• AMPK
• GAS6
• IDHP
• Inflammatory response
• Myocardial injury
• Sepsis

• Animals
• Mice
• AMP-Activated Protein Kinases
• Myocardium
• Signal Transduction
• Mice, Knockout
• Sepsis/drug therapy
• Wound Infection
• Mitochondrial Diseases

Many widespread intractable diseases are caused or supported by chronic inflammation. Such conditions include the 2nd type of diabetes mellitus, atherosclerosis, neurodegenerative diseases, chronic inflammatory diseases of the connective tissue - ankylosing spondylitis, rheumatoid arthritis, autoimmune myositis, etc. Therefore, the search for targeted treatment of these illnesses is extremely in high demand. Immunomodulatory activity of mesenchymal stem cells is one of their remarkable properties. Several biomarkers (cytokines and nonspecific proteins) are known to be associated with chronic inflammation.

Our study aimed to investigate the serum levels of tumor necrosis factor-alpha, interleukin 6 and C-reactive protein in carrageenan myositis in rats, because there is more and more evidence of the significance of these markers in the course and resolution of the diseases mentioned above. For the first time in our experiment, it was shown and evaluated using analysis of variance, how MSCs influence the indicators of proinflammatory cytokines on the model of carrageenan myositis. The levels of α-TNF, IL-6 and CRP in the plasma of rats were studied in groups with chronic carrageenan inflammation and chronic inflammation with local injection of MSCs into the affected area.

Our study proved the effectiveness of MSCs by showing a significant decrease in the levels of inflammatory mediators in the plasma of the studied animals.

Thus, the administration of MSCs is a promising tool in the pathogenic treatment of chronic inflammation and concomitant conditions.

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• C-reactive protein
• carrageenan
• chronic inflammation
• interleukin-6
• mesenchymal stem cells
• tumor necrosis factor-alpha

• engraftment
• immunomodulatory properties
• mesenchymal stem cells
• somatic cell therapy
• transplantation

Mesenchymal stromal cells (MSCs) exert immunosuppressive effects on immune cells including dendritic cells (DCs). However, many details of the bidirectional interaction of MSCs with DCs are still unsolved and information on key molecules by which DCs can modulate MSC functions is limited. Here, we report that osteopontin (OPN), a cytokine involved in homeostatic and pathophysiologic responses, is constitutively expressed by DCs and regulated in the DC/MSC cocultures depending on the activation state of MSCs. Resting MSCs promoted OPN production, whereas the production of OPN was suppressed when MSCs were activated by proinflammatory cytokines (i.e., TNF-α, IL-6, and IL-1β). OPN induction required cell-to-cell contact, mediated at least in part, by β1 integrin (CD29). Conversely, activated MSCs inhibited the release of OPN via the production of soluble factors with a major role played by Prostaglandin E₂ (PGE₂). Accordingly, pretreatment with indomethacin significantly abrogated the MSC-mediated suppression of OPN while the direct addition of exogenous PGE₂ inhibited OPN production by DCs. Furthermore, DC-conditioned medium promoted osteogenic differentiation of MSCs with a concomitant inhibition of adipogenesis. These effects were paralleled by the repression of the adipogenic markers PPARγ, adiponectin, and FABP4, and induction of the osteogenic markers alkaline phosphatase, RUNX2, and of the bone-anabolic chemokine CCL5. Notably, blocking OPN activity with RGD peptides or with an antibody against CD29, one of the OPN receptors, prevented the effects of DC-conditioned medium on MSC differentiation and CCL5 induction. Because MSCs have a key role in maintenance of bone marrow (BM) hematopoietic stem cell niche through reciprocal regulation with immune cells, we investigated the possible MSC/DC interaction in human BM by immunohistochemistry. Although DCs (CD1c⁺) are a small percentage of BM cells, we demonstrated colocalization of CD271⁺ MSCs with CD1c⁺ DCs in normal and myelodysplastic BM. OPN reactivity was observed in occasional CD1c⁺ cells in the proximity of CD271⁺ MSCs. Altogether, these results candidate OPN as a signal modulated by MSCs according to their activation status and involved in DC regulation of MSC differentiation.

• adipogenesis
• ccl5
• dendritic cells
• mesenchymal stromal cells
• osteogenesis
• osteopontin

• Cell cycle
• Cord
• Differentiation
• Magnetic field
• Mesenchymal stem cell
• Proliferation
• Viability

• adult stem cells
• embryonic stem cells
• end stage renal disease
• glomerular disease
• regeneration
• stem cell therapy

Bone marrow multipotent mesenchymal stromal cells (MSCs) are a diverse subset of precursors that contribute to the homeostasis of the hematopoietic niche. MSCs can be isolated and expanded in vitro and have unique immunomodulatory and regenerative properties that make them attractive for the treatment of autoimmune diseases, including type 1 diabetes (T1D). Whether autologous or allogeneic MSCs are more suitable for therapeutic purposes has not yet been established. While autologous MSCs may present abnormal function, allogeneic cells may be recognized and rejected by the host immune system. Thus, studies that investigate biological characteristics of MSCs isolated from T1D patients are essential to guide future clinical applications.

Bone marrow-derived MSCs from recently diagnosed type 1 diabetes patients (T1D-MSCs) were compared with those from healthy individuals (C-MSCs) for morphological and immunophenotypic characteristics and for differentiation potential. Bioinformatics approaches allowed us to match absolute and differential gene expression of several adhesion molecules, immune mediators, growth factors, and their receptors involved with hematopoietic support and immunomodulatory properties of MSCs. Finally, the differentially expressed genes were collated for functional pathway enrichment analysis.

T1D-MSCs and C-MSCs were similar for morphology, immunophenotype, and differentiation potential. Our absolute gene expression results supported previous literature reports, while also detecting new potential molecules related to bone marrow-derived MSC functions. T1D-MSCs showed intrinsic abnormalities in mRNA expression, including the immunomodulatory molecules VCAM-1, CXCL12, HGF, and CCL2. Pathway analyses revealed activation of sympathetic nervous system and JAK STAT signaling in T1D-MSCs.

Collectively, our results indicate that MSCs isolated from T1D patients present intrinsic transcriptional alterations that may affect their therapeutic potential. However, the implications of these abnormalities in T1D development as well as in the therapeutic efficacy of autologous MSCs require further investigation.

The online version of this article (doi:10.1186/s13287-016-0351-y) contains supplementary material, which is available to authorized users.

• Bone marrow
• Cell therapy
• Mesenchymal stromal cells
• Microarrays
• Transcriptome
• Type 1 diabetes

• Angiogenesis
• Gene therapy
• Mesenchymal stem cells
• Myocardial infarction
• Thioredoxin-1

• Cell therapy
• differentiation
• immunomoldulatory
• mesenchymal stem cells
• regenerative medicine

• Immunomodulation
• Mesenchymal stromal cells
• Paracrine effects

Mesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD.

Clinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05–3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12–4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06–8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III–IV (CR: OR = 3.22, 95%CI: 1.24–8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09–0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17–4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01–5.73, p = 0.05).

Age, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD.

• Acute Disease/therapy
• Adolescent
• Adult
• Aged
• Child
• Child, Preschool
• Clinical Trials as Topic
• Double-Blind Method
• Female
• Graft vs Host Disease/drug therapy
• Graft vs Host Disease/therapy
• Hematopoietic Stem Cell Transplantation/methods
• Humans
• Infant
• Male
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Middle Aged
• Remission Induction/methods
• Steroids/therapeutic use
• Young Adult

• Angiogenesis
• Gene therapy
• Mesenchymal stem cells
• Myocardial infarction
• Thioredoxin 1
• VEGF

Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been an increasing interest in the study of undifferentiated progenitors that have the ability to proliferate and differentiate into various tissues. Stem cells (SC) with different potency can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue, or Wharton's Jelly are of potential interest for clinical applications in regenerative medicine because they are easily available without ethical problems for their uses. During the last 10 years, these multipotent cells have generated considerable interest and have particularly been shown to escape to allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone and cartilage deterioration, diabetes, urology, liver, ophthalmology, and organ's reconstruction). This review focuses mainly on tissue and organ regeneration using SC and in particular MSC.

Mesenchymal stem cells (MSCs) have rapidly been applied in a broad field of immune-mediated disorders since the first successful clinical use of MSCs for treatment of graft-versus-host disease. Despite the lack of supporting data, expectations that MSCs could potentially treat most inflammatory conditions led to rushed application and development of commercialized products. Today, both pre-clinical and clinical studies present mixed results for MSC therapy and the discrepancy between expected and actual efficacy of MSCs in various diseases has evoked a sense of discouragement. Therefore, we believe that MSC therapy may now be at a critical milestone for re-evaluation and re-consideration. In this review, we summarize the current status of MSC-based clinical trials and focus on the discrepancy between expected and actual outcome of MSC therapy from bench to bedside. Importantly, we discuss the underlying limitations of MSCs and suggest a new guideline for MSC therapy in hopes of improving their therapeutic efficacy.

• Clinical trial
• Immune modulation
• Limitation
• Mesenchymal stem cells

AIM: To investigate the effects of mesenchymal stem cells (MSCs) on dextran sulfate sodium-induced inflammatory bowel disease (IBD).

METHODS: C57BL/6 mice were fed 3.5% (g/L) dextran sulfate sodium. On day seven, the mice received intraperitoneal injections of 1 × 10⁶ MSCs. The survival rate, disease activity index values, and body weight, were monitored daily. On day ten, colon lengths and histopathologic changes were assessed. In addition, immunoregulatory changes following MSC administration were evaluated by determining the levels of effector T cell responses in the spleen and mesenteric lymph nodes, and the expression levels of inflammatory cytokines in homogenized colons.

RESULTS: Intraperitoneal administration of MSCs did not prevent development of colitis and did not reduce the clinicopathologic severity of IBD. No significant difference was evident in either survival rate or disease activity index score between the control and MSC-treated group. Day ten-sacrificed mice exhibited no significant difference in either colon length or histopathologic findings. Indeed, the MSC-treated group exhibited elevated levels of interleukin (IL)-6 and transforming growth factor-β, and a reduced level of IL-10, in spleens, mesenteric lymph nodes, and homogenized colons. The IL-17 level was lower in the mesenteric lymph nodes of the MSC-treated group (P = 0.0126). In homogenized colons, the IL-17 and tumor necrosis factor-α (P = 0.0092) expression levels were also lower in the treated group.

CONCLUSION: MSC infusion provided no significant histopathologic or clinical improvement, thus representing a limited therapeutic approach for IBD. Functional enhancement of MSCs is needed in further study.

• Crohn’s disease
• Dextran sulfate sodium
• Inflammatory bowel disease
• Mesenchymal stem cells
• Ulcerative colitis

• Animals
• Cells, Cultured
• Colitis/chemically induced
• Colitis/immunology
• Colitis/metabolism
• Colitis/pathology
• Colitis/surgery
• Colon/immunology
• Colon/metabolism
• Colon/pathology
• Cytokines/metabolism
• Dextran Sulfate
• Disease Models, Animal
• Female
• Inflammation Mediators/metabolism
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/metabolism
• Mice, Inbred C57BL
• Phenotype
• Severity of Illness Index
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Time Factors

• bone marrow
• cells
• immune system
• immunomodulatory
• mesenchymal stem cells

• bone marrow niche
• bone marrow stromal cells
• cell therapy
• pericyte
• transplantation

• R01 CA089868 NCI NIH HHS

Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.

In this review, we discuss the migration and homing ability of mesenchymal stem cells (MSCs) and MSC-like cells and factors influencing this. We also discuss studies related to the mechanism of migration and homing and the approaches undertaken to enhance it. Finally, we describe the different methods available and frequently used to track and identify the injected cells in vivo.

Since the discovery of the immunomodulation property of mesenchymal stem cells (MSCs) about a decade ago, it has been extensively investigated whether MSCs can be used for the treatment of immune-related diseases, such as graft-versus-host disease (GvHD). However, how to evaluate the efficacy of human MSCs for the clinical trial is still unclear. We used an MHC-mismatched model of GvHD (B6 into BALB/c). Surprisingly, the administration of the human MSCs (hMSCs) could reduce the GvHD-related mortality of the mouse recipients and xenogeneically inhibit mouse T-cell proliferation and IFN-γ production in vitro. We recently established a new protocol for the isolation of a homogeneous population of MSCs called subfractionation culturing methods (SCM), and established a library of clonal MSC lines. Therefore, we also investigated whether MSCs isolated by the conventional gradient centrifugation method (GCM) and SCM show different efficacy in vivo. Intriguingly, clonal hMSCs (hcMSCs) isolated by SCM showed better efficacy than hMSCs isolated by GCM. Based on these results, the MHC-mismatched model of GvHD may be useful for evaluating the efficacy of human MSCs before the clinical trial. The results of this study suggest that different MSC lines may show different efficacy in vivo and in vitro.

• Efficacy
• IFN-γ
• Mesenchymal stem cells
• T-cell
• graft-versus-host disease

• Autologous platelet rich product
• Cell-based regenerative therapy
• Mesenchymal stem cell

• Clinical trial
• Graft vs host disease
• Mesenchymal stromal cells
• Tissue therapy

• Animals
• Cell Differentiation
• Cell Lineage
• Cell Movement
• Cell Proliferation
• Gene Expression Regulation
• Humans
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/physiology
• Regeneration
• Regenerative Medicine/methods
• Treatment Outcome

• ISCT
• MSC
• immune regulation
• mesenchymal stromal cells
• regulatory properties
• standardization

• Animals
• Cell- and Tissue-Based Therapy/methods
• Humans
• Mesenchymal Stem Cells/immunology
• Multipotent Stem Cells/immunology

Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease.

• cell transplantation
• human mesenchymal stem cells
• macrophages
• neuropathic pain

Background: Neuropathic pain (NP) is an incurable disease caused by a primary lesion in the nervous system. NP is a progressive nervous system disease that results from poorly defined neurophysiological and neurochemical changes. Its treatment is very difficult. Current available therapeutic drugs have a generalized nature, sometime acting only on the temporal pain properties rather than targeting the several mechanisms underlying the generation and propagation of pain. Methods: Using biomolecular and immunohistochemical methods, we investigated the effect of the systemic injection of human mesenchymal stem cells (hMSCs) on NP relief. We used the spared nerve injury (SNI) model of NP in the mouse. hMSCs were injected into the tail vein of the mouse. Stem cell injection was performed 4 days after sciatic nerve surgery. Neuropathic mice were monitored every 10 days starting from day 11 until 90 days after surgery. Results: hMSCs were able to reduce pain-like behaviors, such as mechanical allodynia and thermal hyperalgesia, once injected into the tail vein. An anti-nociceptive effect was detectable from day 11 post surgery (7 days post cell injection). hMSCs were mainly able to home in the spinal cord and pre-frontal cortex of neuropathic mice. Injected hMSCs reduced the protein levels of the mouse pro-inflammatory interleukin IL-1β and IL-17 and increased protein levels of the mouse anti-inflammatory interleukin IL-10, and the marker of alternatively activated macrophages CD106 in the spinal cord of SNI mice. Conclusion: As a potential mechanism of action of hMSCs in reducing pain, we suggest that they could exert their beneficial action through a restorative mechanism involving: (i) a cell-to-cell contact activation mechanism, through which spinal cord homed hMSCs are responsible for switching pro-inflammatory macrophages to anti-inflammatory macrophages; (ii) secretion of a broad spectrum of molecules to communicate with other cell types. This study could provide novel findings in MSC pre-clinical biology and their therapeutic potential in regenerative medicine.

• cell transplantation
• human mesenchymal stem cells
• macrophages
• neuropathic pain

Mesenchymal stem cells (MSCs) were first discovered by Friedenstein and his colleagues in 1976 from bone marrow. The unique property of these cells was their potential to develop into fibroblastic colony forming cells. Since Friedenstein’s discovery of these cells the interest in adult MSCs has been progressively growing. Nowadays MSCs are defined as undeveloped biological cells capable of proliferation, self renewal and regenerating tissues. All these properties of MSCs have been discovered in the past 35 years. MSCs can play a crucial role in tissue engineering, organogenesis, gene therapy, transplants as well as tissue injuries. These cells were mainly extracted from bone marrow but there have been additional sources for MSCs discovered in the laboratories including: muscle, dermis, trabecular bone, adipose tissue, periosteum, pericyte, blood, synovial membrane and so forth. The discovery of the alternative sources of MSCs helps widen the application of these cells in different areas of medicine. By way of illustration, they can be used in various therapeutic purposes such as tissue regeneration and repair in musculoskeletal diseases including osteonecrosis of femoral head, stimulating growth in children with osteogenesis imperfecta, disc regeneration, osteoarthritis and duchenne muscular dystrophy. In order to fully comprehend the characteristics and potential of MSCs future studies in this field are essential.

• Mesenchymal stem cells
• muscular dystrophy
• musculoskeletal applications
• tissue engineering.

• stem cell
• mesenchymal stem cell
• blood vessel
• pericyte
• tunica adventitia
• tissue regeneration

• Adult
• Cell Lineage
• Humans
• Organogenesis
• Pericytes/cytology
• Stem Cells/cytology
• Tissue Engineering
• Wound Healing

• G1000816 Medical Research Council

• Adolescent
• Bone Marrow Cells/cytology
• Bone Marrow Cells/immunology
• Cell Communication
• Cell Differentiation
• Cell Proliferation
• Cell Separation
• Cell Survival
• Cells, Cultured
• Coculture Techniques
• Female
• Flow Cytometry
• Humans
• Immunomodulation/immunology
• Male
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/immunology
• Receptors, CCR4/immunology
• Receptors, CCR6/immunology
• Spondylitis, Ankylosing/immunology
• T-Lymphocyte Subsets/cytology
• T-Lymphocyte Subsets/immunology
• T-Lymphocytes, Regulatory/cytology
• T-Lymphocytes, Regulatory/immunology
• Young Adult