Biology subjects

Spurrell, M.

Publications and source records attributed to Spurrell, M..

3 recordsLinked to original sources

bioRxiv2024

Integrating spatial transcriptomics count data with Crescendo improves visualization and detection of spatial gene patterns

Spatial transcriptomics allows for the analysis of a cells gene expression in the context of its physical location. With spatial transcriptomics data, investigators often want to find genes of interest whose spatial patterns are biologically relevant in multiple samples. However, due to confounding factors in spatial data that produce noise across samples, datasets, and technologies, it is challenging to visualize genes and their spatial patterns across samples. We present Crescendo, an integration algorithm that performs correction directly on gene expression counts to reduce variation from technical confounders. We first apply Crescendo to a 3-sample spatial transcriptomics mouse brain dataset to show how Crescendo enables accurate visualization of gene expression across these spatial transcriptomic samples. We then demonstrate Crescendos scalability by integrating a 16-sample immuno-oncology dataset of 7 million cells. Finally, we show that Crescendo can perform cross-technology integration by merging a colorectal cancer (CRC) scRNA-seq dataset with two CRC spatial transcriptomics samples. By transferring information between technologies, Crescendo can impute poorly expressed genes to improve detection of gene-gene colocalization, such as ligand-receptor interactions.

bioinformatics↗

bioRxiv2023

Intrarenal myeloid subsets associated with kidney injury are comparable in mice and patients with lupus nephritis

Resident macrophages and infiltrating monocytes in kidneys of patients with lupus nephritis are altered both in frequency and function relative to their counterparts in healthy kidneys. The extent to which mouse models might be useful in developing approaches to target these cells for treating lupus nephritis is poorly understood. Here, we studied four common lupus mouse models that share clinical, serologic, and histopathologic kidney changes with humans. Using single-cell profiling and multiplex spatial imaging to analyze the intrarenal myeloid compartment with the onset of clinical disease in these models, we identified monocyte and macrophage subsets that expand or contract in kidneys with clinical nephritis. A unique subset of classical monocytes expanded with the onset of disease and expressed genes such as CD9, Spp1, Ctsd, Cd63, Apoe, and Trem2 that were previously shown to be induced by tissue injury and play a role in inflammation, lipid metabolism and tissue repair in other organs. Resident macrophages transitioned from a pro-inflammatory to a similar injury-associated state with onset of disease. To test whether these findings in mouse models were also observed in humans, we re-analyzed monocytes and macrophages in a single-cell RNAseq dataset of kidney biopsies from 155 patients with lupus nephritis and 30 healthy donors, collected by the NIH AMP RA/SLE consortium. Human monocytes and macrophages showed conserved changes in gene expression programs associated with lupus nephritis disease indices, and localized to similar kidney microenvironments as in mice. By identifying myeloid subsets and disease-associated alterations in biological processes that are conserved across species, we provide a strong rationale for functional studies of these cells and pathways in mice to uncover mechanisms and find targets relevant to human lupus nephritis. One sentence summaryThis study characterizes intrarenal myeloid cells from four lupus mouse models and 155 patients with lupus nephritis using single-cell RNA-seq and imaging, and identifies novel infiltrating and resident myeloid subsets that are conserved between mouse and human lupus nephritis, thus providing a map and strong rationale for functional studies in mice with relevance to human disease.

immunology↗

bioRxiv2023

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular immunity hubs defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11+ macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7+LAMP3+ dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.

immunology↗