title: Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential.
abstract: 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.
authors.affiliation: Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Sweden.
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Shabnam
authors.initials: S
authors.lastname: Kharazi
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Charlotta
authors.initials: C
authors.lastname: Böiers
authors.forename: Christina T
authors.initials: CT
authors.lastname: Jensen
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ma
authors.forename: Lilian
authors.initials: L
authors.lastname: Wittmann
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D018398:Homeodomain Proteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; C064658:RAG-1 protein; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3