Distinct routes of lineage development reshape the human blood hierarchy across ontogeny

Abstract

Classically, blood arises from stem cells through a series of oligopotent progenitors that become increasingly restricted to unipotent progenitors, each slotted into a hierarchical layer based on their differentiation potential. The presence of oligopotent cells is critical to the standard model of blood differentiation as they define the path from stem cells to unipotent progenitors. We developed a new cell-sorting scheme to resolve myeloid (My), erythroid (Er) and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with entangled My, Er and Mk fates. Unexpectedly in adult bone marrow, few oligopotent progenitor intermediates were present with multipotent and unipotent progenitors predominating, and now Er-Mk lineages emerged from multipotent cells. The developmental shift to an adult 'two-tier' hierarchy challenges current dogma and provides a new framework to understand normal and disease states of human hematopoiesis. ‡

Tree-ensemble analysis tests for presence of multifurcations in single cell data

“…The small branch cell counts (37-380) precluded recursive application of TreeTop (Supp Fig 13, Online Methods). The results from TreeTop are therefore consistent with recent findings in favour of a flat hierarchy [5][6][7] .…”

“…Each sample of the datasets described above was generated from an n-dimensional space, where n was uniformly sampled from [6,30]. Of these, we found that the distributions of branching scores observed for triangular data were higher than the other topologies considered by a considerable margin (Supp Figs 1-2).…”

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

“…Prenatally, oligopotent progenitor cells residing in the fetal liver give rise to myeloid, erythroid, and megakaryocyte fates. Multipotent or unipotent progenitor classes predominate in the bone marrow, giving rise to the adult megakaryocyte and erythroid classes 14. Interestingly it has been recently shown that the murine lung is a reservoir for hematopoietic progenitors and megakaryocytes, and a site for platelet biogenesis,15 although the significance of these findings in human megakaryopoiesis is still unknown.…”

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

“…Nota et al [15] deined the MPPs that were CD90 − CD49f − as transiently engrafting cells (2-4 weeks in NSG mice) or short-term repopulating HSCs and concluded that most HSCs reside in the CD90+ fraction, but 1 in 5.5 UCB HSCs lacked CD90 expression, and approximately 10% of the UCB CD90+CD49f+ cells fraction are HSCs [15]. More recent experiments from Nota et al [86] have added further to our understanding of the human hematopoietic lineage and the developmental changes it undergoes from fetal liver to UCB to bone marrow hematopoiesis. Importantly, these investigators developed an in vitro single-cell assay that exclusively assesses myeloid, including erythroid and megakaryocytic, lineage potential of individual CD34+ cells by combining MS-5 stromal cultures with LDL and eight cytokines, stem cell factor, thrombopoietin, FMS-like tyrosine kinase 3 ligand, interleukin 6, interleukin 3, interleukin 11, granulocyte macrophage colony stimulating factor and erythropoietin (SCF, TPO, Flt3L, IL6, IL3, IL11, GM-CSF and Epo respectively) and found that 2% of the enriched UCB CD49f+ HSCs gave rise to such clones [86].…”

“…More recent experiments from Nota et al [86] have added further to our understanding of the human hematopoietic lineage and the developmental changes it undergoes from fetal liver to UCB to bone marrow hematopoiesis. Importantly, these investigators developed an in vitro single-cell assay that exclusively assesses myeloid, including erythroid and megakaryocytic, lineage potential of individual CD34+ cells by combining MS-5 stromal cultures with LDL and eight cytokines, stem cell factor, thrombopoietin, FMS-like tyrosine kinase 3 ligand, interleukin 6, interleukin 3, interleukin 11, granulocyte macrophage colony stimulating factor and erythropoietin (SCF, TPO, Flt3L, IL6, IL3, IL11, GM-CSF and Epo respectively) and found that 2% of the enriched UCB CD49f+ HSCs gave rise to such clones [86]. Of these, approximately half formed high proliferative potential (HPP)-CFU [86].…”