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Embryo models offer opportunities for understanding development and advancing medicine but rely on intricate procedures with limitations in efficiency and developmental fidelity. Here, we employ a small-molecule-only approach to induce mouse embryonic stem cells into 8- to 16-cell-like embryo founder cells, enabling the generation of a complete embryo model. These founder cells specify all blastocyst lineages, both embryonic and extraembryonic, in vivo and in vitro. The embryo model made only from embryo founder cells faithfully recapitulates development through organogenesis. During gastrulation, it forms a primitive streak via epithelial-to-mesenchymal transition, generates the three germ layers, and develops an ectoplacental cone. The model proceeds to form 6-14 somite pairs, fore-/mid-/hindbrain, a looping heart tube, optic buds, allantois, tail bud, migrating primordial germ cells, and well-defined gut. Altogether, our system using embryo founder cells enables a direct, rapid, efficient, and accurate in vitro model of embryogenesis.
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http://dx.doi.org/10.1016/j.cell.2025.07.018 | DOI Listing |
Front Immunol
September 2025
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Background: Multiplex gene-edited chimeric antigen receptor (CAR) T-cell therapies face significant challenges, including potential oncogenic risks associated with double-strand DNA breaks. Targeted microRNAs (miRNAs) may provide a safer, functional, and tunable alternative for gene silencing without the need for DNA editing.
Methods: As a proof of concept for multiplex gene silencing, we employed an optimized miRNA backbone and gene architecture to silence T-cell receptor (TCR) and major histocompatibility complex class I (MHC-I) in mesothelin-directed CAR (M5CAR) T cells.
Cell
September 2025
Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Baden-Württemberg 69117, Germany; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Metabolomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Baden-Württe
Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses.
View Article and Find Full Text PDFESMO Open
September 2025
Aminex Therapeutics, Inc., Kenmore, USA. Electronic address:
Background: Dysregulation of polyamine synthesis has been observed in various cancer cell types. A novel approach to depriving cancer cells of polyamines involves the use of difluoromethylornithine (DFMO) to block polyamine biosynthesis in combination with AMXT 1501, a potent inhibitor of polyamine transport. Preclinical mouse tumor models showed that the combination of AMXT 1501 plus DFMO had strong antitumor activity, together with evidence of a stimulated immune response against tumors.
View Article and Find Full Text PDFJ Neurochem
September 2025
Toxicology Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Polar metabolic profiling, as well as bioenergetic assays, were used to characterize microglial responses to lipopolysaccharide, which induces a pro-inflammatory state, and interleukin-4, which is associated with an anti-inflammatory phenotype. BV2 microglial cells and primary microglia were used for these investigations. Results revealed that lipopolysaccharide-treated microglia exhibited an increased aerobic glycolytic activity measured by extracellular flux analysis, accompanied by increased levels of endogenous itaconate, a metabolite produced by the IRG1 enzyme.
View Article and Find Full Text PDFNat Aging
September 2025
IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage.
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