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

Abstract

IntroductionWhereas considerable knowledge has been gained with regard to the identity and roles of extrinsic and intrinsic regulators of blood lineage development, much less is known about the molecular mechanisms regulating lineage commitment of hematopoietic stem cells (HSCs). 1,2 Unraveling the involved molecular determinants and mechanisms of lineage restriction will be facilitated by, and most likely depend on, a more complete understanding of the cellular pathways of the lineage restriction process from pluripotent HSCs to lineage-restricted progenitor cells.It remains unclear and debated 2-4 exactly how the lineage commitment process from pluripotent HSCs to lineage-restricted progenitors occurs in adult bone marrow (BM), and even unequivocal evidence for one such pathway would not exclude the existence of alternative routes for HSC lineage commitment. In the prevailing model of HSC lineage commitment, 1-3 HSCs (long-term and short-term) and multipotent progenitors (MPPs) distinguish themselves from each other, only through gradual loss of self-renewal potential while sustaining the same degree of pluripotentiality, with the first lineage commitment event resulting in a strict separation of myelopoiesis and lymphopoiesis. This model for HSC lineage commitment was supported by the identification of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively). 5,6 However, the degree to which the identified CMPs and CLPs represent obligatory or even main intermediates for myeloid and lymphoid development in adult hematopoiesis remains to be established.Although conclusively established for long-term HSCs (LTHSCs), 7,8 the existence of short-term HSCs (ST-HSCs) and MPPs in the BM Lin Ϫ Sca-1 ϩ Kit ϩ (LSK) stem and primitive progenitor cell compartment, with sustained pluripotentiality has yet to be demonstrated at the single cell level. 3 Rather, more recent studies have uncovered considerable heterogeneity in the LSK MPP compartment. Through the use of different but overlapping markers such as FMS-like tyrosine kinase 3 (Flt3), 9-11 vascular cell adhesion molecule-1 (Vcam-1), 12,13 and an Ikaros-reporter, 14 the existence of lymphoid-primed MPPs (LMPPs) with combined granulocyte/monocyte (GM) and lymphoid potentials, but little or no megakaryocyte (Mk)/erythroid (E) potentials has been proposed. 3,10,12,14,15 Further, molecular analysis of putative LMPPs show down-regulated transcriptional priming of genes specific for the MkE lineage, and up-regulation of lymphoid-specific genes, not yet expressed in HSCs. 15,16 The identification of a putative LMPP, representing the earliest lineage-restricted lympho-myeloid progenitor identified in adult hematopoiesis, has provided a potential avenue toward uncovering alternative HSC lineage commitment pathways. 2,3,17 However, the existence of the LMPP remains contentious, 2,3,[18][19][20] largely reflecting functional heterogeneity of phenotypically defined candidate LMPPs. 9,10,[12][13][14] While the evidence for a large fraction of LSKFlt3 hi BM cell...

Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development

“…on May 9, 2018. by guest www.bloodjournal.org From cells, the LMPPs, coexpressed cell-surface FLT3 and THPO receptor, (THPOR, also called c-Mpl), as previously demonstrated. 36 Notably, although THPOR hi LMPPs, in agreement with previous studies, failed to respond to THPO alone, 26 a potent synergy was observed between FL and THPO in promoting the clonal growth and proliferative burst of THPOR hi LMPPs but not of THPOR neg LMPPs (Figure 4A-B). This interaction between FL and THPO was also seen in preGMPs, but to a smaller degree ( Figure 4C).…”

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

“…1,2 In further support of the lymphoid commitment pathway sustaining GM (but not MkE) potential, the earliest thymic progenitors have combined T and GM potential. 3,4 The existence of adult and fetal GMlymphoid-restricted mouse MPPs has been confirmed through alternative approaches, 2,[5][6][7][8] and recently a similar progenitor was also identified in human hematopoiesis. 9,10 The restriction of mouse LMPPs to the fraction of LIN Ϫ SCA1 ϩ KIT ϩ (LSK) cells with high cell-surface FMS-like tyrosine kinase receptor 3 (FLT3) expression and of long-term self-renewing HSCs to LSK cells lacking detectable cell-surface FLT3 expression [11][12][13] raises the question as to what stage of lineage commitment FLT3 (protein) and Flt3 (mRNA) expression is initiated.…”

“…5 For details, see supplemental Methods. The publication costs of this article were defrayed in part by page charge payment.…”

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

“…However, rather than a sudden loss of MegE potential, it is more likely that there is a gradual decrease in the ability to commit to these lineages, coinciding with an increase in lymphoid priming. 39 Thus, in this model, LMPPs mainly give rise to CLPs and GMPs but still exhibit limited MegE potential ( Figure 1C) …”