Clump sequencing exposes the spatial expression programs of intestinal secretory cells

Area of Science:

• Cellular and Molecular Biology
• Genomics
• Tissue Engineering

Background:

• Spatial transcriptomics allows for the creation of cell atlases but struggles with rare cell types due to diluted mRNA signals.
• The zonation patterns of rare intestinal cell types, like goblet and tuft cells, remain largely uncharacterized.
• Enterocytes, the most abundant intestinal cell type, display known zonation along the crypt-villus axis.

Purpose of the Study:

• To develop a novel method, ClumpSeq, for reconstructing spatially-resolved atlases of rare cell types.
• To characterize the spatial distribution and gene expression patterns of all epithelial cell types in the small intestine.
• To investigate the immune-modulatory roles of villus tip goblet and tuft cells and enteroendocrine cell migration.

Main Methods:

• Developed ClumpSeq, an approach for sequencing small, attached cell clumps.
• Utilized enterocyte landmark genes to infer the crypt-villus location of each cell clump.
• Integrated spatial information with single-cell RNA sequencing data.

Main Results:

• Established comprehensive spatial atlases for all epithelial cell types in the small intestine.
• Identified elevated expression of immune-modulatory genes in goblet and tuft cells at the villus tip.
• Observed heterogeneous migration patterns among enteroendocrine cells.

Conclusions:

• ClumpSeq successfully reconstructs spatial atlases for rare cell types in the small intestine.
• The method highlights the immune-modulatory functions of specific rare cell populations.
• ClumpSeq is a versatile approach applicable to rare cell type atlasing in diverse tissues and tumors.