ABSTRACT
Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.
ABSTRACT
Cancer leads to nearly 10 million deaths worldwide per year. The tumour microenvironment (TME) is fundamental for tumour growth and progression. A key component of the TME, the extracellular matrix (ECM) has recently become a focus of interest in cancer research. Dysregulation of ECM synthesis and proteolysis leads to uncontrolled tumour growth and metastasis. Matrix remodelling enzymes, secreted by cancer cells and stromal cells, modify the overall structure and organisation of ECM proteins, therefore influencing biochemical interactions, tissue integrity and tissue turnover. While A Disintegrin and Metalloproteinases (ADAMs)' and matrix metalloproteinases' role in cancer has been deeply investigated, other proteolytic enzymes, like ADAMs with thrombospondin(-like) motifs (ADAMTSs) have been gaining interest due to their roles in modulating cancer cell-ECM interactions and oncogenic signalling pathways. In this review, we will discuss the dysregulation of ADAMTSs in cancer and their roles in regulating cancer development and progression, via ECM remodelling and cell signalling modulation.
ABSTRACT
RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.
Subject(s)
CELF Proteins , Leukemia, Myeloid, Acute , Mechanistic Target of Rapamycin Complex 1 , Nerve Tissue Proteins , RNA-Binding Proteins , Animals , Humans , Mice , CELF Proteins/genetics , CELF Proteins/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mice, Knockout , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/geneticsABSTRACT
Bone marrow macrophages (Mφ) are essential components of the bone marrow niche that regulate the function of hematopoietic stem cells. Poor graft function and inhibition of hematopoietic production can result from abnormal macrophage function; however, the underlying mechanism is unclear. Clodronate liposomes (Clo-Lip) have been used widely to deplete macrophages and study their functions. Our previous results showed that Clod-Lip-mediated clearance of macrophages plays a vital role in regulating hematopoietic reconstruction after allogeneic hematopoietic cell transplantation (HCT). In this study, using an isogenic hematopoietic stem cell transplantation model, we found that Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction by inhibiting the homing process of hematopoietic cells. We also demonstrated that macrophage depletion inhibited the direct supportive effect of macrophages on hematopoietic stem and progenitor cells and erythroid differentiation but promoted the production of megakaryocytic progenitors ex vivo. We showed that macrophages increase CD49e expression on hematopoietic stem and progenitor cells (HSPCs). However, CD49e inhibitors did not support the proliferative effect of macrophages on hematopoietic cells. In contrast, macrophage E-selectin/ intercellular cell adhesion molecule-1 (ICAM-1) may be involved in directly regulating HSPCs. In conclusion, macrophage depletion with Clo-Lip partially disrupts bone marrow hematopoiesis after HCT by impeding donor cell homing and macrophage-HSPCs interactions.
Subject(s)
Hematopoietic Stem Cell Transplantation , Integrin alpha5 , Integrin alpha5/metabolism , Hematopoietic Stem Cells , Hematopoietic Stem Cell Transplantation/methods , Hematopoiesis , Macrophages/metabolismABSTRACT
Transforming growth factor ß1 (TGFB1) refers to a pleiotropic cytokine exerting contrasting roles in hematopoietic stem cells (HSCs) functions in vitro and in vivo. However, the understanding of hematopoiesis in vivo, when TGFB1 is constantly deactivated, is still unclear, mainly due to significant embryonic lethality and the emergence of a fatal inflammatory condition, which makes doing these investigations challenging. Our study aims to find the specific role of TGFB1 in regulating hematopoiesis in vivo. We engineered mice strains (Vav1 or Mx1 promoter-driven TGFB1 knockout) with conditional knockout of TGFB1 to study its role in hematopoiesis in vivo. In fetal and adult hematopoiesis, TGFB1 KO mice displayed deficiency and decreased self-renewal capacity of HSCs with myeloid-biased differentiation. The results were different from the regulating role of TGFB1 in vitro. Additionally, our results showed that TGFB1 deficiency from fetal hematopoiesis stage caused more severe defect of HSCs than in the adult stage. Mechanistically, our findings identified TGFB1-SOX9-FOS/JUNB/TWIST1 signal axis as an essential regulating pathway in HSCs homeostasis. Our study may provide a scientific basis for clinical HSC transplantation and expansion.
Subject(s)
Hematopoiesis , Hematopoietic Stem Cells , Transforming Growth Factor beta1 , Animals , Mice , Cell Differentiation , Cytokines/metabolism , Hematopoiesis/genetics , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/physiology , Transforming Growth Factor beta1/metabolismABSTRACT
Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.
ABSTRACT
Bone marrow ablation is routinely performed before hematopoietic stem cell transplantation (HSCT). Hematopoietic stem and progenitor cells (HSPCs) require a stable bone marrow microenvironment to expand and refill the peripheral blood cell pool after ablation. Roundabout guidance receptor 4 (Robo4) is a transmembrane protein exclusive to endothelial cells and is vital in preserving vascular integrity. Hence, the hypothesis is that Robo4 maintains the integrity of bone marrow endothelial cells following radiotherapy. We created an endothelial cell injury model with γ-radiation before Robo4 gene manipulation using lentiviral-mediated RNAi and gene overexpression techniques. We demonstrate that Robo4 and specific mesenchymal proteins (Fibronectin, Vimentin, αSma, and S100A4) are upregulated in endothelial cells exposed to irradiation (IR). We found that Robo4 depletion increases the expression of endoglin (CD105), an auxiliary receptor for the transforming growth factor (TGF-ß) family of proteins, and promotes endothelial-to-mesenchymal transition (End-MT) through activation of both the canonical (Smad) and non-canonical (AKT/NF-κB) signaling pathways to facilitate Snail1 activation and its nuclear translocation. Endothelial Robo4 overexpression stimulates the expression of immunoglobulin-like adhesion molecules (ICAM-1 and VCAM-1) and alleviates irradiation-induced End-MT. Our coculture model showed that transcriptional downregulation of endothelial Robo4 reduces HSPC proliferation and increases HSC quiescence and apoptosis. However, Robo4 overexpression mitigated the damaged endothelium's suppressive effects on HSC proliferation and differentiation. These findings indicate that by controlling End-MT, Robo4 preserves microvascular integrity after radiation preconditioning, protects endothelial function, and lessens the inhibitory effect of damaged endothelium on hematopoietic reconstitution.
Subject(s)
Hematopoietic Stem Cell Transplantation , Receptors, Cell Surface , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Endothelial Cells/metabolism , Endothelium , Hematopoietic Stem Cells/metabolismABSTRACT
In this work, we extracted cellulose from agricultural waste and produced a new straw coating material (ethyl cellulose, EC) through a series of modification operations. The slow-release properties of ethyl cellulose-coated urea (EU) and its absorption and utilization by plants were evaluated. The surface of EU can form a smooth and fine film, and the initial nutrient release rate is only 37.91% that of the uncoated fertilizer. Compared with common urea, the nitrogen of plants cultivated with EU increased by 17.69%, and the leached nitrogen decreased by 61.29%, indicating that EU can reduce nitrogen waste to the greatest extent and continuously supply nutrients to crops. Therefore, the application of EU could be a more practical, environmentally friendly, and sustainable alternative to nitrogen fertilizers.
ABSTRACT
Acute myeloid leukemia (AML) is a major hematopoietic malignancy characterized by the accumulation of immature and abnormally differentiated myeloid cells in bone marrow. Here with in vivo and in vitro models, we demonstrate that the Plant homeodomain finger gene 6 (PHF6) plays an important role in apoptosis and proliferation in myeloid leukemia. Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML in mice. PHF6 depletion inhibited the NF-κB signaling pathways by disrupting the PHF6-p50 complex and partially inhibiting the nuclear translocation of p50 to suppress the expression of BCL2. Treating PHF6 over-expressed myeloid leukemia cells with NF-κB inhibitor (BAY11-7082) significantly increased their apoptosis and decreased their proliferation. Taken together, in contrast to PHF6 as a tumor suppressor in T-ALL as reported, we found that PHF6 also plays a pro-oncogenic role in myeloid leukemia, and thus potentially to be a therapeutic target for treating myeloid leukemia patients.
Subject(s)
Leukemia, Myeloid, Acute , NF-kappa B , Mice , Animals , NF-kappa B/metabolism , Signal Transduction , Leukemia, Myeloid, Acute/pathology , Genes, Tumor Suppressor , Genes, Homeobox , Repressor Proteins/geneticsABSTRACT
Wooden partitions are extensively used as formwork for pouring concrete in wood-concrete composite beams, especially in the restoring of wood structures. However, limited research has been conducted on the shear properties of pitched screw connectors in wood-concrete composite beams with wooden partitions. Therefore, this study investigated the shear performance of pitched screws in wood-concrete composite beams with wooden partitions through push-out tests and finite element analysis. The test results revealed that the failure mode of pitched screws was characterized by the pulling failure of the screws under tensile-shear action. The finite element analysis accurately predicted the failure mode, stress distribution, and load-slip behavior of pitched screws. Furthermore, the effects of the screw embedding angle, wooden partition thickness, concrete strength, and the length-diameter ratio of the screw were investigated through parametric analyses. It was found that when the screw diameter was 12 mm, the shearing capacity of the pitched screws with embedding angles of ±45°, ±60°, and ±75° decreased by 3.9%, 11.9%, and 26.9%, respectively, compared to the screws with an embedding angle of ±30°. The shearing capacity of pitched screws improved with the increase in the concrete strength and length-diameter ratio of the screw. However, the improvement in shearing capacity became less significant as the concrete strength and length-diameter ratio of the screw increased. Moreover, an increase in wooden partition thickness reduced the shearing capacity of pitched screws.
ABSTRACT
The PHD finger protein 6 (PHF6) mutations frequently occurred in hematopoietic malignancies. Although the R274X mutation in PHF6 (PHF6R274X) is one of the most common mutations identified in T cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients, the specific role of PHF6R274X in hematopoiesis remains unexplored. Here, we engineered a knock-in mouse line with conditional expression of Phf6R274X-mutated protein in the hematopoietic system (Phf6R274X mouse). The Phf6R274X mice displayed an enlargement of hematopoietic stem cells (HSCs) compartment and increased proportion of T cells in bone marrow. More Phf6R274X T cells were in activated status than control. Moreover, Phf6R274X mutation led to enhanced self-renewal and biased T cells differentiation of HSCs as assessed by competitive transplantation assays. RNA-sequencing analysis confirmed that Phf6R274X mutation altered the expression of key genes involved in HSC self-renewal and T cell activation. Our study demonstrated that Phf6R274X plays a critical role in fine-tuning T cells and HSC homeostasis.
ABSTRACT
BACKGROUND: Nervonic acid (C24:1∆15, 24:1 ω-9, cis-tetracos-15-enoic acid; NA), a long-chain monounsaturated fatty acid, plays an essential role in prevention of metabolic diseases, and immune regulation, and has anti-inflammatory properties. As a chronic, immune-mediated inflammatory disease, ulcerative colitis (UC) can affect the large intestine. The influences of NA on UC are largely unknown. PURPOSE: The present study aimed to decipher the anti-UC effect of NA in the mouse colitis model. Specifically, we wanted to explore whether NA can regulate the levels of inflammatory factors in RAW264.7 cells and mouse colitis model. METHODS: To address the above issues, the RAW264.7 cell inflammation model was established by lipopolysaccharide (LPS), then the inflammatory factors tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and Interleukin-10 (IL-10) were detected by Enzyme-linked immunosorbent assay (ELISA). The therapeutic effects of NA for UC were evaluated using C57BL/6 mice gavaged dextran sodium sulfate (DSS). Hematoxylin and eosin (H&E) staining, Myeloperoxidase (MPO) kit assay, ELISA, immunofluorescence assay, and LC-MS/MS were used to assess histological changes, MPO levels, inflammatory factors release, expression and distribution of intestinal tight junction (TJ) protein ZO-1, and metabolic pathways, respectively. The levels of proteins involved in the nuclear factor kappa-B (NF-κB) pathway in the UC were investigated by western blotting and RT-qPCR. RESULTS: In vitro experiments verified that NA could reduce inflammatory response and inhibit the activation of key signal pathways associated with inflammation in LPS-induced RAW264.7 cells. Further, results from the mouse colitis model suggested that NA could restore intestinal barrier function and suppress NF-κB signal pathways to ameliorate DSS-induced colitis. In addition, untargeted metabolomics analysis of NA protection against UC found that NA protected mice from colitis by regulating citrate cycle, amino acid metabolism, pyrimidine and purine metabolism. CONCLUSION: These results suggested that NA could ameliorate the secretion of inflammatory factors, suppress the NF-κB signaling pathway, and protect the integrity of colon tissue, thereby having a novel role in prevention or treatment therapy for UC. This work for the first time indicated that NA might be a potential functional food ingredient for preventing and treating inflammatory bowel disease (IBD).
Subject(s)
Colitis, Ulcerative , Colitis , Animals , Mice , Chromatography, Liquid , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colon/pathology , Dextran Sulfate , Disease Models, Animal , Fatty Acids, Monounsaturated/pharmacology , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Mice, Inbred C57BL , NF-kappa B/metabolism , Signal Transduction , Tandem Mass SpectrometryABSTRACT
In this research, experimental research and finite element modelling of glulam-concrete composite (GCC) beams were undertaken to study the flexural properties of composite beams containing timber board interlayers. The experimental results demonstrated that the failure mechanism of the GCC beam was the combination of bend and tensile failure of the glulam beam. The three-dimensional non linear finite element model was confirmed by comparing the load-deflection curve and load-interface slip curve with the experimental results. Parametric analyses were completed to explore the impacts of the glulam beam height, shear connector spacing, timber board interlayer thickness and concrete slab thickness on the flexural properties of composite beams. The numerical outcomes revealed that with an increase of glulam beam height, the bending bearing capacity and flexural stiffness of the composite beams were significantly improved. The timber boards were placed on top of the glulam members and used as the formwork for concrete slab casting. In addition, the flexural properties of composite beams were improved with the increase of the timber board thickness. With the elevation of the shear connector spacing, the ultimate bearing capacity and bending stiffness of composite beams were decreased. The bending bearing capacity and flexural rigidity of the GCC beams were ameliorated with the increase of concrete slab thickness.
ABSTRACT
Liposomes are the most widely used nanocarrier platform for the delivery of therapeutic and diagnostic agents, and a number of liposomes have been approved for use in clinical practice. After systemic administration, most liposomes are cleared by macrophages in the mononuclear phagocyte system, such as the liver and bone marrow (BM). However, the majority of studies have focused on investigating the therapeutic results of liposomal drugs, and too few studies have evaluated the potential side effects of empty nanocarriers on the functions of macrophages in the mononuclear phagocyte system. Here, we evaluate the potential effects of empty liposomes on the functions of BM niche macrophages. Following liposome administration, we observed lipid droplet (LD) accumulation in cultured primary macrophages and BM niche macrophages. We found that these LD-accumulating macrophages, similar to foam cells, exhibited increased expression of inflammatory cytokines, such as IL-1ß and IL-6. We further provided evidence that liposome deposition and degradation induced LD biogenesis on the endoplasmic reticulum membrane and subsequently disturbed endoplasmic reticulum homeostasis and activated the inositol-requiring transmembrane kinase/endoribonuclease 1α/NF-κB signaling pathway, which is responsible for the inflammatory activation of macrophages after liposome engulfment. Finally, we also showed the side effects of dysfunctional BM niche macrophages on hematopoiesis in mice, such as the promotion of myeloid-biased output and impairment of erythropoiesis. This study not only draws attention to the safety of liposomal drugs in clinical practice but also provides new directions for the design of lipid-based drug carriers in preclinical studies.
Subject(s)
Bone Marrow , Liposomes , Mice , Animals , Liposomes/metabolism , NF-kappa B/metabolism , Interleukin-6/metabolism , Macrophages/metabolism , Hematopoiesis , Drug Carriers/metabolism , Drug Carriers/pharmacology , Cytokines/metabolism , Endoribonucleases , Inositol/metabolism , LipidsABSTRACT
Ordinary biochar has the disadvantages of low strength and fragility, and it is difficult to be separated in heavy metal contaminated soil after the remediation process. In order to realize the recovery and reuse of biochar, we prepared silicate composite biochar (SCB) and the magnetic silicate composite biochar (MSCB) with consistent particle size and high hardness. As well as the passivation effect and mechanism of the material on cadmium in soil was also investigated. The results showed that: (1) The MSCB had good hydraulic properties and strong magnetism, which can be quickly separated from the soil under the condition of external magnetic field. (2) The MSCB can remove 30.32%-38.80% of cadmium in the soil after three times of "application-separation-desorption-reuse", as well as the SCB can remove 28.30%-35.78% of cadmium from the soil. (3) The recovered SCB and MSCB had a certain mass loss, the mass loss rate of the biochar particles was in the range of 2.65%-4.90% after each time of recycling. (4) MSCB mainly immobilized cadmium ions through pore interception, complexation of oxygen-containin/iron-containin functional group and precipitation reaction.
Subject(s)
Cadmium , Soil Pollutants , Adsorption , Charcoal , Silicates , Soil , Soil Pollutants/analysisABSTRACT
Rapamycin, also known as sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), is a regulatory kinase responsible for multiple signal transduction pathways. Although rapamycin has been widely used in treating various hematologic diseases, the effects of rapamycin are still not fully understood. Here we found that both oral and intraperitoneal administration of rapamycin led to the expansion of myeloid lineage, while intraperitoneal administration of rapamycin impaired granulocyte differentiation in mice. Rapamycin induced bone marrow mesenchymal stem cells to produce more G-CSF in vitro and in vivo, and promoted the myeloid cells expansion. Our results thus demonstrated that intraperitoneal administration of rapamycin might promote the expansion of myeloid lineage while impair myeloid cell differentiation in vivo.
ABSTRACT
As the slow-release fertilizer, oil-coated fertilizer can not only slow down the nutrients loss, but also have outstanding advantages in controlling the nutrients release. Based on a large number of literature, this paper systematically investigated the composition, classification, properties and preparation of oil-coated fertilizers, summarizes the challenges faced by the oil-coated fertilizers and offers a few suggestions for the future research. Through literature research, some important conclusions were found: (1) Oil-coated fertilizers are generally composed of core fertilizers and coated oil layers, and some have active interlayers. (2) Vegetable oils has the characteristics of easy degradation, water resistance and impact resistance, and the nutrient release curves of vegetable oil coated fertilizer in soil and still water are "S" type. (3) The modified polyurethane exhibits good compatibility with urea, and can control the release of N in a long period of time, which is 30 days longer than the N release life of ordinary polyurethane-coated fertilizers. (4) Oil-coated fertilizers can reduce the loss of N by slowing down the hydrolysis rate of urea and the nitrification from NH4+ to NO3-, which reduces the N2O release by 70-80% compared to the uncoated fertilizers. Moreover, the paper also proposes a new preparation method of oil-coated material.
Subject(s)
Fertilizers , Polyurethanes , Fertilizers/analysis , Nitrogen , Urea , WaterABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 inhibitor (tofacitinib) and a MDM2 inhibitor (idasanutlin) reduces the Phf6 KO and JAK3M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.
Subject(s)
Cell Transformation, Neoplastic/pathology , Janus Kinase 3/metabolism , Mutation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Repressor Proteins/physiology , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Humans , Janus Kinase 3/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Signal TransductionABSTRACT
Myeloid cells have been identified as hematopoietic stem cell (HSC)-regulating cells. However, the mechanisms by which myeloid cells regulate the function of HSCs are not fully defined. Our previous study indicated that the HSCs are over-expanded in Vav1-Cre;Rheb1 f l/fl mice. Here, using in vivo and in vitro models, we found that Rheb1-deficient neutrophils remodeled the bone marrow environment and induced expansion of HSCs in vivo. Further studies showed that loss of Rheb1 impaired neutrophils' ability to secrete IL-6, led mesenchymal stem cells (MSCs) to produce more SCF, and promote HSC proliferation. We further found that IL-6 suppressed SCF mRNA expression in human MSCs. Interesting, the high level of IL-6 was also related with poor survival of chronic myeloid leukemia (CML) patients, and higher expression of IL-6 in CML cells is associated with the lower expression of SCF in MSCs in patients. Our studies suggested that blocking IL-6 signaling pathway might stimulate MSCs to secrete more SCF, and to support hematopoietic stem/progenitor cells proliferation.
ABSTRACT
Magnesium (Mg) and its alloys have attached more and more attention because of their potential as a new type of biodegradable metal materials. In this work, AZ31/ZrO2 nanocomposites with good uniformity were prepared successfully by friction stir processing (FSP). The scanning electron microscope (SEM) and transmission electron microscope (TEM) were used to characterize the microstructure of the composites. The mechanical properties, electrochemical corrosion properties and biological properties were evaluated. In addition, the effect of reinforced particles (ZrO2) on the microstructure and properties of the composite was studied comparing with FSP AZ31 Mg alloy. The results show that compared with the base metal (BM), the AZ31/ZrO2 composite material achieves homogenization, densification, and grain refinement after FSP. The combination of dynamic recrystallization and ZrO2 particles leads to grain refinement of Mg alloy, and the average grain size of AZ31/ZrO2 composites is 3.2 µm. After FSP, the c-axis of grain is deflected under the compression stress of shoulder and the shear stress of pin. The ultimate tensile strength (UTS) and yield strength (YS) of BM were 283 and 137 MPa, respectively, the UTS and YS of AZ31/ZrO2 composites were 427 and 217 MPa, respectively. The grain refinement and Orowan strengthening are the major strengthening mechanisms. Moreover, the corrosion resistance in simulated body fluid of Mg alloy is improved by grain refinement and the barrier effect of ZrO2.