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

TLDR

Hematopoiesis has traditionally been viewed as a hierarchical cascade from multipotent stem cells through oligopotent intermediates to unipotent progenitors. The authors used a single‑cell CD34⁺ sorting strategy to delineate myeloid, erythroid, and megakaryocytic fates and chart the progenitor hierarchy throughout human development. They found that fetal liver harbors numerous oligopotent progenitors with mixed fates, whereas adult bone marrow contains only multipotent and unipotent classes, revealing a two‑tier hierarchy that revises the conventional model.

Abstract

In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a 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 intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult "two-tier" hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.