Spatiotemporal single cell transcriptomic analysis of human gut macrophages reveals multiple functional and niche-specific subsets

Macrophages are a heterogeneous population of cells involved in tissue homeostasis, inflammation and cancer. Although macrophages are densely distributed throughout the human intestine, our understanding of how gut macrophages maintain tissue homeostasis is limited. Here we show that colonic lamina propria (LpM) and muscularis macrophages (MM) consist of monocyte-like cells that differentiate into multiple transcriptionally distinct subsets. LpM comprise subsets with proinflammatory properties and subsets high antigen presenting and phagocytic capacity. The latter are strategically positioned close to the surface epithelium. Most MM differentiate along two trajectories; one that upregulates genes associated with immune activation and angiogenesis, whereas the other upregulates genes associated with neuronal homeostasis. Importantly, MM are located adjacent to neurons and vessels. Cell-cell interaction and gene network analysis indicated that survival, migration, transcriptional reprogramming, and niche-specific localization of LpM and MM are controlled by an extensive interaction with tissue-resident cells and a few key transcription factors.