A Xenotransplant Model of Human Brain Tumors in Wild-Type Mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Hoffmann N
PROVIDER: S-EPMC6957874 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundAlzheimer's disease is widely described since the discovery of histopathological lesions in Mrs. Auguste Deter in 1906. However to date, there is no effective treatment to deal with the many cellular and molecular alterations. The complexity is even higher with the growing evidence of involvement of the peripheral blood mononuclear cells (PBMCs). Indeed, monocytes and T cells are shown in the cerebral parenchyma of AD patients, and these cells grafted to the periphery are able to go through the blood-brain barrier (BBB) in transgenic mouse models. It is known that BBB is disrupted at a late stage of AD. Chemokines represent major regulators of the transmigration of PBMCs, but many data were obtained on AD animal models. No data are available on the role of AD BBB in a healthy brain parenchyma. Therefore, the purpose of this study was to analyze the longitudinal chemokine profile expression in a BBB model from AD transgenic mice versus wild-type (WT) mice.MethodsA primary mouse BBB model was used with a luminal compartment either AD or WT and an abluminal compartment WT consisting of astrocytes and microglia. PBMCs were extracted by a ficoll gradient and incubated in the transwell with a direct contact with the luminal side, including the endothelial cells and pericytes. Then, the complete BBB model was incubated during 48 h, before supernatants and cell lysates were collected. Chemokines were quantified by X-MAP® luminex technology.ResultsAbluminal CX3CL1 production increased in 12-month-old AD BBB while CX3CL1 levels decreased in luminal lysates. CCL3 in luminal compartment increased with aging and was significantly different compared to AD BBB at 12 months. In addition, abluminal CCL2 in 12-month-old AD BBB greatly decreased compared to levels in WT BBB. On the contrary, no modification was observed for CCL4, CCL5, and CXCL10.ConclusionThese first findings highlighted the impact of AD luminal compartment on chemokine signature in a healthy brain parenchyma, suggesting new therapeutic or diagnostic approaches.
| S-EPMC6001165 | biostudies-literature
Project description:Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (?-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human ?-Gal A in wild-type (WT) mice, ?-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-?-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of ?-Gal A in tissues and plasma. Single intravenous administration of h-?-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-?-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.
| S-EPMC6451694 | biostudies-literature
Project description:Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating "wildlings." These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.
| S-EPMC7377314 | biostudies-literature
Project description:Energy drinks containing significant quantities of caffeine and sugar are increasingly consumed, particularly by adolescents and young adults. Chronic ingestion of energy drinks may potentially regulate vascular risk factors. This study investigated the effects of chronic ingestion of energy drinks on blood-brain barrier (BBB) integrity and neuroinflammation. Male C57BL/6J mice were maintained on water (control), MotherTM (ED), sugar-free MotherTM (sfED), or Coca ColaTM soft drink (SD) for 13 weeks. The BBB integrity and neuroinflammation were analyzed with semi-quantitative immunofluorescent microscopy. Blood pressure, plasma inflammatory cytokine levels and blood glucose were also considered. Following 13 weeks of intervention, mice treated with ED, sfED, and SD showed significant disruption of BBB. However, marked neuroinflammation was observed only in sfED group mice. The consumption of ED and sfED significantly altered the blood pressure and plasma concentrations of inflammatory cytokines, TNF-a, IL-4, IL-6, and IL-10, and both increased plasma glucose. Correlation analyses showed significant associations between BBB dysfunction and hypotension, hyperglycaemia and cytokine dyshomeostasis. The intake of energy drink, particularly the sugar free formulation, may compromise the integrity of BBB and induce neuroinflammation via hypotension, hyperglycaemia and inflammatory pathways.
| S-EPMC8126614 | biostudies-literature
Project description:Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014-2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 101 pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures.
| S-EPMC8310124 | biostudies-literature
Project description:In order to help determine the genes involved in resistance of breast cancer to endocrine therapy, we compared global gene expression profiles of tamoxifen-resistant MCF-7 WT xenograft tumors with E2-supplemented tumors. Experiment Overall Design: MCF7 xenografts were established in ovariectomized five to six week-old nu/nu athymic nude mice supplemented with 0.25 mg 21 day release estrogen pellets by inoculating subcutaneously (s.c.) 5E-6 cells. When tumors reached the size of 150-200 mm3 (3-5 weeks), the animals were randomly allocated to continued estrogen (E2) and estrogen withdrawal plus tamoxifen citrate. Tumors were harvested for molecular studies when they became resistant to treatment and reached the size of 1000 mm3 (n=7).
| S-ECPF-GEOD-7327 | biostudies-other
Project description: Not available
| S-EPMC10433134 | biostudies-literature
Project description:Microglia in the brain and macrophages in peripheral organs are cell types responsible for immune response to challenges. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme of the tryptophan pathway that is expressed in the brain. The higher activity of IDO1 in response to immune challenge has been implicated in behavioral disorders. The impact of IDO1 depletion on the microglia transcriptome has not been studied. An investigation of the transcript networks in the brain microglia from IDO1-knockout (IDO1-KO) mice was undertaken, relative to peripheral macrophages and to wild-type (WT) mice under unchallenged conditions. Over 105 transcript isoforms were differentially expressed between WT and IDO1-KO within cell type. Within microglia, Saa3 and Irg1 were over-expressed in IDO1-KO relative to WT. Within macrophages, Csf3 and Sele were over-expressed in IDO1-KO relative to WT. Among the genes differentially expressed between strains, enriched biological processes included ion homeostasis and ensheathment of neurons within microglia, and cytokine and chemokine expression within macrophages. Over 11,110 transcript isoforms were differentially expressed between microglia and macrophages and of these, over 10,800 transcripts overlapped between strains. Enriched biological processes among the genes over- and under-expressed in microglia relative to macrophages included cell adhesion and apoptosis, respectively. Detected only in microglia or macrophages were 421 and 43 transcript isoforms, respectively. Alternative splicing between cell types based on differential transcript isoform abundance was detected in 210 genes including Phf11d, H2afy, and Abr. Across strains, networks depicted a predominance of genes under-expressed in microglia relative to macrophages that may be a precursor for the different response of both cell types to challenges. The detected transcriptome differences enhance the understanding of the role of IDO1 in the microglia transcriptome under unchallenged conditions.
| S-EPMC4912085 | biostudies-literature
Project description:As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, Nf1 murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline NF1 mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.
| S-EPMC7212913 | biostudies-literature
Project description:Animal models are vital to the study of transfusion and development of new blood products. Post-transfusion recovery of human blood components can be studied in mice, however, there is a need to identify strains that can best tolerate xenogeneic transfusions, as well as to optimize such protocols. Specifically, the importance of using immunodeficient mice, such as NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, to study human transfusion has been questioned. In this study, strains of wild-type and NSG mice were compared as hosts for human transfusions with outcomes quantified by flow cytometric analyses of CD235a+ erythrocytes, CD45+ leukocytes, and CD41+CD42b+ platelets. Complete blood counts were evaluated as well as serum cytokines by multiplexing methods. Circulating human blood cells were maintained better in NSG than in wild-type mice. Lethargy and hemoglobinuria were observed in the first hours in wild-type mice along with increased pro-inflammatory cytokines/chemokines such as monocyte chemoattractant protein-1, tumor necrosis factor α, keratinocyte-derived chemokine (KC or CXCL1), and interleukin-6, whereas NSG mice were less severely affected. Whole blood transfusion resulted in rapid sequestration and then release of human cells back into the circulation within several hours. This rebound effect diminished when only erythrocytes were transfused. Nonetheless, human erythrocytes were found in excess of mouse erythrocytes in the liver and lungs and had a shorter half-life in circulation. Variables affecting the outcomes of transfused erythrocytes were cell dose and mouse weight; recipient sex did not affect outcomes. The sensitivity and utility of this xenogeneic model were shown by measuring the effects of erythrocyte damage due to exposure to the oxidizer diamide on post-transfusion recovery. Overall, immunodeficient mice are superior models for xenotransfusion as they maintain improved post-transfusion recovery with negligible immune-associated side effects.
| S-EPMC7394438 | biostudies-literature