CD66b-CD64dimCD115- cells in the human bone marrow represent neutrophil-committed progenitors

Here, we report the identification of human CD66b-CD64dimCD115-neutrophil-committed progenitor cells (NCPs) within the SSCloCD45dimCD34+ and CD34dim/- subsets in the bone marrow. NCPs were either CD45RA+ or CD45RA-, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b+neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. scRNA-seq analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene (ISG) signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express ISGs in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described eNePs, proNeus and COVID-19 proNeus. Altogether, data shed light on the very early phases of neutrophil ontogeny.