Single-cell states versus single-cell atlases - two classes of heterogeneity that differ in meaning and method

Recent advances have created new opportunities to dissect cellular heterogeneity at the omics level. The enthusiasm for deep single-cell profiling has obscured a discussion of different types of heterogeneity and the most-appropriate techniques for studying each type. Here, I distinguish heterogeneity in regulation from heterogeneity in lineage. Snapshots of lineage heterogeneity provide a cell atlas that catalogs cellular diversity within complex tissues. Profiles of regulatory heterogeneity seek to interrogate one lineage deeply to capture an ensemble of single-cell states. Single-cell atlases require molecular signatures from many cells at a throughput afforded by mass cytometry-based, microfluidic-based, and microencapsulation-based methods. Single-cell states are more dependent on time, microenvironment, and low-abundance transcripts, emphasizing in situ methods that stress depth of profiling and quantitative accuracy.