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

被引:24
作者
Lee, Sang Hun [1 ,2 ]
Lee, Jun Hee [3 ]
Han, Yong-Seok [1 ]
Ryu, Jung Min [4 ,5 ]
Yoon, Yeo Min [1 ]
Han, Ho Jae [4 ,5 ]
机构
[1] Soonchunhyang Univ Seoul Hosp, Med Sci Res Inst, Seoul 140743, South Korea
[2] Soonchunhyang Univ Coll Med, Dept Biochem, Cheonan 330930, South Korea
[3] Pusan Natl Univ, Lab Vasc Med & Stem Cell Biol, Sch Med, Dept Physiol,Med Res Inst, Yangsan 626870, South Korea
[4] Seoul Natl Univ, Coll Vet Med, Res Inst Vet Sci, Dept Vet Physiol, Seoul 151742, South Korea
[5] Seoul Natl Univ, PLUS Creat Vet Res Ctr BK21, Seoul 151742, South Korea
来源
STEM CELL RESEARCH & THERAPY | 2015年 / 6卷
基金
新加坡国家研究基金会;
关键词
MESENCHYMAL STEM-CELLS; PROGENITOR CELLS; EXPRESSION; PROLIFERATION; ANGIOGENESIS; ACTIVATION; CANCER; DIFFERENTIATION; TRANSPLANTATION; MIGRATION;
D O I
10.1186/s13287-015-0128-8
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
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页数:13
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