Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors

J Exp Med. 2019 Jul 1;216(7):1599-1614. doi: 10.1084/jem.20181399. Epub 2019 May 10.

Abstract

Before the emergence of hematopoietic stem cells (HSCs), lineage-restricted progenitors, such as erythro-myeloid progenitors (EMPs), are detected in the embryo or in pluripotent stem cell cultures in vitro. Although both HSCs and EMPs are derived from hemogenic endothelium, it remains unclear how and when these two developmental programs are segregated during ontogeny. Here, we show that hepatic leukemia factor (Hlf) expression specifically marks a developmental continuum between HSC precursors and HSCs. Using the Hlf-tdTomato reporter mouse, we found that Hlf is expressed in intra-aortic hematopoietic clusters and fetal liver HSCs. In contrast, EMPs and yolk sac hematopoietic clusters before embryonic day 9.5 do not express Hlf HSC specification, regulated by the Evi-1/Hlf axis, is activated only within Hlf+ nascent hematopoietic clusters. These results strongly suggest that HSCs and EMPs are generated from distinct cohorts of hemogenic endothelium. Selective induction of the Hlf+ lineage pathway may lead to the in vitro generation of HSCs from pluripotent stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Basic-Leucine Zipper Transcription Factors / physiology*
  • Cell Lineage
  • Erythroid Precursor Cells / metabolism*
  • Female
  • Hematopoiesis*
  • Hematopoietic Stem Cells / metabolism*
  • Liver / embryology
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Myeloid Progenitor Cells / metabolism*
  • Pluripotent Stem Cells / metabolism
  • Yolk Sac / metabolism

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Hlf protein, mouse