BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo

Stem Cell Reports. 2016 Mar 8;6(3):383-95. doi: 10.1016/j.stemcr.2016.01.016. Epub 2016 Feb 25.

Abstract

Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment.

Keywords: AGM; BMP; HPSCs; Hh; VEGF; development; hematopoiesis; hematopoietic stem/progenitor cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Hedgehog Proteins / metabolism*
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Smad Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Hedgehog Proteins
  • Smad Proteins
  • Vascular Endothelial Growth Factor A