Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Endothelial Cells
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Macaca nemestrina
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Stem Cell Niche

MeSH Major

  • Endothelium, Vascular
  • Hematopoietic Stem Cells
  • Induced Pluripotent Stem Cells
  • Multipotent Stem Cells

abstract

  • Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC-derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina-induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain-null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood-derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence.

publication date

  • March 2, 2015

has subject area

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Endothelial Cells
  • Endothelium, Vascular
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Humans
  • Induced Pluripotent Stem Cells
  • Macaca nemestrina
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Multipotent Stem Cells
  • Stem Cell Niche

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4362238

Digital Object Identifier (DOI)

  • 10.1172/JCI79328

PubMed ID

  • 25664855

Additional Document Info

start page

  • 1243

end page

  • 1254

volume

  • 125

number

  • 3