Notch Activation Confers Enhanced Lymphoid Potential in Murine ESC/iPSC-derived HSC and Reconstitutes Adaptive Immunity In Vivo
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71796 | GEO | 2016/12/21
SECONDARY ACCESSION(S): PRJNA292093
REPOSITORIES: GEO
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Project description:Hematopoietic stem cell (HSC) transplantation has the potential to cure blood disorders but is limited by donor availability. Hence innovative approaches to engineer HSC are critically needed. HoxB4 over-expression in mouse embryonic stem cell-derived HSC (ESC-HSC) confers long-term engraftment, yet lacks efficient lymphogenesis. Transcriptome comparison of ESC-HSC versus embryo-derived HSC showed that ESC-HSC are deficient in expression programs activated by Notch. Therefore, we aim to improve ESC-HSC by further providing Notch signals through Notch1 intra-cellular domain transgene activation or by ligand stimulation. Here, we report that Notch-enhanced ESC-HSC (nESC-HSC) confer clonal multipotentiality with robust lymphopoiesis that endows adaptive immunity. Notably, nESC-HSC further evolve to a hybrid cell-type co-expressing gene regulatory networks of hematopoietic stem/progenitor cells and differentiated lineages at single-cell level that accounts for multipotentiality. Our work reveals a proof-of-concept model of HSC engineering by assembling self-renewing factor and lineage-guiding pathway into one product-cell that functionally recapitulate HSC in vivo.
2016-12-21 | GSE71793 | GEO
Project description:Hematopoietic stem cell (HSC) transplantation has the potential to cure blood disorders but is limited by donor availability. Hence innovative approaches to engineer HSC are critically needed. HoxB4 over-expression in mouse embryonic stem cell-derived HSC (ESC-HSC) confers long-term engraftment, yet lacks efficient lymphogenesis. Transcriptome comparison of ESC-HSC versus embryo-derived HSC showed that ESC-HSC are deficient in expression programs activated by Notch. Therefore, we aim to improve ESC-HSC by further providing Notch signals through Notch1 intra-cellular domain transgene activation or by ligand stimulation. Here, we report that Notch-enhanced ESC-HSC (nESC-HSC) confer clonal multipotentiality with robust lymphopoiesis that endows adaptive immunity. Notably, nESC-HSC further evolve to a hybrid cell-type co-expressing gene regulatory networks of hematopoietic stem/progenitor cells and differentiated lineages at single-cell level that accounts for multipotentiality. Our work reveals a proof-of-concept model of HSC engineering by assembling self-renewing factor and lineage-guiding pathway into one product-cell that functionally recapitulate HSC in vivo.
2016-12-21 | GSE71794 | GEO
Project description:Notch Activation Confers Enhanced Lymphoid Potential in Murine ESC/iPSC-derived HSC and Reconstitutes Adaptive Immunity In Vivo
| PRJNA292093 | ENA
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Project description:Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health.
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Project description:The potential uniformity between differentiation and therapeutic potential of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) remains debatable. We studied the gene expression profiles, pathways analysis and the ability to differentiated into neural progenitor cells (NPCs) and motor neurons (MNs) of genetically unmatched integration-free hiPSC versus hESC to highlight possible differences/similarities between them at the molecular level. We also provided the functional information of the neurons derived from the different hESCs and hiPSCs lines using the Neural Muscular Junction (NMJ) Assay. The hiPSC line was generated by transfecting human epidermal fibroblasts (HEF) with episomal DNAs expressing Oct4, Sox2, Klf4, Nanog, L-Myc and shRNA against p53. For the hESCs line, we used the NIH-approved H9 cell line. Using unsupervised clustering both hESCs and hiPSCs were clustered together implying homogeneous genetic states. The genetic profiles of hiPSCs and hESCs were clearly similar but not identical. Collectively, our data indicate close molecular similarities between genetically unmatched hESCs and hiPS in term of gene expression, and signaling pathways. Moreover, both cell types exhibited similar cholinergic motor neurons differentiation potential with marked ability of the differentiated hESCs and hiPSCs-derived MNs to induce contraction of myotubes after 4 days of co-culture.
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Project description:Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (T(H)2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)-IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
| S-EPMC3417123 | biostudies-literature
Project description:It is generally considered that mouse embryonic stem cell (ESC) differentiation into blood cells in vitro recapitulates yolk sac (YS) hematopoiesis. As such, similar to YS-derived B-progenitors, we demonstrate here that ESC-derived B-progenitors differentiate into B-1 and marginal zone B cells, but not B-2 cells in immunodeficient mice after transplantation. ESC-derived B-1 cells were maintained in the recipients for more than 6 months, secreting natural IgM antibodies in vivo. Gene expression profiling displayed a close relationship between ESC- and YS-derived B-1 progenitors. Because there are no hematopoietic stem cells (HSCs) detectable in our ESC differentiation culture, successful long-term engraftment of ESC-derived functional B-1 cells supports the presence of HSC-independent B-1 cell development.
| S-EPMC6409422 | biostudies-literature
Project description:BackgroundAsthma has been considered an immunologic disease mediated by T(H)2 cells and adaptive immunity. However, clinical and experimental observations suggest that additional pathways might regulate asthma, particularly in its nonallergic forms, such as asthma associated with air pollution, stress, obesity, and infection.ObjectivesOur goal was to understand T(H)2 cell-independent conditions that might lead to airway hyperreactivity (AHR), a cardinal feature of asthma.MethodsWe examined a murine model of experimental asthma in which AHR was induced with glycolipid antigens, which activate natural killer T (NKT) cells.ResultsIn this model AHR developed rapidly when mice were treated with NKT cell-activating glycolipid antigens, even in the absence of conventional CD4(+) T cells. The activated NKT cells directly induced alveolar macrophages to produce IL-33, which in turn activated NKT cells, as well as natural helper cells, a newly described non-T, non-B, innate lymphoid cell type, to increase production of IL-13. Surprisingly, this glycolipid-induced AHR pathway required not only IL-13 but also IL-33 and its receptor, ST2, because it was blocked by an anti-ST2 mAb and was greatly reduced in ST2(-/-) mice. When adoptively transferred into IL-13(-/-) mice, both wild-type natural helper cells and NKT cells were sufficient for the development of glycolipid-induced AHR.ConclusionBecause plant pollens, house dust, and some bacteria contain glycolipids that can directly activate NKT cells, these studies suggest that AHR and asthma can fully develop or be greatly enhanced through innate immune mechanisms involving IL-33, natural helper cells, and NKT cells.
| S-EPMC3246069 | biostudies-literature
Project description:Background: Epigenetic processes play an important role in the plant response to adverse environmental conditions. A role for DNA hypomethylation has recently been suggested in the pathogenic interaction between bacteria and plants, yet it remains unclear whether this phenomenon reflects a conserved and general plant immunity response. We therefore investigated the role of DNA methylation in the plant defence against damaging parasitic nematodes. Methods and results: Treatment of roots of rice (monocot plant) and tomato (dicot plant) by a nematode-associated molecular pattern (NAMP) from different parasitic nematodes revealed global DNA hypomethylation using ELISA based quantification, suggesting conservation among plants. Focusing on root-knot induced gall tissue in rice, the causal impact of hypomethylation on immunity was revealed by a significantly reduced plant susceptibility upon 5-Azacitidine treatment. Whole genome bisulfite sequencing revealed that hypomethylation was massively present in the CHH context, while absent for CpG or CHG nucleotide contexts. CHH hypomethylated regions were predominantly associated with gene promoter regions, which was not correlated with activated gene expression at the same time point, but rather showed a delayed effect on transcriptional gene activation. Finally, the relevance of CHH hypomethylation in plant defence was confirmed in rice mutants of the RNA-directed DNA methylation pathway (RdDM) and DDM1, which are known to be steering DNA methylation in CHH context. Conclusions: We demonstrated that DNA hypomethylation confers enhanced defence in rice towards root-parasitic nematodes and is likely to be part of the basal NAMP-triggered immunity response in plants.
2020-07-07 | GSE130064 | GEO