Downregulation of Mpl Marks the Transition to Lymphoid-Primed Multipotent Progenitors with Gradual Loss of Granulocyte-Monocyte Potential.

Evidence for a novel route of adult hematopoietic stem cell (HSC) lineage commitment through Lin⁻Sca-1⁺Kit⁺Flt3^hi (LSKFlt3^hi) lymphoid-primed multipotent progenitors (LMPPs) with granulocyte/monocyte (GM) and lymphoid but little or no megakaryocyte/erythroid (MkE) potential was recently challenged, as LSKFlt3^hi cells were reported to possess MkE potential. Herein residual MkE potential segregated almost entirely with LSKFlt3^hi cells expressing the thrombopoietin receptor (Thpor), whereas LSKFlt3^hiThpor⁻ LMPPs lacked significant MkE potential in vitro and in vivo, but sustained combined GM and lymphoid potentials, and co-expressed GM and lymphoid but not MkE transcriptional lineage programs. Gradually increased transcriptional lymphoid priming in single LMPPs from Rag1^GFP mice was shown to occur in the presence of maintained GM lineage priming, but gradually reduced GM lineage potential. These functional and molecular findings reinforce the existence of GM-lymphoid progenitors with dramatically downregulated probability for committing towards MkE fates, and support that lineage restriction occurs through gradual rather than abrupt changes in specific lineage potentials.