DACH1 DOWNREGULATION DELINEATE A LYMPHOID PRIMED PROGENITOR (LPP) POPULATION WITHIN THE MPP4 CLUSTER

Abstract

Classical models of haematopoiesis dictate that a single hematopoietic stem cell (HSC) with self-renewal capacity can give rise to all the hematopoietic lineage through subsequent division and loss of potential. This loss of potential is captured through surface markers that classify different stem and progenitor stages including long-term (LT-) and short-term haematopoietic stem cells (ST-HSC) that give rise to 4 categories of multipotent progenitor (MPP) subpopulations 1-4. The MPP4 cluster Lin–c-kit+Sca1+Flt3+ is also known as the lymphoid multipotent primed progenitor (LMPPs) and lack of megakaryocyte and erythroid potential. We demonstrate through cellular barcoding and scRNA-seq that the MPP4 cluster is heterogenous for fate. In particular, Dach1 expression is heterogenous and co-expressed with myeloid and stem-like genes but inversely correlates with lymphoid genes. Through the generation of a Dach1-GFP reporter mouse we demonstrate that Dach1– MPP4s represents a novel progenitor subpopulation that definitively lacks myeloid potential but retains lymphoid potential, thus termed lymphoid-primed progenitors or LPPs. This work describes the earliest definitive branch point of lymphoid development in within haematopoiesis and shows the power of scRNA-seq in identifying progenitor subpopulations.