Regulation of stem and progenitor cell populations is critical in the development, maintenance, and regeneration of tissues. Here, we define a novel mechanism by which a niche-secreted RNase, ...angiogenin (ANG), distinctively alters the functional characteristics of primitive hematopoietic stem/progenitor cells (HSPCs) compared with lineage-committed myeloid-restricted progenitor (MyePro) cells. Specifically, ANG reduces the proliferative capacity of HSPC while simultaneously increasing proliferation of MyePro cells. Mechanistically, ANG induces cell-type-specific RNA-processing events: tRNA-derived stress-induced small RNA (tiRNA) generation in HSPCs and rRNA induction in MyePro cells, leading to respective reduction and increase in protein synthesis. Recombinant ANG protein improves survival of irradiated animals and enhances hematopoietic regeneration of mouse and human HSPCs in transplantation. Thus, ANG plays a non-cell-autonomous role in regulation of hematopoiesis by simultaneously preserving HSPC stemness and promoting MyePro proliferation. These cell-type-specific functions of ANG suggest considerable therapeutic potential.
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•HSPC quiescence and progenitor cell proliferation are simultaneously enhanced by ANG•The dichotomous effect of ANG is related to differential RNA processing•ANG prevents and mitigates radiation-induced bone marrow failure•ANG dramatically improves transplantation efficiency of mouse and human HSPCs
A new niche-specific modulator maintains the stemness of hematopoetic stem/progenitor cells while promoting the proliferation of myeloid progenitor cells through the regulation of RNA metabolism.
Sarcoidosis is a multisystemic inflammatory and granulomatous disease that occurs in almost all populations and affects multiple organs. Meanwhile, its most common manifestation is pulmonary ...sarcoidosis. This study aimed to identify effective biomarkers for the diagnosis and therapy of pulmonary sarcoidosis.
GSE16538 was downloaded from Gene Expression Omnibus, including 6 pulmonary sarcoidosis samples and 6 normal lung samples. Then, differentially expressed genes (DEGs) were identified by limma package in R. After the expression values of the DEGs were extracted, hierarchical clustering analysis was performed for the DEGs using the pheatmap package in R. Subsequently, protein-protein interaction (PPI) pairs among the DEGs were searched by STRING or REACTOME databases, and then PPI networks were visualized by Cytoscape software. Using DAVID and KOBAS, functional and pathway enrichment analyses separately were performed for the DEGs involved in the PPI network.
Total 208 DEGs were identified in pulmonary sarcoidosis samples, including 179 up-regulated genes and 29 down-regulated genes. Hierarchical clustering showed that the DEGs could clearly distinguish the pulmonary sarcoidosis samples from the normal lung samples. In the PPI network constructed by STRING database, CXCL9, STAT1, CCL5, CXCL11 and GBP1 had higher degrees and betweenness values, and could interact with each other. Functional enrichment showed that CXCL9, CXCL11 and CCL5 were enriched in immune response. Moreover, STAT1 was enriched in pathways of chemokine signaling pathway and JAK-STAT signaling pathway.
CXCL9, CXCL11, STAT1, CCL5 and GBP1 might be implicated in pulmonary sarcoidosis through interacting with each other.
•There were 208 differentially expressed genes in pulmonary sarcoidosis samples.•CXCL9, CXCL11 and CCL5 were enriched in immune response and defense response.•CXCL9, CXCL11, STAT1, CCL5 and GBP1 might affect sarcoidosis via interactions.
We previously described the isolation of Tax 18 and Tax 11-6, two paclitaxel-dependent cell lines that assemble low amounts of microtubule polymer and require the drug for cell division. In the ...present studies, fluorescence time-lapse microscopy was used to measure microtubule dynamic instability behavior in these cells. The mutations were found to cause small decreases in microtubule growth and shortening, but the changes seemed unable to explain the defects in microtubule polymer levels or cell division. Moreover, paclitaxel further suppressed microtubule dynamics at low drug concentrations that were insufficient to rescue the mutant phenotype. Wild-type (WT) cells treated with similar low drug concentrations also had highly suppressed microtubules, yet experienced no problems with cell division. Thus, the effects of paclitaxel on microtubule dynamics seemed to be unrelated to cell division in both WT and mutant cell lines. The higher drug concentrations needed to rescue the mutant phenotype instead inhibited the formation of unstable microtubule fragments that appeared at high frequency in the drug-dependent, but not WT, cell lines. Live cell imaging revealed that the fragments were generated by microtubule detachment from centrosomes, a process that was reversed by paclitaxel. We conclude that paclitaxel rescues mutant cell division by inhibiting the detachment of microtubule minus ends from centrosomes rather than by altering plus-end microtubule dynamics.
Cyclin-dependent kinases (CDKs) control the progression of the cell cycle. D-type cyclin (CYCD) is generally believed to form a complex with CDK and control the G1/S transition. In plants, CYCD and ...CDK gene families can be divided into 6 (D1-D7) and 7 (CDKA-CDKG) subclasses, respectively. Different subclasses in the CYCD and CDK families have different numbers, structures and functions. In some heterologous woody plants, the functions of these subclass family members remain unclear. In this study, 43 CYCD and 27 CDK gene family members were identified in the allodiploid Populus tomentosa Carr. Phylogenetic analysis suggested that these CYCDs and CDKs were divided into 6 and 7 subclasses, respectively, which were the same as other species. The analysis of protein properties, gene structure, motifs, domains, cis-acting elements and tissue-specific expression of all members of these CYCDs and CDKs showed that the differences between members of different subclasses varied widely, but members of the same subclass especially in the CDK gene family were very similar. These findings also demonstrated a strong correlation between CYCD and CDK gene family members in response to hormones and specific expression. The collinear analysis of P. tomentosa, Populus trichocarpa and Arabidopsis thaliana showed that the expansion patterns of CYCD and CDK gene families were predominantly whole genome duplications (WGD). The protein interaction prediction results of different subclasses of CYCD and CDKs showed that the interaction between different subclasses of CYCD and CDKs was significantly different. Our previous study found that transgenic PtoCYCD2;1 and PtoCYCD3;3 poplars exhibited opposite phenotypes. Y2H and BIFC results showed that the interaction between PtoCYCD2;1 and PtoCYCD3;3 was significantly different with CDKs. This finding might suggest that the functional differences of different CYCD subclasses in plant growth and development were closely related to the different interactions between CYCD and CDK. Our results provide a good idea and direction for the functional study of CYCD and CDK proteins in woody plants.
Novel red-emitting phosphor Cs2NbOF5:Mn4+ was prepared via the ion exchange method, and its crystal structure, composition and morphology were characterized by powder X-ray diffraction, ...energy-dispersive X-ray spectroscopy and scanning electron microscopy. Meanwhile, the influence of Mn4+ molar ratio on luminescence properties of Cs2NbOF5:Mn4+ has been investigated. The phosphor prepared with the Nb2O5/K2MnF6 molar ratio of 20:1 can emit intense red light under blue light excitation and improve the performances of white light-emitting diode with high color rendering index of 88.4 and low correlated color temperature of 3631 K, so this new red-emitting phosphor could find application on solid-state emitting diode.
Novel red-emitting “oxyfluoride” phosphor Cs2NbOF5:Mn4+ has been successfully synthesized for warm white light-emitting diodes. Display omitted
•New red-emitting phosphor Cs2NbOF5:Mn4+ was synthesized by ion exchange method.•This red phosphor exhibits excellent PL properties.•Cs2NbOF5:Mn4+ can obviously improve the performance of white light-emitting diodes.
Angiogenin (ANG) is a secreted ribonuclease (RNase) with cell-type- and context-specific roles in growth, survival, and regeneration. Although these functions require receptor-mediated endocytosis ...and appropriate subcellular localization, the identity of the cell surface receptor remains undefined. Here, we show that plexin-B2 (PLXNB2) is the functional receptor for ANG in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells. Mechanistically, PLXNB2 mediates intracellular RNA processing that contribute to cell growth, survival, and regenerative capabilities of ANG. Antibodies generated against the ANG-binding site on PLXNB2 restricts ANG activity in vitro and in vivo, resulting in inhibition of established xenograft tumors, ANG-induced neurogenesis and neuroprotection, levels of pro-self-renewal transcripts in hematopoietic and patient-derived leukemic stem and progenitor cells, and reduced progression of leukemia in vivo. PLXNB2 is therefore required for the physiological and pathological functions of ANG and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases.
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•PLXNB2 is the receptor of ANG in physiological and pathological cell types•ANG acts through PLXNB2 to either restrict or promote cell proliferation•PLXNB2 mediates cell-type-specific signaling and RNA-processing activities of ANG•Anti-PLXNB2 therapy is relevant in cancer, neurodegeneration, and stem cells
Plexin-B2 acts as a functional angiogenin receptor in a variety of physiological and pathological contexts, suggesting that the ANG-PLXNB2 axis could be harnessed for therapeutic applications.
Arthritis treatment has been challenging because of low drug exposure to the articular cavity. This study was intended to develop hyaluronic acid (HA)-functionalized bilosomes for targeted delivery ...of tripterine (Tri), an antiphlogistic phytomedicine, to the inflamed joint via ligand-receptor interaction. Tri-loaded bilosomes (Tri-BLs) with cationic lipid (DOTAP) were prepared by a thin film hydration method followed by HA coating to form HA@Tri-BLs. HA@Tri-BLs were then characterized by particle size (PS), entrapment efficiency (EE), and structural morphology. The in vitro drug release, hemocompatibility test and cellular uptake were performed to examine the formulation performances of HA@Tri-BLs. The in vivo pharmacokinetics and antiarthritic efficacy were evaluated in arthritic models, respectively. The obtained HA@Tri-BLs possessed a PS of 118.5 nm around with an EE of 99.56%. HA@Tri-BLs exhibited excellent cellular uptake and targeted delivery efficiency for Tri, which resulted in elongation of circulatory residence time and enhancement of intra-arthritic bioavailability (799.9% relative to Tri solution). The in vivo antiarthritic efficacy of HA@Tri-BLs was also significantly superior to uncoated Tri-BLs that gave rise to obvious inflammation resolution. Our findings suggest that HA-functionalized bilosomes are a promising vehicle for articular delivery of antiphlogistic drugs to potentiate their efficacy.
D-type cyclin (cyclin D, CYCD), combined with cyclin-dependent kinases (CDKs), participates in the regulation of cell cycle G1/S transition and plays an important role in cell division and ...proliferation. CYCD could affect the growth and development of herbaceous plants, such as
, by regulating the cell cycle process. However, its research in wood plants (e.g., poplar) is poor. Phylogenetic analysis showed that in
,
genes expanded to six members, namely
.
genes were amplified based on the CDS region of
genes.
showed the highest expression in the shoot tip, and the higher expression in young leaves among all members. Therefore, this gene was selected for further study. The overexpression of
in plants demonstrated obvious morphological changes during the observation period. The leaves became enlarged and wrinkled, the stems thickened and elongated, and multiple branches were formed by the plants. Anatomical study showed that in addition to promoting the differentiation of cambium tissues and the expansion of stem vessel cells,
facilitated the division of leaf adaxial epidermal cells and palisade tissue cells. Yeast two-hybrid experiment exhibited that 12 PtoCDK proteins could interact with PtoCYCD3;3, of which the strongest interaction strength was PtoCDKE;2, whereas the weakest was PtoCDKG;3. Molecular docking experiments further verified the force strength of PtoCDKE;2 and PtoCDKG;3 with PtoCYCD3;3. In summary, these results indicated that the overexpression of
significantly promoted the vegetative growth of
, and PtoCYCD3;3 may interact with different types of CDK proteins to regulate cell cycle processes.
Cell division plays an indispensable role in leaf morphogenesis, which is regulated via the complexes formed by cyclin and cyclin-dependent kinase (CDK). In this study, gene family analysis, ...exogenous auxin stimulation, RNA-seq and WGCNA analysis were all used to investigate the molecular mechanisms by which cell-cycle-related factors participated in the auxin signaling pathway on leaf morphogenesis. Sixty-three cyclin members and seventeen CDK members in Populus alba were identified and systematically analyzed. During the evolution, WGD was the main reason that resulted in the expansion of cyclin and CDK genes. Firstly, after a short time treating with auxin to matured leaves of seedlings, genes related to cell division including GRF and ARGOS were both upregulated to restart the transition of cells from G1-to-S phase. Secondly, with three days of continuous auxin stimulation to leaves at different developmental stages, leaves area variation, transcriptomes and hormones were analyzed. By PCA, PCoA and WGCNA analyses, the turquoise module was both positively related to leaf development and auxin. Based on the co-expression analysis and Y2H experiment, PoalbCYCD1;4, PoalbCYCD3;3 and PoalbCYCD3;5 were supposed to interact with PoalbCDKA;1, which could be the trigger to promote the G1-to-S phase transition. The ARF transcription factor might play the key role of connecting the auxin signaling pathway and cell division in leaf morphogenesis by affecting CYC–CDK complexes.
Angiogenin is a multifunctional secreted ribonuclease that is upregulated in human cancers and downregulated or mutationally inactivated in neurodegenerative diseases. A role for angiogenin in ...glioblastoma was inferred from the inverse correlation of angiogenin expression with patient survival but had not been experimentally investigated.
Angiogenin knockout mice were generated and the effect of angiogenin deficiency on glioblastoma progression was examined. Angiogenin and plexin-B2 genes were knocked down in glioblastoma cells and the changes in cell proliferation, invasion and vascular association were examined. Monoclonal antibodies of angiogenin and small molecules were used to assess the therapeutic activity of the angiogenin-plexin-B2 pathway in both genetic and xenograft animal models.
Deletion of Ang1 gene prolonged survival of PDGF-induced glioblastoma in mice in the Ink4a/Arf
:Pten
background, accompanied by decreased invasion, vascular association and proliferation. Angiogenin upregulated MMP9 and CD24 leading to enhanced invasion and vascular association. Inhibition of angiogenin or plexin-B2, either by shRNA, monoclonal antibody or small molecule inhibitor, decreases sphere formation of patient-derived glioma stem cells, reduces glioblastoma proliferation and invasion and inhibits glioblastoma growth in both genetic and xenograft animal models.
Angiogenin and its receptor, plexin-B2, are a pair of novel regulators that mediate invasion, vascular association and proliferation of glioblastoma cells. Inhibitors of the angiogenin-plexin-B2 axis have therapeutic potential against glioblastoma.
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