Clonal Analysis of the Human Hematopoietic Hierarchy Reveals An Early Lymphoid Progenitor with Extensive Monocytic Potential.

Abstract 1503

Poster Board I-526

The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. Although the validity of this model in the mouse has recently been questioned, its status in human hematopoiesis is unclear, since little is known concerning lineage potential of human progenitors at the clonal level. We isolated and clonally mapped the developmental potential of each major progenitor class from neonatal cord blood and adult bone marrow providing the first comprehensive analysis of the human hematopoietic hierarchy. Human myeloid commitment follows the classical pattern of lineage restriction, however lymphoid development is initiated by a novel cell type, termed lympho-myeloid progenitor (LMP), which displays extensive monocytic potential. However, this myeloid capacity is lost following B- or T/NK-cell lineage commitment. The myeloid potential of LMPs is sensitive to extrinsic signals and can be directed towards differentiation into dendritic cells (DCs). Thus, human lymphoid development does not follow a rigid model of segregation of myeloid-lymphoid lineages, but proceeds through LMPs. LMPs can be massively expanded and differentiated into mature T-cells and DCs that are functionally indistinguishable from DCs derived from peripheral blood monocytes. The prospective isolation and elucidation of clonal lineage potential of human progenitors provides the basis for novel cellular therapeutics and a powerful means to uncover the cellular and molecular regulators that govern human lineage commitment.