Biology subjects

Morell, M.

Publications and source records attributed to Morell, M..

3 recordsLinked to original sources

bioRxiv2025

Assessing the Molecular Validity of Spontaneous Lupus Mouse Models and Its Implication for Human Studies

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by a loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Animal models have advanced our understanding of SLEs molecular basis, but the FDAs recent elimination of animal testing requirements for drug approval has raised concerns about their validity, prompting a reevaluation of their role in basic research, especially for heterogeneous diseases like SLE. MethodsFour different spontaneous SLE mouse models were studied: MRLlpr/lpr, NZB/W, BXSB.Yaa, and Tlr7.Tg6. Transcriptome sequencing from blood, spleen, and kidney, flow cytometry from the spleen, and cytokines and autoantibody measurement in plasma were performed at four time points. Similar molecular data from human SLE patients was used for the integration. ResultsThe study identified specific molecular pathways driving the phenotype in each mouse model and established optimal time points for future experimental designs. By comparing these pathways to human SLE, the most similar ones and their relationship with disease activity were identified, providing crucial insight into translational relevance. Importantly, disease severity across models was linked to the extent and timing of molecular dysregulations. As expected, MRLlpr/lpr showed the most aggressive phenotype with early immune activation and apoptosis dysregulation, while Tlr7.Tg6 presented late-onset signatures associated with interferon and inflammation. Shared molecular features with human SLE included interferon responses, T and B cell depletion, and neutrophil activation. Integration analysis revealed distinct yet overlapping immune pathways between models and species, with some signatures such as age-associated B cells and double-negative memory T cells being model-specific but potentially relevant to early disease processes. ConclusionsThese findings build a valuable framework for future SLE research, reinforcing the utility of mouse models in studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse data with human transcriptomes highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.

immunology↗

bioRxiv2019

LINE-1 retrotransposition impacts the genome of human pre implantation embryos and extraembryonic tissues

Long Interspersed Element 1 (LINE-1/L1) is an abundant retrotransposon that has greatly impacted human genome evolution. LINE-1s are responsible for the generation of millions of insertions in the current human population. The characterization of sporadic cases of mosaic individuals carrying pathogenic L1-insertions, suggest that heritable insertions occurs during early embryogenesis. However, the timing and potential genomic impact of LINE-1 mobilization during early embryogenesis is unknown. Here, we demonstrate that inner cell mass of human pre-implantation embryos support the expression and retrotransposition of LINE -1s. Additionally, we show that LINE-1s are expressed in trophectoderm cells of embryos, and identify placenta-restricted endogenous LINE-1 insertions in newborns. Using human embryonic stem cells as a model of post-implantation epiblast cells, we demonstrate ongoing LINE-1 retrotransposition, which can impact expression of targeted genes. Our data demonstrate that LINE-1 retrotransposition starts very shortly after fertilization and may represent a previously underappreciated factor in human biology and disease.

genomics↗

bioRxiv2017

Correction of autoimmune IL2RA mutations in primary human T cells using non-viral genome targeting

Human T cells are central to physiological immune homeostasis, which protects us from pathogens without collateral autoimmune inflammation. They are also the main effectors in most current cancer immunotherapy strategies1. Several decades of work have aimed to genetically reprogram T cells for therapeutic purposes2-5, but as human T cells are resistant to most standard methods of large DNA insertion these approaches have relied on recombinant viral vectors, which do not target transgenes to specific genomic sites6, 7. In addition, the need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells through homology-directed repair (HDR), but to date in human T cells this still requires viral transduction8, 9. Here, we developed a non-viral, CRISPR-Cas9 genome targeting system that permits the rapid and efficient insertion of individual or multiplexed large (>1 kilobase) DNA sequences at specific sites in the genomes of primary human T cells while preserving cell viability and function. We successfully tested the potential therapeutic use of this approach in two settings. First, we corrected a pathogenic IL2RA mutation in primary T cells from multiple family members with monogenic autoimmune disease and demonstrated enhanced signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR redirecting T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized the tumour antigen, with concomitant cytokine release and tumour cell killing. Taken together, these studies provide preclinical evidence that non-viral genome targeting will enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

genetics↗