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A study of myeloid cells in gliomas, a type of brain tumour, used a factor-based computational framework to reveal four immunomodulatory gene-expression programs that are expressed across myeloid cell types, driven by microenvironmental cues and predictive of therapeutic response.

On 15–16 June 2022, the National Institute of Allergy and Infectious Diseases hosted a virtual workshop on the topic of T cell technologies to discuss assays, novel technology development, bench and clinical application of those technologies, and challenges and innovations in the field.

Spatial transcriptomics aims to pair omic data with tissue structure. Here the authors report Spatially PhotoActivatable Colour Encoded Cell Address Tags (SPACECAT) to track and isolate live cells by location; this enables spatially informed downstream assays like scRNA-seq and flow cytometry.

Phenotypic screens in organoids and primary cells are scaled up using perturbation pooling.

Large-scale single-cell RNA-seq of stimulated primary mouse bone-marrow-derived dendritic cells highlights positive and negative intercellular signalling pathways that promote and restrain cellular variation.

Organoid models of intestinal stem cell differentiation into Paneth cells allow for the identification, via high-throughput phenotypic screening, of biological targets and small molecules regulating the composition of intestinal epithelium.

Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

Modlin and colleagues examined the skin lesions of human leprosy patients using single-cell RNA sequencing coupled to cellular spatial mapping. Their analysis maps the architecture of granulomas in leprosy lesions from patients with leprosy with localized disease (tuberculoid leprosy, reversal reaction) to those with progressive infection (lepromatous leprosy).

Single-cell analysis of lung, heart, kidney and liver autopsy samples shows the molecular and cellular changes and immune response resulting from severe COVID-19 infection.

The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.

To mark the 15th anniversary of Nature Methods, we asked scientists from across diverse fields of basic biology research for their views on the most exciting and essential methodological challenges that their communities are poised to tackle in the near future.

Ordovas-Montanes and colleagues describe the composition of the nasal cellular ecosystem and signatures of disease severity in vaccinated and unvaccinated adults during infection with the ancestral, Delta and Omicron variants of SARS-CoV-2.

Existing single-cell RNA-seq methods provide the transcriptome of a cellular phenotype at a single time point. Here, Kimmerlinget al. present a microfluidic platform that enables off-chip single-cell RNA-seq after multigenerational lineage tracking under controlled culture conditions.

Current methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) that form metastases have several limitations. Here, the authors show an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts.

In this Technical Report, the authors present CellLENS, a computational method that enhances immune cell identification and analyses by integrating cross-domain information in spatial multiomics data.

A newly developed genetically engineered mouse model enables the analysis of specific antigen presentation in vivo, providing insights into the tumour immunopeptidome and cancer progression.

A global view of the genetic networks regulating the differentiation of T_H17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation.

Multiomics and ecological spatial analysis (MESA) calculates ecodiversity-inspired metrics in spatially resolved omics integrated with single-cell data, enabling the quantitative comparison of tissue states across a range of conditions.

As the genetic and phenotypic heterogeneities among cells become more appreciated, there is increasing demand for technologies that facilitate high-throughput and high-efficiency single-cell 'omic' analyses in miniaturized and automated formats. This Review discusses the diverse microfluidic methodologies — with a primary focus on valve-, droplet- and nanowell-based platforms — for characterization of the genomes, epigenomes, transcriptomes and proteomes of single cells, and addresses technical considerations and future opportunities.

Single-cell RNA-sequencing of blood from HIV-1-infected individuals obtained before initiation of antiretroviral therapy provides insights into the initial immune responses during early infection that might shape future outcomes.

Single-cell RNA sequencing is used to characterize cell types in nasal tissues from human patients with chronic rhinosinusitis, revealing a role for tissue stem cells in allergic inflammatory memory.

The interaction between the host immune response and the component organisms forming the microbiota is critical during homeostatic but all pathological contexts. Here the authors use a multi-omics spatial approach to dissect and characterise host and microbiome in a murine model of intestinal inflammation.

Seq-Well provides similar scale and data quality to massively parallel, droplet-based single-cell RNA-seq methods in an easy to use, inexpensive and portable microwell format compatible with low-input samples.

Differences between humans and experimental models create a translational gap that makes it difficult to extrapolate research findings. The authors review systems-focused approaches to identify and control the translational distance between a complex disease process being studied and the experimental model used for testing.

Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance.

Arrays of vertical silicon nanowires can record and stimulate neuronal activity from within mammalian nerve cells, and can also map multiple individual synaptic connections between these cells.

Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Cell–cell communication pathways are dissected at the level of individual cells.

“Genome-wide association studies have identified variants associated with age-related macular degeneration (AMD); however, other than identifying this as a complement mediated inflammatory disease, little biology has emerged. Here, authors used novel computational tools from the Broad Institute to examine the relationship of single-cell transcriptomics and genome-wide association studies (GWAS) in the human retina and demonstrate that GWAS-associated risk alleles associated with AMD are enriched in glia and vascular cells and that human retinal glia are more diverse than previously thought

A mouse model of invasive breast cancer in which Pten and Trp53 are simultaneously inactivated links PTEN loss with STAT3 activation and indicates that immune escape in PTEN-null tumours is mediated by PI3Kβ.

Glioblastomas (GBM) are frequently resistant to immune checkpoint blockade therapy. Here the authors show that treatment with an agonistic anti-GITR antibody converts tumor infiltrating regulatory T cells to effector cells, overcoming resistance to PD1 blockade in preclinical models of GBM.

Pilocytic astrocytoma is a low-grade pediatric glioma, characterized by a single BRAF rearrangement. Here, Reitman and colleagues use single-cell RNA sequencing to reveal molecular hallmarks of the disease that might be targeted therapeutically.

Haplotype reconstruction of distant genetic variants is problematic in short-read sequencing. Here, the authors describe HapTree-X, a probabilistic framework that uses differential allele-specific expression to better reconstruct paternal haplotypes from diploid and polyploid genomes.

The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.

The Human Cell Atlas (HCA) aims to characterize cells from diverse individuals across the globe to better understand human biology. Here, the authors lay out principles and action items that have been adopted to affirm HCA’s commitment to equity so that the atlas is beneficial to all of humanity.

The delivery route and dose of the BCG vaccine profoundly alters the protective outcome after Mycobacterium tuberculosis challenge in non-human primates.

The Human Cell Atlas has been undergoing a massive effort to support global scientific equity. The co-leaders of its Equity Working Group share some lessons learned in the process.

Single-cell RNA sequencing is used to investigate the transcriptional response of 18 mouse bone-marrow-derived dendritic cells after lipopolysaccharide stimulation; many highly expressed genes, such as key immune genes and cytokines, show bimodal variation in both transcript abundance and splicing patterns. This variation reflects differences in both cell state and usage of an interferon-driven pathway involving Stat2 and Irf7.

Current high-throughput 3′ single-cell RNA-sequencing (scRNA-seq) techniques are limited in their ability to elucidate the variable sequences of antigen receptors. Love and colleagues describe a strategy that enables simultaneous analysis of TCR sequences and the corresponding full transcriptomes from 3′-barcoded scRNA-seq samples.

Sivanand et al. survey different types of cancers and study how the metabolic profile of the primary cancer site influences the metabolism of the metastatic cells, thus influencing sites of metastasis.

Humanized mice are an enabling technology to explore human immunity and disease. Here, Douam et al. provide an in-depth comparison of immune responses to yellow fever vaccine in human vaccinees, conventional and second-generation humanized mice and define a workflow to evaluate and refine these models.

This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile.

Group 3 innate lymphoid cells are recruited to the lung and involved in the immune response to infection with tuberculosis in humans and mice, as a reduction in group 3 innate lymphoid cells in the lung impaired early immune control of Mycobacterium tuberculosis in mice.

An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.