Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Academic Article uri icon

Overview

MeSH

  • Adult Stem Cells
  • Animals
  • Aorta
  • Cell Lineage
  • Female
  • Gene Expression Regulation
  • Gonads
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Lymphocytes
  • Mesonephros
  • Mice
  • Myeloid Cells
  • Pluripotent Stem Cells
  • Time Factors
  • Transcription Factors
  • Transgenes

MeSH Major

  • Cellular Microenvironment
  • Cellular Reprogramming
  • Endothelial Cells
  • Hematopoietic Stem Cells
  • Multipotent Stem Cells

abstract

  • Generating engraftable human haematopoietic cells from autologous tissues is a potential route to new therapies for blood diseases. However, directed differentiation of pluripotent stem cells yields haematopoietic cells that engraft poorly. Here, we have devised a method to phenocopy the vascular-niche microenvironment of haemogenic cells, thereby enabling reprogramming of human endothelial cells into engraftable haematopoietic cells without transition through a pluripotent intermediate. Highly purified non-haemogenic human umbilical vein endothelial cells or adult dermal microvascular endothelial cells were transduced with the transcription factors FOSB, GFI1, RUNX1 and SPI1 (hereafter referred to as FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of haematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPPs). These endothelial cells that have been reprogrammed into human MPPs (rEC-hMPPs) acquire colony-forming-cell potential and durably engraft into immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (natural killer and B cell) progenies. Conditional expression of FGRS transgenes, combined with vascular induction, activates endogenous FGRS genes, endowing rEC-hMPPs with a transcriptional and functional profile similar to that of self-renewing MPPs. Our approach underscores the role of inductive cues from the vascular niche in coordinating and sustaining haematopoietic specification and may prove useful for engineering autologous haematopoietic grafts to treat inherited and acquired blood disorders.

publication date

  • July 17, 2014

has subject area

  • Adult Stem Cells
  • Animals
  • Aorta
  • Cell Lineage
  • Cellular Microenvironment
  • Cellular Reprogramming
  • Endothelial Cells
  • Female
  • Gene Expression Regulation
  • Gonads
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Humans
  • Lymphocytes
  • Mesonephros
  • Mice
  • Multipotent Stem Cells
  • Myeloid Cells
  • Pluripotent Stem Cells
  • Time Factors
  • Transcription Factors
  • Transgenes

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4159670

Digital Object Identifier (DOI)

  • 10.1038/nature13547

PubMed ID

  • 25030167

Additional Document Info

start page

  • 312

end page

  • 318

volume

  • 511

number

  • 7509