What are your thoughts on single-cell sequencing vs. population averaging methods in confirming/evaluating differentiation?

Answer

Each method has its own advantages and some disadvantages.

Biological phenotype is a result of a complex cellular architecture and multiple interactions of several cell types (sometimes single cells) based on their environmental niche with in the human body. Recently, advances in single cell genomic profiling approaches has created an opportunity to see and understand these developmental opportunities which were not previously available.

Population averaging methods provide the benefit of assessing the collective activity/performance of cells, but does not account for where activity may be originating in the cell. In this case, specificity is lost, but output of the population is still valuable.
In summary, the best approach for you should be determined based on what you need to measure. For example, if you are interested in clonal expansion or differentiation abilities of one cell, the single cell approach can provide the specificity needed. Should you require an understanding of multiple cell type interactions, as would be the case with studying hepatic differentiation for example, then population averaging methods would be most valuable.