Optical Cell Tagging for Spatially Resolved Single‐Cell RNA Sequencing

Single‐cell RNA sequencing (scRNA‐seq) has emerged as a powerful tool for profiling gene expression of distinct cell populations at the single‐cell level. However, the information of the positions of cells within the multicellular samples is missing in scRNA‐seq datasets. To overcome this limitation, we herein develop OpTAG (optical cell tagging) as a new chemical platform for attaching functional tags onto cell surfaces in a spatially resolved manner. With OpTAG, we establish OpTAG‐seq, which enables spatially resolved scRNA‐seq. We apply OpTAG‐seq to investigate the spatially defined transcriptional program in migrating cancer cells and identified a list of genes that are potential regulators for cancer cell migration and invasion. OpTAG‐seq provides a convenient method for mapping cellular heterogeneity with spatial information within multicellular biological systems. OpTAG (optical cell tagging) is a novel chemical platform for attaching functional tags onto cell surfaces in a spatially resolved manner. In combination with cell sorting and single‐cell RNA sequencing (scRNA‐seq), OpTAG‐seq enables spatially resolved scRNA‐seq.