A new chapter: hematopoietic stem cells are direct players in immunity

Several lines of evidence support the hypothesis that hematopoietic stem cells (HSCs) directly interact with the immune system and have potential for immune privilege. Although the microenvironment or niche provides protection for HSCs from immune attack, HSCs are also capable of interacting with the immune system as signal "providers" and signal "receivers". On the one hand, HSCs display surface immune inhibitory molecules to evade the attack from the innate and adaptive immune systems; on the other hand, HSCs are capable of directly sensing the signals from the immune system through their surface receptors. Thus, HSCs are important direct players in the immune system

Ex Vivo Expanded Hematopoietic Stem Cells Overcome the MHC Barrier in Allogeneic Transplantation

SummaryThe lack of understanding of the interplay between hematopoietic stem cells (HSCs) and the immune system has severely hampered the stem cell research and practice of transplantation. Major problems for allogeneic transplantation include low levels of donor engraftment and high risks of graft-versus-host disease (GVHD). Transplantation of purified allogeneic HSCs diminishes the risk of GVHD but results in decreased engraftment. Here we show that ex vivo expanded mouse HSCs efficiently overcame the major histocompatibility complex barrier and repopulated allogeneic-recipient mice. An 8-day expansion culture led to a 40-fold increase of the allograft ability of HSCs. Both increased numbers of HSCs and culture-induced elevation of expression of the immune inhibitor CD274 (B7-H1 or PD-L1) on the surface of HSCs contributed to the enhancement. Our study indicates the great potential of utilizing ex vivo expanded HSCs for allogeneic transplantation and suggests that the immune privilege of HSCs can be modulated

Experimental study of aerospace solid propellant fracturing in simulated coal sample

Coal reservoirs with high gas content and low permeability seriously restrict the efficient production of coal and coalbed methane. It is necessary to fracture and enhance the permeability of coal reservoirs. Aerospace solid propellant deflagration can generate a large amount of high-energy gas to impact coal reservoirs, which can achieve the purpose of fracturing and enhancing permeability of coal reservoirs. To study the characteristics of aerospace solid propellant for fracturing coal, a solid propellant for fracturing and permeability enhancement of coal reservoir was firstly researched and developed based on the formula of civil aerospace solid propellant, was, and its performance, sensitivity, pressure and temperature resistance were tested. The aerospace solid propellant fracturing test was then carried out using simulated coal samples, and the borehole wall pressure and strain within the simulated coal samples were monitored during the test. Finally, the destruction characteristics of simulated coal samples were analyzed according to the test results. The results shown that the aerospace solid propellant had good performance, with the advantages of waterproof, pressure resistant, and no CO generation, which could be adapted to the underground environment of coal mine. During the test, the time curve of the borehole wall pressure shown the stages of rapid pressure rise, slow pressure rise, and nonlinear pressure drop, in which the rise time of the borehole wall pressure was about 18 ms. The peak pressure in the borehole was low and unevenly distributed. The peak pressure in the middle of the borehole was 118.1 MPa, and the peak pressure at the bottom of the borehole was 85.3 MPa. Stress wave generated in simulated coal sample during aerospace solid propellant fracturing was composed of compressive and tensile phases with low intensity, long duration and slow decay with distance. The aerospace solid propellant fracturing technology was dominated by the quasi-static action of high-energy gas, with high utilization of stress wave energy. The research results provide a reference for the application of aerospace solid propellant in the field of coalbed methane mining

Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow

How stem cells interact with the microenvironment to regulate their cell fates and metabolism is largely unknown. Here we demonstrated that the deletion of the cytoskeleton-modulating protein profilin 1 (pfn1) in hematopoietic stem cell (HSCs) led to bone marrow failure, loss of quiescence, and mobilization and apoptosis of HSCs in vivo. A switch from glycolysis to mitochondrial respiration with increased reactive oxygen species (ROS) level was also observed in HSCs on pfn1 deletion. Importantly, treatment of pfn1-deficient mice with the antioxidant N-acetyl-l-cysteine reversed the ROS level and loss of quiescence of HSCs, suggesting that the metabolism is mechanistically linked to the cell cycle quiescence of stem cells. The actin-binding and proline-binding activities of pfn1 are required for its function in HSCs. Our study provided evidence that pfn1 at least partially acts through the axis of pfn1/Gα13/EGR1 to regulate stem cell retention and metabolism in the bone marrow

Components of the Hematopoietic Compartments in Tumor Stroma and Tumor-Bearing Mice

Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment

Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair

The nonhomologous end-joining (NHEJ) pathway is essential for radioresistance and lymphocyte-specific V(D)J (variable [diversity] joining) recombination. Defects in NHEJ also impair hematopoietic stem cell (HSC) activity with age but do not affect the initial establishment of HSC reserves. In this paper, we report that, in contrast to deoxyribonucleic acid (DNA)–dependent protein kinase catalytic subunit (DNA-PKcs)–null mice, knockin mice with the DNA-PKcs(3A/3A) allele, which codes for three alanine substitutions at the mouse Thr2605 phosphorylation cluster, die prematurely because of congenital bone marrow failure. Impaired proliferation of DNA-PKcs(3A/3A) HSCs is caused by excessive DNA damage and p53-dependent apoptosis. In addition, increased apoptosis in the intestinal crypt and epidermal hyperpigmentation indicate the presence of elevated genotoxic stress and p53 activation. Analysis of embryonic fibroblasts further reveals that DNA-PKcs(3A/3A) cells are hypersensitive to DNA cross-linking agents and are defective in both homologous recombination and the Fanconi anemia DNA damage response pathways. We conclude that phosphorylation of DNA-PKcs is essential for the normal activation of multiple DNA repair pathways, which in turn is critical for the maintenance of diverse populations of tissue stem cells in mice

Marx for his times. Book Review of: 'Karl Marx : greatness and illusion' by Gareth Stedman Jones

Potential downstream targets for CD274. RNA-sequencing was performed with WT and CD274-null LICs, and the candidate genes related to proliferation and cell cycle was analyzed. (PDF 116 kb

Experimental Study on Strain Penetration Effects in Fixed-End Rotation of RC Beam-Column Connections with High-Strength Reinforcement

The additional fixed-end rotation resulting from the strain penetration of longitudinal reinforcement in a reinforced concrete beam-column connection is a crucial factor for the plastic hinge rotation capacity. When it comes to high-strength reinforcement, the effects of strain penetration on fixed-end rotation become more obvious because of the increase in yield strength. In this study, 42 beam-column connections with high-strength hot rolled ribbed bars were designed and tested under monotonic loading at the beam end. The test results show that the rebar strains gradually decrease from the critical section towards the beam-column connection, thereby proving the existence of strain penetration in the beam-column connection. The slippage of the embedment reinforcement at the beam-column interface and additional fixed-end rotations were obtained from the test results. In addition, a parametric study involving the yield strength and diameter of reinforcement, concrete tensile strength, and embedment length in the beam-column connection was performed to investigate the effects of various parameters on the additional fixed-end rotation. Finally, a new simple and practical calculation model for predicting the additional fixed-end rotation was proposed. The prediction shows good agreement with the experimental results