Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to differentiate into different tissue cell types such as chondrocytes, osteocytes, and adipocytes. In addition, they can home to damaged, in-flamed, and malignant tissues and display immunomodulatory properties. Since tissue-derived factors might modulate these properties, we decided to explore the impact of prototypic tissue-derived inflammatory cytokines such as TNF-alpha and IFN-gamma on immunomodulatory MSCs functions. To this end, we used primary bone marrow and cord blood-derived MSCs as well as an immortalized MSC line (V54/2) as model systems. We demonstrate that under unstimulated conditions, V54/2 cells constitutively express low levels of indoleamine 2,3-dioxygenase (IDO), exert an immunosuppressive effect on activated T-lymphocyte proliferation, secrete a distinct set of cytokines, and express a wide range of chemokine receptors. Upon stimulation, the proinflammatory cytokines IFN-gamma and TNF-alpha did not inhibit suppression of T-cell proliferation, although IDO expression was up-regulated by IFN-gamma. In contrast, TNF-alpha but not IFN-gamma amplified the cytokine production of V54/2 and primary MSCs. Interestingly, IFN-gamma was superior to TNF-alpha in up-regulating expression of chemokine receptors and migration of the V54/2 cell line, while TNF-alpha was the predominant regulator of migration in primary MSCs. Altogether, our data show that properties of MSCs depend on local environmental factors. In particular, we have shown that IFN-gamma and TNF-alpha differentially regulate cytokine expression and migration of MSCs.

Human MSCs may respond to TLR ligation, and recent research has suggested that many tissues contain tissue-specific MSCs, possibly located in periendothelial and perivascular regions. At present, the functional consequences of these findings are unclear. We hypothesized that tissue-specific MSCs could play an instructional role during early phases of bacterial challenge. To investigate this hypothesis further, we set up a coculture system of glandular MSCs and peripheral blood neutrophils so that we could analyze the cellular interactions of these cells in response to LPS challenge. We found that stimulation with bacterial endotoxin induced chemokine receptor expression and mobility of MSCs. Activated MSCs secreted large amounts of inflammatory cytokines and recruited neutrophils in an IL-8- and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS. Our findings demonstrate a complex, functional interaction between tissue-resident MSCs and peripheral blood neutrophils upon bacterial challenge and suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.

BackgroundMesenchymal stem cells (MSCs) participate in the regulation of inflammation and innate immunity, for example by responding to pathogen-derived signals and by regulating the function of innate immune cells. MSCs from the bone-marrow and peripheral tissues share common basic cell-biological functions. However, it is unknown whether these MSCs exhibit different responses to microbial challenge and whether this response subsequently modulates the regulation of inflammatory cells by MSCs.Methodology/Principal FindingsWe isolated MSCs from human bone-marrow (bmMSCs) and human salivary gland (pgMSCs). Expression levels of TLR4 and LPS-responsive molecules were determined by flow cytometry and quantitative PCR. Cytokine release was determined by ELISA. The effect of supernatants from unstimulated and LPS-stimulated MSCs on recruitment, cytokine secretion, bacterial clearance and oxidative burst of polymorphonuclear neutrophil granulocytes (PMN) was tested in vitro. Despite minor quantitative differences, bmMSCs and pgMSCs showed a similar cell biological response to bacterial endotoxin. Both types of MSCs augmented anti-microbial functions of PMNs LPS stimulation, particularly of bmMSCs, further augmented MSC-mediated activation of PMN.Conclusions/SignificanceThis study suggests that MSCs may contribute to the resolution of infection and inflammation by promoting the anti-microbial activity of PMNs. This property is exerted by MSCs derived from both the bone-marrow and peripheral glandular tissue.

Multipotent mesenchymal stromal cells (MSC) are present in bone marrow and other tissues such as adipose tissue, muscle, pancreas, liver, and so on. Recent evidence suggests that MSC migrate to sites of infection, inflammation, and cancer, and interact with different immune cell subsets. Here, we report for the first time on the isolation and characterization of multipotent nasal mucosa-derived mesenchymal stromal cells (nm-MSC). nm-MSC showed a plastic adherent and fibroblast-like morphology and were able to form colonies. They expressed the typical bone marrow MSC marker antigens CD29, CD44, CD73, CD90, and CD105 and were able to differentiate along the adipogenic, chondrogenic, and osteogenic pathways. nm-MSC produced a set of inflammatory cytokines, expressed chemokine receptors, and were responsive to stimulation with cytokines, chemokines, and TLR4 ligand LPS. Thus, these cells may serve as an alternative adult stromal cell resource for regenerative tissue repair and may represent important regulators of local mucosal immunity.

Endovascular treatment proves to be effective for prolonged and life-threatening epistaxis. It is easily repeatable if the first procedure is not successful and offers a good risk-benefit profile.

Background MicroRNAs (miRNA) recently evolved as potential cancer biomarkers. Therefore, the aim of the present study was to evaluate the prognostic impact of eight miRNAs connected to oral squamous cell carcinoma (OSCC). Method Expression levels of hsa‐mir‐21‐5p, hsa‐mir‐29b‐3p, hsa‐mir‐31‐5p, hsa‐mir‐99a‐5p, hsa‐mir‐99b‐3p, hsa‐mir‐100‐5p, hsa‐mir‐143‐3p and hsa‐mir‐155‐5p were analyzed in tumor tissue (n = 36) and healthy oral mucosal tissue (n = 17) and correlated with clinical variables. Results of the study cohort were validated in an OSCC cohort of The Cancer Genome Atlas. Results Increased hsa‐mir‐99b‐3p expression level showed a tendency toward advanced tumor stages, and high levels of hsa‐mir‐100‐5p expression were associated with extracapsular extension. While a high expression level of hsa‐mir‐99b‐3p was associated with better survival, a high expression level of hsa‐mir‐100‐5p was correlated with a poorer survival in the study cohort. Conclusion Our results indicate that hsa‐mir‐99b‐3p and hsa‐mir‐100‐5p may serve as novel prognostic biomarkers in OSCC.

Mesenchymal stem/stromal cells (MSCs) are emerging as important regulators of innate and adaptive immunity. In this context, both proinflammatory and anti-inflammatory effects have been described for MSCs. The mechanisms mediating this functional plasticity are poorly characterized at present. Here, we investigated the inflammatory responses of MSCs isolated from human nasal mucosa (nmMSCs) upon challenge with different Toll-like receptor (TLR) ligands. We found that TLR3 ligands induced the strongest release of both proinflammatory cytokines [interleukin (IL)-6 and IL-8] and type I interferon by nmMSCs compared with other TLR ligands. Notably, TLR3 ligands triggered a biphasic cytokine response, with an early peak of type I interferon at 4 h poststimulation and a late release of proinflammatory cytokines at 24 h poststimulation. While the early interferon response was subject to direct stimulation, the proinflammatory response was regulated by factors released during the early cytokine response, which subsequently enhanced sensitivity to TLR3 ligation and amplified the production of IL-6 and IL-8 but not that of interferon. Taken together, our findings indicate that TLR3 ligands polarize the inflammatory phenotype of MSCs in a time-dependent manner. Thus, our study proposes a novel model that helps to explain the strikingly dichotomous functionality of MSCs in inflammation and immunoregulation.