Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth

PLoS One. 2014 Nov 24;9(11):e112106. doi: 10.1371/journal.pone.0112106. eCollection 2014.

Abstract

Eph and ephrin proteins are essential cell guidance cues that orchestrate cell navigation and control cell-cell interactions during developmental tissue patterning, organogenesis and vasculogenesis. They have been extensively studied in animal models of embryogenesis and adult tissue regeneration, but less is known about their expression and function during human tissue and organ regeneration. We discovered the hypoxia inducible factor (HIF)-1α-controlled expression of EphA3, an Eph family member with critical functions during human tumour progression, in the vascularised tissue of regenerating human endometrium and on isolated human endometrial multipotent mesenchymal stromal cells (eMSCs), but not in other highly vascularised human organs. EphA3 affinity-isolation from human biopsy tissue yielded multipotent CD29+/CD73+/CD90+/CD146+ eMSCs that can be clonally propagated and respond to EphA3 agonists with EphA3 phosphorylation, cell contraction, cell-cell segregation and directed cell migration. EphA3 silencing significantly inhibited the ability of transplanted eMSCs to support neovascularisation in immunocompromised mice. In accord with established roles of Eph receptors in mediating interactions between endothelial and perivascular stromal cells during mouse development, our findings suggest that HIF-1α-controlled expression of EphA3 on human MSCs functions during the hypoxia-initiated early stages of adult blood vessel formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Cell Hypoxia
  • Cells, Cultured
  • Endometrium / cytology
  • Female
  • Gene Expression
  • Heterografts / blood supply
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mesenchymal Stem Cell Transplantation / methods
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microscopy, Fluorescence
  • Multipotent Stem Cells / metabolism*
  • Multipotent Stem Cells / transplantation
  • Neovascularization, Physiologic*
  • RNA Interference
  • Receptor, EphA3 / genetics*
  • Receptor, EphA3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Heterologous
  • Young Adult

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptor, EphA3

Grants and funding

This work was supported in part by research funding from KaloBios Pharmaceuticals to ML and AMS and by National Health and Medical Research Council Australia Grants #384241, 487922, Human Frontiers Science Program Grant #RGP0039/2009-C, a Victorian Government's Operational Infrastructure Support Program (CEG) and a Monash Postgraduate Scholarship to CT. ML and CEG are NH&MRC Senior Research Fellows. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.