The mammalian haematopoietic system is a progressively lineage-restricted branching hierarchy that replenishes mature blood cells throughout the life of an organism. Self-renewing haematopoietic stem cells (HSCs) reside at the apex of the hierarchy and give rise to multipotent progenitors that undergo increasingly restricted lineage commitments, until they finally assume a single cell fate at the exclusion of all others. Several competing models of the haematopoietic hierarchy have been proposed, and it is yet unclear if all mechanisms of lineage commitment in definitive haematopoiesis are identical between foetal liver (FL) and adult bone marrow (BM). Herein we explored early lineage fate decisions in the first branches of the lymphoid-primed multipotent progenitor (LMPP) model of haematopoiesis. We prospectively isolated the earliest known immune-restricted progenitor from early FL and yolk sac, prior to the establishment of definitive haematopoiesis in the embryo. These progenitors express early lymphoid-affiliated genes – recombination-activating gene 1 (Rag1), interleukin-7 receptor (Il7r), and Fms-like tyrosine kinase 3 (Flt3) – and were shown to be equivalent to the adult BM LMPP compartment, having robust combined lympho-myeloid potentials but little or no megakaryocyte/erythroid potentials. Moreover, the physiological contribution of this immune-restricted progenitor to embryonic myelopoiesis was conclusively demonstrated, supporting the relevance of the LMPP model of the haematopoietic hierarchy in early embryonic lymphoid commitment. In other studies pertaining to the myeloid/megakaryocyte/erythroid branch of the LMPP model, we characterised the function of individual platelet-biased and platelet-restricted HSCs in adult BM. Based on our findings we propose a revised model of the LMPP hierarchy, with the addition of a primitive megakaryocyte-restricted pathway of HSC differentiation. In contrast, we found that platelet-biased reconstitution behaviour is very rare in FL HSCs, but is promptly acquired by FL-derived adult HSCs. Therefore, the megakaryocyte-restricted differentiation branch proposed might be exclusive to adult haematopoiesis. </p
