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 Blood, 1 April 2008, Vol. 111, No. 7, pp. 3424-3434.
Prepublished online as a Blood First Edition Paper on January 24, 2008; DOI 10.1182/blood-2007-08-108324.

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HEMATOPOIESIS AND STEM CELLS

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Sidinh Luc1,2, Kristina Anderson1, Shabnam Kharazi1, Natalija Buza-Vidas1,2, Charlotta Böiers1, Christina T. Jensen1,2, Zhi Ma1, Lilian Wittmann1, and Sten Eirik W. Jacobsen1,2

1 Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden; and 2 Haematopoietic Stem Cell Laboratory, University of Oxford, The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, United Kingdom

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 coexpressed 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 down-regulated probability for committing toward MkE fates, and support that lineage restriction occurs through gradual rather than abrupt changes in specific lineage potentials.


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