Identification of unipotent megakaryocyte progenitors in human hematopoiesis

Abstract

The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34CD38IL-3RαCD45RA common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41 CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.

Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

“…The CD41 + fraction of human CD38 + CD34 + lin -CD45RA -HSPCs contains megakaryocyte-biased progenitors with significant erythroid differentiation potential as well as unipotent MkP (Miyawaki et al, 2017;Psaila et al, 2016). However, the phenotype of CD41 + cells within the CD38 -HSC/MPP compartment has not previously been defined.…”

Concise Review: Bipotent Megakaryocytic-Erythroid Progenitors: Concepts and Controversies

“…Even though CD34+CD38high human cells have been published as being greatly enriched for erythroid committed cells,[10] papers still use this gate to isolate what they refer to as human “MEP.” Consequently, single cell RNA sequencing data from this population shows that many of these cells are erythroid committed, which would lead investigators to question the existence of human MEPs. [27, 28]…”

Effects of vascular endothelial growth factors and their receptors on megakaryocytes and platelets and related diseases

“…Recently, it was shown that MKPs could be generated directly from a subset of CD41 + LSK (Lin − Sca‐1 + c‐Kit + ) cells bypassing megakaryocyte‐erythrocyte progenitors (MEPs) in mice (Nishikii et al , ). More recently, Miyawaki et al () identified a unipotent MKP within the CD34 + CD38 + IL‐3Rα dim CD45RA – common myeloid progenitor (CMP) population in humans by using CD41 as a positive marker. These CD34 + CD38 + IL‐3Rα dim CD45RA – CD41 + CMPs (CD41 + CMPs) were strictly committed to the megakaryocyte (MK) lineage, and their potential to produce megakaryocytes and platelets far exceeded that of the MEPs (Miyawaki et al , ).…”

“…More recently, Miyawaki et al () identified a unipotent MKP within the CD34 + CD38 + IL‐3Rα dim CD45RA – common myeloid progenitor (CMP) population in humans by using CD41 as a positive marker. These CD34 + CD38 + IL‐3Rα dim CD45RA – CD41 + CMPs (CD41 + CMPs) were strictly committed to the megakaryocyte (MK) lineage, and their potential to produce megakaryocytes and platelets far exceeded that of the MEPs (Miyawaki et al , ). Therefore, the expression of CD41 begins at the HPC (mouse) or CMP (human) stage and the expression of CD42b begins at the MKP stage during megakaryocytopoiesis (Woolthuis & Park, ).…”