Lymphocytes/metabolism
• Glucose/metabolism
• Umbilical Cord/cytology
• Female
• Mesenchymal Stem Cell Transplantation
• Animals
• Adult
• Signal Transduction
• Mice
• Male
• Coculture Techniques

• H2019206387, H2023206264) Natural Science Foundation of Hebei Province
• 19277721D Hebei Provincial Department of Science and Technology

• T cells
• autoimmunity
• cancer
• immunometabolism
• viral infection

• Humans
• Energy Metabolism
• Animals
• Phenotype
• T-Lymphocytes/metabolism
• T-Lymphocytes/immunology
• Inflammation/metabolism
• Inflammation/immunology
• T-Lymphocyte Subsets/metabolism
• T-Lymphocyte Subsets/immunology

• 361210922/GRK2408 - (Project 12) Deutsche Forschungsgemeinschaft (DFG)
• 361210922/GRK2408 - (Project 13) Deutsche Forschungsgemeinschaft (DFG)
• 2023_EKEA.128 Else Kröner-Fresenius-Stiftung (EKFS)

• Autoimmunity
• CD8+ T cells
• Immunotherapy
• Mesenchymal stem/stromal cells
• Mitochondrial transfer

• Animals
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/cytology
• Mitochondria/metabolism
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Mice
• Mice, Transgenic
• Mice, Inbred C57BL
• Coculture Techniques
• Interferon-gamma/metabolism
• T-Box Domain Proteins/metabolism
• T-Box Domain Proteins/genetics
• Cell Differentiation
• Lymphocyte Activation

• ANR-14-CE12-0002 ANR
• Labex Mabimprove (FR) Labex Mabimprove (FR)
• Campus France Pakistan Campus France Pakistan

• Cardiovascular diseases
• Mesenchymal stem cells (MSCs): regenerative therapies
• Neurological disorders
• Reproductive disorders, endocrine-related diseases
• Respiratory diseases
• Skin burns

• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Regenerative Medicine/methods
• Translational Research, Biomedical
• Adipose Tissue/cytology
• Animals
• Cell Differentiation
• Umbilical Cord/cytology

• ALF
• HUCMSCs
• Inflammation
• Liver function
• Pre-transplantation

• Humans
• Rats
• Animals
• Galactosamine
• Liver Failure, Acute/therapy
• Liver Failure, Acute/surgery
• Mesenchymal Stem Cells
• Umbilical Cord
• Mesenchymal Stem Cell Transplantation

• Autoimmune-related fibrotic skin diseases
• Chronic graft-versus-host disease
• MSC-based therapy
• Mesenchymal stem cells
• Sclerodermatous graft-versus-host disease
• Systemic sclerosis

• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Scleroderma, Systemic
• Skin Diseases/pathology
• Autoimmune Diseases
• Fibrosis
• Skin/pathology
• Graft vs Host Disease/therapy
• Mesenchymal Stem Cells

• Autophagy
• Cell therapy
• Liver
• Mesenchymal stem cells
• Reperfusion injury
• T-lymphocytes

• acute liver failure (ALF)
• animal models
• cell therapy
• culture strategy
• mesenchymal stem cells (MSCs)
• surface markers

• Animals
• Liver Failure, Acute/therapy
• Liver Transplantation
• Cell Differentiation
• Mesenchymal Stem Cells
• Models, Animal

• Immunomodulatory properties
• Mesenchymal stromal/stem cells (MSCs)
• Metabolism
• Therapy

• angiogenesis
• cell proliferation
• cell survival
• glucose
• immunosuppression
• in silico models
• mesenchymal stromal cells
• metabolism

• Autoimmunity
• CD4+ T cells
• Immunotherapy
• Mesenchymal stem/stromal cells
• Mitochondrial transfer

• Activity
• Asciminib
• CML
• Metabolism
• T cell
• TKI

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular functions, such as cell proliferation, metabolism, autophagy, survival and cytoskeletal organization. Furthermore, mTOR is made up of three multisubunit complexes, mTOR complex 1, mTOR complex 2, and putative mTOR complex 3. In recent years, increasing evidence has suggested that mTOR plays important roles in the differentiation and immune responses of mesenchymal stem cells (MSCs). In addition, mTOR is a vital regulator of pivotal cellular and physiological functions, such as cell metabolism, survival and ageing, where it has emerged as a novel therapeutic target for ageing-related diseases. Therefore, the mTOR signaling may develop a large impact on the treatment of ageing-related diseases with MSCs. In this review, we discuss prospects for future research in this field.

• Natural Science Foundation of Chongqing

Gastric cancer (GC) is one of the most prevalent and deadly malignancies worldwide. We aimed to assess the functional role and clinical significance of pyruvate dehydrogenase kinase (PDK) in GC and explored the underlying mechanisms. The bioinformatics method was used to investigate the expression of PDKs in GC, the effect on clinical outcomes, enriched pathways, interactive network, and the correlation between PDK4 and immune infiltration. Next, PDK expression in the GC cells and tissues were verified by qRT-PCR and western blotting. A Cell Counting Kit-8 (CCK8), colony-formation, Flow cytometry, Transwell and wound healing assays were carried out to evaluate the influence of PDK4 on cell proliferation, invasion and migration. Among PDKs, PDK4 expression was aberrant in GC and identified as an independent prognostic factor. GO analysis, GSEA, and PPI showed that PDK4 expression may regulate cell adhesion, metal ion transport, synaptic activity, and cancer cell metabolism in GC. Analyses of immune infiltration showed that PDK4 correlated with the abundant expression of various immunocytes. Finally, we verified that upregulation of PDK4 expression enhanced the ability of GC cells to proliferate, migrate, and invade. In conclusion, PDK4 was identified as a potential candidate diagnostic biomarker and therapeutic target for GC patients.

Mesenchymal stem cells (MSCs) as a therapeutic promise are often quickly cleared by innate immune cells of the host including natural killer (NK) cells. Efforts have been made to generate immune-escaping human embryonic stem cells (hESCs) where T cell immunity is evaded by defecting β-2-microglobulin (B2M), a common unit for human leukocyte antigen (HLA) class I, and NK cells are inhibited via ectopic expression of HLA-E or -G. However, NK subtypes vary among recipients and even at different pathologic statuses. It is necessary to dissect and optimize the efficacy of the immune-escaping cells against NK subtypes. Here, we first generated B2M knockout hESCs and differentiated them to MSCs (EMSCs) and found that NK resistance occurred with B2M^-/- EMSCs expressing HLA-E and -G only when they were transduced via an inducible lentiviral system in a dose-dependent manner but not when they were inserted into a safe harbor. HLA-E and -G expressed at high levels together in transduced EMSCs inhibited three major NK subtypes, including NKG2A⁺/LILRB1⁺, NKG2A⁺/LILRB1^-, and NKG2A^-/LILRB1⁺, which was further potentiated by IFN-γ priming. Thus, this study engineers MSCs with resistance to multiple NK subtypes and underscores that dosage matters when a transgene is used to confer a novel effect to host cells, especially for therapeutic cells to evade immune rejection.

• Human embryonic stem cells
• immune rejection
• innate immunity
• mesenchymal stem cells
• natural killer cells

• HMG-CoA reductase inhibitor
• cellular immunity
• immune thrombocytopenia
• mevalonate pathway
• statin

• 81900124 National Natural Science Foundation of China
• 81973994 National Natural Science Foundation of China
• 81770114 National Natural Science Foundation of China
• 82000123 National Natural Science Foundation of China
• 81900121 National Natural Science Foundation of China
• ZR2019BH055 Shandong Provincial Natural Science Foundation
• ZR201807061123 Shandong Provincial Natural Science Foundation
• State Key Clinical Specialty of China for Hematological Diseases
• tsqn201812133 Young Taishan Scholar Foundation of Shandong Province
• tsqn201909175 Young Taishan Scholar Foundation of Shandong Province
• 2019GSF108240 Major Research Plan of Shandong Province
• 2020QNQT001 The Fundamental Research Funds of Shandong University

Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions.

In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis.

We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro.

In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

The online version contains supplementary material available at 10.1186/s13287-021-02560-x.

• Concanavalin A (Con A)
• Fulminant hepatitis
• Glycolysis
• Human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs)
• Immunomodulation
• NF-κB

• acute respiratory distress syndrome
• asthma
• chronic obstructive pulmonary disease
• idiopathic pulmonary fibrosis
• mesenchymal stem cells

• National Natural Science Foundation of China

• T helper 17 cell
• kidney injury
• mTOR
• mesenchymal stem cell
• regulatory T cell

• autophagy
• interleukin-15
• mesenchymal stem cells
• mucosal-associated invariant T cell

Background: Cervical cancer is a common malignant disease in female patients accompanied by activation of autophagy in tumor cells. However, the exact regulatory factors of autophagy and its effects on the immune response remain unknown.

Methods: The induction of autophagy in HeLa and SiHa cells treated with IFN-γ, tryptophan depletion, kynurenine and epacadostat was detected by western blot analysis and by an autophagy detection kit. Following co-culture with pre-treated HeLa and SiHa cells, U937 cells were analyzed by flow cytometry to detect CD80, CD86, CD163 and CD206 expression and the induction of phagocytosis.

Results: IFN-γ caused a significant increase in the autophagy levels of HeLa and SiHa cells by promoting indoleamine-2,3-dioxygenase-1 (IDO1) expression. The induction of phagocytosis in HeLa and SiHa cells and the expression levels of CD80 and CD86 in U937 cells were increased significantly following treatment with recombinant human IFN-γ. This effect was associated with the induction of tumor cell autophagy. IFN-γ treatment and IDO1 overexpression promoted tryptophan depletion and kynurenine accumulation in cervical cancer cells. The latter was more potent in inducing autophagy of cervical cancer cells and promoting phagocytosis of macrophages. In vivo, IDO1 overexpression restricted tumor growth in C57 mice and enhanced the induction of phagocytosis in macrophages.

Conclusions: IFN-γ promoted induction of autophagy and macrophage phagocytosis in cervical cancer cells possibly via IDO1 expression and kynurenine metabolism.

• IDO1
• IFN-γ
• autophagy
• cervical cancer
• kynurenine
• macrophage
• phagocytosis

• cancer metabolism
• immune response
• immune-nutrition
• immunotherapy
• nutrition

• Chinese medicine
• graft-versus-host disease
• hematopoietic stem cell transplantation

• immune modulation
• immune modulators
• mesenchymal stem cell
• stem cell therapy

• Animals
• Humans
• Immune Tolerance
• Immunotherapy
• Inflammation/immunology
• Inflammation/pathology
• Inflammation/therapy
• Mesenchymal Stem Cells/immunology

• A2018308 Medical Foundation of Guangdong
• JCYJ20170302152735071, KQJSCX20180328093434771 Natural Science Foundation of Shenzhen
• JCYJ20180305163407913 Natural Science Foundation of Shenzhen
• 2017083 Natural Science Foundation of SZU
• 2017A030313904，2018A030310643 Natural Science Foundation of Guangdong Province
• Natural Science Foundation of Guangdong Province

Neuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive.

We evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X₄ (P2X₄R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons.

I.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X₄R expression in the spinal cord microglia. BMSC-lysate also reduced P2X₄R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X₄R confirmed that modulation of P2X₄R might be a key mechanism for the analgesic effects of i.t. BMSC.

Altogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC’s analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X₄R downregulation.

• Bone marrow stromal cells
• Neuropathic pain
• P2X4R
• TRPV4

Acute myeloid leukemia (AML) is the acute leukemia with highest incidence amongst adults. Despite significant improvements in understanding the genomic landscape and the introduction of novel drugs, long-term outcome remains unsatisfactory. Recently, immunotherapeutic approaches have heralded a new era in cancer treatment. The success of allogeneic hematopoietic stem cell transplantation in AML highlights the disease's immunoresponsiveness. Several immunotherapeutic applications are currently under clinical evaluation and include immune checkpoint blockades, T cell-engaging antibodies, and genetically engineered T cells. However, immunoevasive mechanisms employed by AML blasts severely hamper our endeavors. A better understanding of the underlying mechanisms remains a prerequisite for improving treatment efficacy. One of the hallmarks of the cancer cells is metabolic reprogramming, introduced by Otto Warburg's seminal studies during the beginnings of the last century. Nowadays, it is well established that metabolic adaptation is not just an epiphenomenon during oncogenesis but rather a necessity for tumor development and progression. Furthermore, accumulating data suggest an important role of aberrant tumor cell metabolism for immune escape. AML blasts display a number of metabolic alterations that could be linked to immunoregulation, and these include competition over substrates, abundant release of bioactive metabolites, and an overall microenvironmental metabolic re-modeling that favors the induction or survival of immunoregulatory cell subsets such as regulatory T cells. In this review, we outline the immunoevasive character of the AML blasts' bioenergetics, set it into context with oncogenic mutations, and discuss potentially suitable countermeasures and their limitations.

• AML—acute myeloid leukemia
• immunoescape mechanisms
• immunotherapy
• microenvironment
• tumor metabolism

• Antioxidants/metabolism
• Female
• Humans
• Placenta/metabolism
• Pregnancy
• Tryptophan/metabolism

Many neurologic diseases are related to autoimmune dysfunction and a variety of molecules or reaction pathways are involved in the regulation of immune function of the nervous system. Soluble CD83 (sCD83) is the soluble form of CD83, a specific marker of mature dendritic cell, which has recently been shown to have an immunomodulatory effect. Indoleamine 2,3-dioxygenase (IDO; corresponding enzyme intrahepatic, tryptophan 2,3-dioxygenase, TDO), a rate-limiting enzyme of extrahepatic tryptophan kynurenine pathway (KP) participates in the immunoregulation through a variety of mechanisms solely or with the synergy of sCD83, and the imbalances of metabolites of KP were associated with immune dysfunction. With the complement of sCD83 to IDO-KP, a previously known immunomodulatory axis, this review focused on an expanded neuroimmunomodulation axis: sCD83-IDO-KP and its involvement in nervous system diseases.

• indoleamine 2 3-dioxygenase
• kynurenine pathway
• neuroimmunomodulation
• neurologic disease
• soluble CD83

D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.

• 2HG
• IDH mutation
• Immunosurveillance
• Inflammation and cancer
• Th17
• Tregs
• acute myeloid leukemia
• immunometabolism
• oncometabolite

Bone marrow mesenchymal stem cells (MSCs) are promising candidates for the treatment of various inflammatory disorders due to their profound immunomodulatory properties. However, the immunosuppressive capacity of MSCs needs activation by an inflammatory microenvironment, which may negatively impact the therapeutic effect because of increased immunogenicity. Here we explore the role of mammalian target of rapamycin (mTOR) signaling on the immunosuppressive capacity of MSCs, and its impact on immunogenicity in the inflammatory microenvironment.

Human bone marrow MSCs were cocultured with activated human peripheral blood mononuclear cells, CD4⁺ T cells, and mouse splenocytes to evaluate the immunosuppressive function. Immunosuppressive factors were assessed by quantitative real-time polymerase chain reaction (PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). The expression of major histocompatibility complex (MHC) was detected by flow cytometry. Short hairpin (sh)RNA was used to downregulate tuberous sclerosis complex (TSC)2, TSC1, and cyclooxygenase (COX)-2 in MSCs.

Inhibition of mTOR signaling using rapamycin enhanced the immunosuppressive functions of MSCs, while prolonged exposure to rapamycin did not. The enhancement of the immunosuppressive function was independent of the inflammatory microenvironment, and occurred mainly through the upregulation of COX-2 and prostaglandin-E₂ (PGE₂) expression. Furthermore, mTOR inhibition did not impact the immunogenicity of MSCs. However, the upregulated expression of MHC class II molecules by interferon (IFN)-γ was attenuated by mTOR inhibition, whereas TSC2 knockdown had the opposite effect.

These results reveal that the mTOR signaling pathway regulates MSC immunobiology, and short-term exposure to rapamycin could be a novel approach to improve the MSC-based therapeutic effect.

The online version of this article (doi:10.1186/s13287-017-0744-6) contains supplementary material, which is available to authorized users.

• Immunogenicity
• Immunosuppressive properties
• Mesenchymal stem cells
• Rapamycin
• TSC-mTOR pathway

• MSC
• T cells
• immunosuppression
• therapy
• tolerance
• transplantation

• Mesenchymal stem cell
• cellular tumor therapy
• engineering
• suicide gene

• Adenosine Triphosphate/biosynthesis
• Animals
• Glycolysis
• Humans
• Immune System/cytology
• Immune System/metabolism
• Immunologic Memory
• Infections/immunology
• Infections/metabolism
• Infections/therapy
• Lymphocytes/classification
• Lymphocytes/immunology
• Lymphocytes/metabolism
• Models, Immunological
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Oxidative Phosphorylation
• Signal Transduction/immunology
• Tumor Microenvironment/immunology
• Tumor Microenvironment/physiology