title: Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis.
abstract: BACKGROUND
  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.
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 140-743, Republic of Korea. ykckss1114@nate.com.|Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 330-930, Republic of Korea. ykckss1114@nate.com.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Laboratory for Vascular Medicine & Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, 626-870, Republic of Korea. j-school@hanmail.net.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 140-743, Republic of Korea. format7000@naver.com.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Han
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-742, Republic of Korea. jmryu1559@gmail.com.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 140-743, Republic of Korea. yoonboo15@naver.com.
authors.forename: Yeo Min
authors.initials: YM
authors.lastname: Yoon
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-742, Republic of Korea. hjhan@snu.ac.kr.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D053614:Janus Kinase 2