A new lymphoid-primed progenitor marked by Dach1 downregulation identified with single cell multi-omics

A classical view of blood cell development is that multipotent hematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. Lin − c-Kit + Sca-1 + Flt3 + cells, termed lymphoid-primed multipotent progenitors (LMPPs), have lost megakaryocyte and erythroid potential but are heterogeneous in their fate. Here, through single-cell RNA sequencing, we identify the expression of Dach1 and associated genes in this fraction as being coexpressed with myeloid/stem genes but inversely correlated with lymphoid genes. Through generation of Dach1 –GFP reporter mice, we identify a transcriptionally and functionally unique Dach1 –GFP − subpopulation within LMPPs with lymphoid potential with low to negligible classic myeloid potential. We term these ‘lymphoid-primed progenitors’ (LPPs). These findings define an early definitive branch point of lymphoid development in hematopoiesis and a means for prospective isolation of LPPs. Exploring transcriptional heterogeneity of cKit + Sca1 + HSPCs using single cell RNA-sequencing, Naik and colleagues identify a population termed ‘lymphoid primed progenitors’ as the earliest stage of lymphoid lineage commitment, marked by downregulation of the stem/myeloid transcription factor Dach1.