Conversion of adult endothelium to immunocompetent haematopoietic stem cells

Nature. 2017 May 25;545(7655):439-445. doi: 10.1038/nature22326. Epub 2017 May 17.

Abstract

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Aging / genetics
  • Animals
  • Cell Differentiation*
  • Cell Line
  • Cell Lineage
  • Cell Self Renewal
  • Cellular Reprogramming*
  • Clone Cells / cytology
  • Clone Cells / transplantation
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Endothelium / cytology*
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • FOSB protein, human
  • GFI1 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • RUNX1 protein, human
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1