Submitted August 20, 2007
Accepted January 16, 2008
Downregulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential
Sidinh Luc, Kristina Anderson, Shabnam Kharazi, Natalija Buza-Vidas, Charlotta Boiers, Christina T Jensen, Zhi Ma, Lilian Wittman, and Sten Eirik W Jacobsen*
Haematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
Haematopoietic Stem Cell Laboratory, University of Oxford, The Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom
* Corresponding author; email: sten.jacobsen{at}med.lu.se.
Evidence for a novel route of adult hematopoietic stem cell lineage commitment through Lin-Sca-1+Kit+Flt3hi (LSKFlt3hi) lymphoid-primed multipotent progenitors (LMPPs) with granulocyte/monocyte (GM) and lymphoid but little or no megakaryocyte/erythroid (MkE) potential was recently challenged, as LSKFlt3hi cells were reported to possess MkE potential. Herein residual (1-2%) MkE potential segregated almost entirely with LSKFlt3hi cells expressing the thrombopoietin receptor (Mpl), whereas LSKFlt3hiMpl- 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 Rag1GFP 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 restricted 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.
