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Overturning the Classical View of the Hematopoietic System

Review of “Distinct routes of lineage development reshape the human blood hierarchy across ontogeny” from Science by Stuart P. Atkinson

The hematopoietic system is one of the most well-studied and well-understood stem cells systems. Or so we thought. A new study in Science from the laboratory of John E. Dick has recently provided evidence that the classical pyramidal view of human adult hematopoiesis requires revision [1] and they now describe a two-tier system to take its place [2]. This new system may provide a new means to view the formation of blood under both normal physiological and disease-induced conditions, and overturns decades of dogma.

The accepted structure of the human hematopoietic system describes rare hematopoietic stem cells (HSCs) HSCs and multipotent progenitors (MPPs) which produce more numerous lineage-specific oligopotent and unipotent progenitors which then produce the vast numbers of differentiated blood cells. This schema had been generally accepted even though a full assessment of myelocytic (My), erythrocytic (Er), and megakaryocytic (Mk) development had yet to be undertaken. This was the job undertaken in this new study, using a more sensitive cell-sorting scheme and an optimized single cell assay in mice.

The authors implemented an extended 11-parameter cell-sorting layout to provide a high-resolution view of the phenotypic heterogeneity of CD34+ cells (primitive HSCs) which allowed the construction of a progenitor hierarchy of blood cells present in the in human fetal liver (FL), neonatal cord blood (CB) and adult bone marrow (BM). This was then partnered with an assay using serum-free conditions supplemented with growth factors and stroma for the high-efficiency assessment of My, Er and Mk lineage potential from single CD34+ cells.

With these improved tools in hand, the authors set to work and soon uncovered something interesting. While they observed large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates in the fetal liver, analysis of the adult bone marrow found something different - only multipotent and unipotent cells and few oligopotent progenitor intermediates. This new finding therefore suggests that a two-tier system exists in the adult, rather than a multilayered hematopoietic continuum, with only multipotent stem cells (HSCs and MPPs) and committed unipotent progenitors existing, with few intermediates.

This mouse study has rocked the foundations of our understanding of the hematopoietic system, and one now hopes of similar assessments in the human system to demonstrate whether this two-tier hierarchy exists and whether the observed developmental differences also exist. Papers will be re-scrutinized, data sets re-mined, strategies re-thought, and, potentially, better models and treatments constructed. The Hematopoietic System is Dead, Long Live the Hematopoietic System!


  1. Till JE and McCulloch EA Hemopoietic stem cell differentiation. Biochim Biophys Acta 1980;605:431-459.
  2. Notta F, Zandi S, Takayama N, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 2016;351:aab2116.