Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antigens, CD
  • Antigens, CD45
  • Cadherins
  • Cells, Cultured
  • Colony-Forming Units Assay
  • Female
  • Graft Survival
  • Hematopoietic Stem Cell Transplantation
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Radiation Chimera
  • Signal Transduction
  • Stromal Cells

MeSH Major

  • Aorta
  • Endothelial Cells
  • Endothelium, Vascular
  • Gonads
  • Hematopoietic System
  • Mesonephros
  • Receptor, Notch1
  • Receptor, Notch2
  • Stem Cell Niche

abstract

  • Hematopoietic stem cells (HSCs) first emerge during embryonic development within vessels such as the dorsal aorta of the aorta-gonad-mesonephros (AGM) region, suggesting that signals from the vascular microenvironment are critical for HSC development. Here, we demonstrated that AGM-derived endothelial cells (ECs) engineered to constitutively express AKT (AGM AKT-ECs) can provide an in vitro niche that recapitulates embryonic HSC specification and amplification. Specifically, nonengrafting embryonic precursors, including the VE-cadherin-expressing population that lacks hematopoietic surface markers, cocultured with AGM AKT-ECs specified into long-term, adult-engrafting HSCs, establishing that a vascular niche is sufficient to induce the endothelial-to-HSC transition in vitro. Subsequent to hematopoietic induction, coculture with AGM AKT-ECs also substantially increased the numbers of HSCs derived from VE-cadherin⁺CD45⁺ AGM hematopoietic cells, consistent with a role in supporting further HSC maturation and self-renewal. We also identified conditions that included NOTCH activation with an immobilized NOTCH ligand that were sufficient to amplify AGM-derived HSCs following their specification in the absence of AGM AKT-ECs. Together, these studies begin to define the critical niche components and resident signals required for HSC induction and self-renewal ex vivo, and thus provide insight for development of defined in vitro systems targeted toward HSC generation for therapeutic applications.

publication date

  • May 2015

has subject area

  • Animals
  • Antigens, CD
  • Antigens, CD45
  • Aorta
  • Cadherins
  • Cells, Cultured
  • Colony-Forming Units Assay
  • Endothelial Cells
  • Endothelium, Vascular
  • Female
  • Gonads
  • Graft Survival
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic System
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mesonephros
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Radiation Chimera
  • Receptor, Notch1
  • Receptor, Notch2
  • Signal Transduction
  • Stem Cell Niche
  • Stromal Cells

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4463208

Digital Object Identifier (DOI)

  • 10.1172/JCI80137

PubMed ID

  • 25866967

Additional Document Info

start page

  • 2032

end page

  • 2045

volume

  • 125

number

  • 5