Investigating and dealing with publication and other biases in meta-analysis

Abstract

<h3>Abstract</h3> <h3>Objective</h3> Obesity drives significant changes in adipose tissue that precede development of tissue and systemic insulin resistance. Immune cell infiltration and inflammation are known contributors to these changes but there is limited understanding of their spatial context tissue-wide. We sought to identify spatial patterning in epididymal adipose tissue immune cells in a time course of diet-induced obesity in mice. <h3>Methods</h3> Using spatial transcriptomics and single-cell RNA-sequencing, we identified dominant cell type signatures preserved in their anatomical context, quantified gene expression patterns at spots throughout adipose tissue, performed cell type network analysis, and investigated ligand-receptor colocalization. <h3>Results</h3> Our data support increased innate immune cells, including macrophages, monocytes, and innate lymphoid cells with tissue-wide interspersion, and dampened adaptive immune cell signatures with obesity. Network analysis identified increased heterogeneity in all major immune cell types, consistent with increased subtypes. To capture tissue dynamics at obesity onset, we draw on mathematical principles from linear algebra and spectral graph theory and provide a framework for better understanding cell cooperation toward emergence of multicellular tissue function. <h3>Conclusion</h3> The culmination of these analyses revealed a widespread paradigm shift in ligand-receptor activity with near-exclusive macrophage-macrophage or monocyte-macrophage interactions at crown-like structures across adipose tissue in early obesity. <h3>Highlights</h3> Spatial transcriptomics shows innate immune cell dominance in obese adipose tissue Increased monocyte signaling accompanies infiltration in obesity Pre-crown-like niches precede crown-like structure formation Influential monocyte-macrophage ligand-receptor pairs emerge at crown-like niches