Murine hematopoietic stem cell reconstitution potential is maintained by osteopontin during aging

Abstract In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow and are in part regulated by the bone marrow microenvironment, called the stem cell niche. We have previously identified the bone marrow morphogen osteopontin (OPN), which is abundantly present in the bone marrow extracellular matrix, as a negative regulator of the size of the HSC pool under physiological conditions. Here, we study the impact of OPN on HSC function during aging using an OPN-knockout mouse model. We show that during aging OPN deficiency is associated with an increase in lymphocytes and a decline in erythrocytes in peripheral blood. In a bone marrow transplantation setting, aged OPN-deficient stem cells show reduced reconstitution ability likely due to insufficient differentiation of HSCs into more mature cells. In serial bone marrow transplantation, aged OPN−/− bone marrow cells fail to adequately reconstitute red blood cells and platelets, resulting in severe anemia and thrombocytopenia as well as premature deaths of recipient mice. Thus, OPN has different effects on HSCs in aged and young animals and is particularly important to maintain stem cell function in aging mice

Synthesis of Magnetic Fe₃O₄ Nano Hollow Spheres for Industrial TNT Wastewater Treatment

The aim of the present work was to synthesize magnetite (Fe3O4) nano hollow spheres (NHS) via simple, one-pot, template-free, hydrothermal method. The structural, morphological, and surface analysis of Fe3O4 NHS were studied by scanning electron microscopy (SEM), x-ray diffraction technique (XRD), Fourier transform infrared spectroscopy FTIR and burner-Emmett-teller (BET). The as obtained magnetic (Fe3O4) NHS were used as an adsorbent for treating industrial trinitrotoluene (TNT) wastewater to reduce its Chemical Oxygen Demand (COD) values. Adsorption capacity (Qe) of the NHS obtained is 70 mg/g, confirming the attractive forces present between adsorbent (Fe3O4 NHS) and adsorbate (TNT wastewater). COD value of TNT wastewater was reduced to >92% in 2 h at room temperature. The adsorption capacity of Fe3O4 NHS was observed as a function of time, initial concentration, pH, and temperature. The applied Fe3O4 NHS was recovered for reuse by simply manipulating its magnetic properties with slight shift in pH of the solution. A modest decrease in Qe (5.0–15.1%) was observed after each cycle. The novel Fe3O4 NHS could be an excellent candidate for treating wastewater generated by the intermediate processes during cyclonite, cyclotetramethylene-tetranitramine (HMX), nitroglycerin (NG) production and other various environmental pollutants/species

Polystyrene-Sepiolite Clay Nanocomposites with Enhanced Mechanical and Thermal Properties

Polystyrene (PS)/sepiolite clay nanocomposites were prepared via the melt extrusion technique using vinyl tri-ethoxy silane (VTES) as the compatibilizer and cross-linking agent. Mechanical, thermal, and flame-retardant properties of the newly developed polystyrene-based nanocomposites were determined. Surface morphology was investigated using scanning electron microscopy (SEM), examining the distribution of the filler in various compositions of fabricated composites. Structural analysis of the samples was carried out using the Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) techniques. Thermal stability was determined by thermal gravimetric analysis (TGA), showing a maximum 30.2 wt.% increase in residue by adding sepiolite clay. The results obtained from the dynamic mechanical analyzer (DMA) in terms of the storage modulus, loss modulus and damping factor exhibited better stress transfer rate and effective interfacial adhesion between the filler and the matrix. The higher filler loaded sample showed greater flame retardancy by decreasing the burning rate up to 48%

The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling

Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders

Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T\ua0cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T\ua0cell infiltration in tumors. This therapeutic effect was independent of\ua0tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition,\ua0neutrophils recruited to T\ua0cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T\ua0cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the\ua0HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors