CXCL12-CXCR4 signalling axis in cellular senescence
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ABSTRACT:
PROVIDER: PRJNA1071660 | ENA |
REPOSITORIES: ENA
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Project description:Gene expression analysis in senescent HeLa cells to examine the differential CXCL12-CXCR4 signalling pathways.
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Project description:Analysis of genes in DNA damage induced senescence using BrdU as a DNA damaging agent in HeLa cells which can trigger cellular senescence and identifying effect of CXCL12-CXCR4 axis during this process.
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2020-05-29 | GSE122257 | GEO
Project description:Liver fibrosis, a common pathological feature of chronic liver injury, faces a lack of effective treatment methods. Albiflorin (ALB), a pinane-type monoterpene compound isolated from the medicinal and edible plant Paeonia lactiflora Pall, has demonstrated a variety of biological activities. Here, we reported on the hepatoprotection and potential mechanisms of ALB against liver fibrosis. The results indicated that ALB significantly alleviated the histological damage and collagen deposition caused by CCl4-induced liver fibrosis and led to a reduction in serum levels of ALT, AST, CRE, and BUN. Meanwhile, ALB downregulated the expression of liver fibrosis markers (α-SMA and Collagen I) and decreased inflammatory cytokines (IL-1β, IL-6, TNF-α, and NLRP3). According to RNA-sequencing analysis, the CXCL12/CXCR4 axis was identified as a potential signaling pathway for ALB's action against liver fibrosis. Further mechanistic data revealed that ALB exerts anti-inflammatory and antifibrotic effects through the JAK1/STAT3 and p38 MAPK pathways mediated by the CXCL12/CXCR4 axis. Notably, treatment with AMD3100 diminished the hepatoprotective effect of ALB on CCl4-induced liver fibrosis. Furthermore, we found that the combination of ALB with metformin (MET) exhibited a significant synergistic effect in the treatment of liver fibrosis, with the CXCL12/CXCR4 axis playing a crucial role in this process. Thus, the findings of this study provided theoretical data support and suggested a new possible treatment strategy for liver fibrosis.
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Project description:Pancreatic cancer (PaCa) has one of the poorest prognoses among gastrointestinal cancers because of rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. As the mechanism by which PaCa becomes resistant to radiotherapy is unknown, we established radiation-resistant PaCa cell lines to investigate the factors involved in radiation resistance. We investigated the role of the C-X-C motif chemokine 12 (CXCL12)/ C-X-C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effect of a CXCR4 antagonist on radiation-resistant PaCa cell lines. As confirmed by immunofluorescence staining, RT-qPCR, and Western blotting, the expression of CXCR4 was higher in the radiation-resistant PaCa cell lines than in normal PaCa cell lines. The invasion ability of radiation-resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and co-culture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation-resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. We believe this result will help develop treatments for PaCa.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by infiltration of the bone marrow and other sites with transformed T cell progenitors. The role of tissue microenvironments in the pathogenesis of T-ALL or any other type of acute leukemia is little understood. In delineating interactions between T-ALL cells and their environment, we initially found that T-ALL cells express high surface levels of the chemokine receptor CXCR4. Intravital imaging of an intact tibia revealed T-ALL cells in direct contact with bone marrow stromal cells producing the CXCR4 ligand, CXCL12. Genetic targeting of CXCR4 on T-ALL cells resulted in a marked reduction of leukemia burden and prolonged disease remission, and disruption of the CXCL12/CXCR4 axis using small molecule inhibitors prevented T-ALL progression in a primary xenograft model. Finally, we were able to show that CXCR4 inhibition significantly decreased expression of Myc and its target genes. Myc expression is a key regulator of T-ALL leukemia initiating cell (LIC) activity, suggesting that CXCR4 inhibition can suppress LIC activity by silencing the Myc response in T-ALL cells. Our data suggest that targeting of CXCL12/CXCR4 signaling could be a powerful new tool for combating T-ALL, a disease with no current targeted therapies. Mouse T-ALL cells were treated ex vivo with Cxcr4 inhibitor AMD3100 or vehicle control. Additionally, mouse T-ALL primary tumors were isolated from control (Cxcr4+/+) or knockout (Cxcr4-/-) animals. Total RNA was extracted from samples using the RNeasy Plus Mini Kit (Qiagen). Samples were then subject to PolyA selection using oligo-dT beads (Life Technologies, Carlsbad, CA) according to the manufacturer's instructions. The resulting RNA samples were then used as input for library construction using the dUTP method as described by Parkhomchuck et al., 2009. RNA libraries were then sequenced on the Illumina HiSeq 2500 using 50bp single-end reads.
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Project description:T cells are essentially involved in safeguarding homeostasis through fighting against the pathogens and malignant cells. T cell immunodeficiency, especially their perturbation in the severe infection, irradiation, chemotherapy, and thymic atrophy in ageing, is detrimental. Therefore, strategies that enhance T cell reconstitution provide considerable benefit and warrant intensive investigation. Here, we constructed a T cells ablation model in Tg(coro1a:DenNTR) zebrafish via administrating a proper volume of metronidazole (MTZ). T cells completely recovered at 6.5 days post treatment (dpt). The nascent regenerated T cells were mainly derived from the immigration of hematopoietic stem/progenitor cells (HSPCs) in the kidney, the functional homologue of BM. cxcr4b, but not ccr9 nor ccr7, was drastically unregulated in the responsive HSPCs. Functional interference of CXCR4 via both genetic and chemical assays yielded limited influence in T lymphopoiesis but notably delayed T cells regeneration by a destroyed HSPCs migration. In contrast, hematopoietic providing cxcr4b in Tg:(coro1a:cxcr4b) accelerates thymus-replenishment of HSPCs. Correspondingly, Cxcl12b, the ligand of Cxcr4, exhibited impressive increment presentation in the thymic epithelial cells of injured animals. Interfering or overacting Cxcl12b in either cxcl12b-/- mutants or Tg(hsp70:cxcl12b) recapitulated the similarly compromised or promoted T cells recovery as that seen in Cxcr4b scenario. Therefore, CXCR4-CXCL12 axis plays a crucial role in promoting thymocyte reconstitution but did not influence T cell development. Our study discloses a special role of CXCR4-CXCL12 signaling in promoting T cells recovery and provides a promising target to mitigate T cell immunodeficiency.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by infiltration of the bone marrow and other sites with transformed T cell progenitors. The role of tissue microenvironments in the pathogenesis of T-ALL or any other type of acute leukemia is little understood. In delineating interactions between T-ALL cells and their environment, we initially found that T-ALL cells express high surface levels of the chemokine receptor CXCR4. Intravital imaging of an intact tibia revealed T-ALL cells in direct contact with bone marrow stromal cells producing the CXCR4 ligand, CXCL12. Genetic targeting of CXCR4 on T-ALL cells resulted in a marked reduction of leukemia burden and prolonged disease remission, and disruption of the CXCL12/CXCR4 axis using small molecule inhibitors prevented T-ALL progression in a primary xenograft model. Finally, we were able to show that CXCR4 inhibition significantly decreased expression of Myc and its target genes. Myc expression is a key regulator of T-ALL leukemia initiating cell (LIC) activity, suggesting that CXCR4 inhibition can suppress LIC activity by silencing the Myc response in T-ALL cells. Our data suggest that targeting of CXCL12/CXCR4 signaling could be a powerful new tool for combating T-ALL, a disease with no current targeted therapies.
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Project description:Niche-associated signals, essential for stem cell maintenance, are spatially confined and exert their influence locally among adjacent cells. Here, we demonstrate that CXCR4+ macrophages are enriched in the mammary ducts and enhance MaSC activity in basal cells in response to the CXCL12 secreted by luminal cells. Conditional knockout of CXCR4 in macrophages or CXCL12 in luminal cells results in similar phenotypes, including impaired branching morphogenesis, decreased stem cell functionality in basal cells, and diminished ductal association of macrophages. CXCL12 stimulation of macrophages triggers an AKT-mediated stabilization of β-catenin, increasing the expression of pro-migratory genes and multiple Wnt ligands. This process enhances the infiltration of macrophages into intraepithelial regions and their ability to support MaSC functions. Our findings elucidate a crucial role of the CXCL12-CXCR4 axis in facilitating a complex interaction among ductal macrophages and two mammary epithelial cell lineages in establishing a supportive environment for MaSCs during mammary gland development.
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Project description:Niche-associated signals, essential for the maintenance of normal stem cells and tumor-initiating cells, are spatially confined and exert their influence locally among adjacent cells. Here, we demonstrate that CXCR4+ macrophages are enriched in the normal mammary ducts and enhance regenerative activity in basal cells in response to the CXCL12 secreted by luminal cells. Conditional knockout of CXCR4 in macrophages or CXCL12 in luminal cells results in similar phenotypes, including impaired branching morphogenesis, decreased regenerative functionality in basal cells, and diminished ductal association of macrophages. CXCL12 stimulation of macrophages triggers an AKT-mediated stabilization of β-catenin, increasing the expression of pro-migratory genes and multiple Wnt ligands, which enhances the infiltration of macrophages and their ability to support stem-like regenerative functions of basal cells. Importantly, the identical CXCR4+ niche macrophages also govern the tumor-initiating activity of breast tumors by promoting the survival and tumor-forming capacity of tumor-initiating cells and inducing early immune evasion through the accumulation of regulatory T cells. Our findings elucidate a crucial role of the CXCL12-CXCR4 axis in facilitating a complex interaction among niche macrophages, two mammary epithelial cell lineages, and other stromal components, thereby establishing a supportive environment for both normal tissue regeneration and mammary tumor initiation.
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