Nature Cell Biology最新文献

Research in the mouse indicates that all three pancreas epithelial compartments derive from a single and transient progenitor. Now, a study of the human fetal pancreas identifies a leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5⁺) cell population capable of generating all exocrine and endocrine pancreatic lineages.

Andersson-Rolf et al. derived pancreas organoid lines from gestational weeks 8–17 human pancreatic samples. They observed that lines derived from 15–16-gestational-week samples could generate all three pancreatic lineages, namely acinar-, ductal- and endocrine-lineage cells, as well as expand in culture for over two years. Further experiments, including single-cell transcriptomics, RNA velocity and reporter organoid analyses, identified a population of LGR5⁺ cells in human fetal pancreas tissue and in the organoids. Finally, the researchers showed that pancreatic organoids derived from single LGR5⁺ cells were capable of long-term expansion in vitro and generating the three pancreas epithelial cell lineages, as shown also with transplantation of the organoids into mice.

Gene therapy strategies against Diamond-Blackfan anaemia (DBA) have been hampered by the multiple and heterogeneous causative mutations. A study now shows that modulating GATA1 expression is sufficient to tackle the erythroid maturation arrest in DBA models and patient-derived samples.

Voit et al. first identified endogenous regulatory elements (hG1E-GATA1) guiding erythroid-restricted expression of GATA1 in human haematopoietic cells and then showed that hG1E-GATA1 treatment supports erythropoiesis without affecting haematopoietic stem cell function. Subsequently, they demonstrated that hG1E-GATA1 treatment can improve erythroid output in DBA models, as well as in samples from individuals with DBA, including in vivo, as suggested by xenotransplantation assays. Using single-cell transcriptomics, Voit et al. found that hG1E-GATA1 treatment reverses the DBA-characteristic erythroid transcriptional dysregulation. Finally, integration site analysis revealed that the genomic integration profile of hG1E-GATA1 lentiviral vector is comparable to that of other lentiviral gene therapy products, thus supporting the presented approach as a good candidate to test in the clinic.

Early assessment of treatment efficacy can be invaluable in cases of aggressive tumours, such as glioblastoma. Logun et al. generated glioblastoma organoids (GBOs) from patients participating in a chimeric antigen receptor (CAR) T cell clinical trial to monitor the therapeutic response in real time.

The authors obtained tumour specimens from six patients with glioblastoma enrolled in a phase 1 CAR T cell clinical trial. Using a previously reported protocol, they developed GBOs from the specimens in 2–3 weeks, which they then co-cultured with patient-matched CAR T cells. These GBOs displayed tumour cytolysis. After 6 days of co-culturing, Logun et al. collected the GBOs and analysed them for target antigen expression, which they found was reduced. Finally, they analysed CAR T cell–GBO co-culture media and found a continuous release of cytokines by the activated T cells, which presented similar temporal dynamics with the in vivo kinetics of CAR T cell activation in patients.

Biomolecular condensate formation requires multivalent interactions and rapid turnover. Stress granules are condensates formed through RNA–protein interactions under stress, requiring the RNA-binding protein G3BP. Parker et al. show that G3BP1 is an RNA condenser and promotes initial RNA–RNA interactions but is dispensable for stability; instead, stability requires RNA–RNA interactions.

The authors tested in vitro models of RNA granules and found that granules persisted despite proteinase digestion of G3BP1 only after sufficient ageing, or time, to form RNA–RNA interactions. RNA denaturation solubilized, whereas crosslinking stabilized, granules. The authors also suggest that RNA–RNA interactions were intermolecular higher-order assemblies.

Retraction to: Nature Cell Biology (2024) 26:1003-1018 https://doi.org/10.1038/s41556-024-01428-5

Double-strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Here we unveil how cell cycle-regulated DSB repair guides disparate cell death outcomes through single-cell analysis of extended live imaging. Following DSB induction in S or G2, passage of unresolved homologous recombination intermediates into mitosis promotes non-immunogenic intrinsic apoptosis in the immediate attempt at cell division. Conversely, non-homologous end joining, microhomology-mediated end joining and single-strand annealing cooperate to enable damaged G1 cells to complete the first cell cycle with an aberrant cell division at the cost of delayed extrinsic lethality and interferon production. Targeting non-homologous end joining, microhomology-mediated end joining or single-strand annealing promotes mitotic death, while suppressing mitotic death enhances interferon production. Together the data indicate that a temporal repair hierarchy, coupled with cumulative DSB load, serves as a reliable predictor of mitotic catastrophe outcomes following genome damage. In this pathway, homologous recombination suppresses interferon production by promoting mitotic lethality.

Gastrulation marks a pivotal stage in mammalian embryonic development, establishing the three germ layers and body axis through lineage diversification and morphogenetic movements. However, studying human gastrulating embryos is challenging due to limited access to early tissues. Here we show the use of spatial transcriptomics to analyse a fully intact Carnegie stage 7 human embryo at single-cell resolution, along with immunofluorescence validations in a second embryo. Employing 82 serial cryosections and Stereo-seq technology, we reconstructed a three-dimensional model of the embryo. Our findings reveal early specification of distinct mesoderm subtypes and the presence of the anterior visceral endoderm. Notably, primordial germ cells were located in the connecting stalk, and haematopoietic stem cell-independent haematopoiesis was observed in the yolk sac. This study advances our understanding of human gastrulation and provides a valuable dataset for future research in early human development.