No evidence that plasmablasts transdifferentiate into developing neutrophils in severe COVID-19 disease

A recent study by Wilk et al. of the transcriptome of peripheral blood mononuclear cells (PBMCs) in seven patients hospitalized with COVID-19 described a population of “developing neutrophils” that were “phenotypically related by dimensionality reduction” to plasmablasts, and that these two cell populations represent a “linear continuum of cellular phenotype”¹. The authors suggest that, in the setting of acute respiratory distress syndrome (ARDS) secondary to severe COVID-19, a “differentiation bridge from plasmablasts to developing neutrophils” connected these distantly related cell types. This conclusion is controversial as it appears to violate several basic principles in cell biology relating to cell lineage identity and fidelity. Correctly classifying cells and their developmental history is an important issue in cell biology and we suggest that this conclusion is not supported by the data as we show here that: (1) regressing out covariates such as unique molecular identifiers (UMIs) can lead to overfitting; and (2) that UMAP embeddings may reflect the expression of similar genes but not necessarily direct cell lineage relationships.