Inhibition of Endothelial ERK Signalling by Smad1/5 Is Essential for Haematopoietic Stem Cell Emergence

Nat Commun. 2014 Mar 11;5:3431. doi: 10.1038/ncomms4431.

Abstract

The earliest HSCs are derived from haemogenic endothelium via endothelial-to-haematopoietic transition during vertebrate embryogenesis; however, the underlying mechanism is largely unclear. Here we show that interplay of Smad1/5 and ERK signalling is essential for haemogenic endothelium-based HSC emergence. Smad1/5 directly inhibits erk expression through recruiting HDAC1 to and inducing de-acetylation of the erk promoter in endothelial cells. Over-activated ERK signalling conferred by inhibition of Smad1/5 promotes the arterial endothelial cell fate and constitutively strengthens the tight junction between endothelial cells, thereby repressing the specification of haemogenic endothelium and the following endothelial-to-haematopoietic transition process. These findings provide new insights into the in vitro generation of transplantable HSCs for potential clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism*
  • Endothelial Cells / metabolism
  • Endothelial Cells / ultrastructure
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / embryology
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / metabolism*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • In Situ Hybridization
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MAP Kinase Signaling System / genetics*
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad1 Protein / genetics*
  • Smad1 Protein / metabolism
  • Smad5 Protein / genetics*
  • Smad5 Protein / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • Luminescent Proteins
  • Smad1 Protein
  • Smad5 Protein
  • Zebrafish Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Histone Deacetylase 1