Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis

Stem Cell Res Ther. 2015 Jul 29;6(1):139. doi: 10.1186/s13287-015-0128-8.


Introduction: Endothelial colony-forming cells (ECFCs) significantly improve tissue repair by providing regeneration potential within injured cardiovascular tissue. However, ECFC transplantation into ischemic tissue exhibits limited therapeutic efficacy due to poor engraftment in vivo. We established an adequate ex vivo expansion protocol and identified novel modulators that enhance functional bioactivities of ECFCs.

Methods: To augment the regenerative potential of ECFCs, functional bioactivities of hypoxia-preconditioned ECFCs (hypo-ECFCs) were examined.

Results: Phosphorylations of the JAK2/STAT3 pathway and clonogenic proliferation were enhanced by short-term ECFC culturing under hypoxia, whereas siRNA-targeting of STAT3 significantly reduced these activities. Expression of BCL3, a target molecule of STAT3, was increased in hypo-ECFCs. Moreover, siRNA inhibition of BCL3 markedly reduced survival of ECFCs during hypoxic stress in vitro and ischemic stress in vivo. In a hindlimb ischemia model of ischemia, hypo-ECFC transplantation enhanced blood flow ratio, capillary density, transplanted cell proliferation and survival, and angiogenic cytokine secretion at ischemic sites.

Conclusions: Hypoxia preconditioning facilitates functional bioactivities of ECFCs by mediating regulation of the STAT3-BCL3 axis. Thus, a hypoxic preconditioned ex vivo expansion protocol triggers expansion and functional bioactivities of ECFCs via modulation of the hypoxia-induced STAT3-BCL3 axis, suggesting that hypo-ECFCs offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Cell Lymphoma 3 Protein
  • Cell Hypoxia*
  • Cell Proliferation
  • Cell Survival
  • Cytokines / metabolism
  • Disease Models, Animal
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Endothelial Cells / transplantation*
  • Hindlimb / blood supply
  • Hindlimb / pathology
  • Immunohistochemistry
  • Ischemia / metabolism
  • Ischemia / pathology
  • Ischemia / therapy*
  • Janus Kinase 2 / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neovascularization, Physiologic
  • Phosphorylation
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Regeneration
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism


  • B-Cell Lymphoma 3 Protein
  • Bcl3 protein, mouse
  • Cytokines
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Janus Kinase 2