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

Lee SH, Lee JH, Han YS, Ryu JM, Yoon YM, Han HJ - Stem Cell Res Ther (2015)

Bottom Line: 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.Hypoxia preconditioning facilitates functional bioactivities of ECFCs by mediating regulation of the STAT3-BCL3 axis.

View Article: PubMed Central - PubMed

Affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 140-743, Republic of Korea. ykckss1114@nate.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of proposed mechanisms by which hypoxia increases clonogenic and proliferative potential, and enhances hypo-ECFC-mediated neovasculogenesis. Hypoxic preconditioning increases the clonogenic and proliferative potential of endothelial colony-forming cells (ECFCs) via the STAT3 pathway and augments the survival of ECFCs via STAT3-mediated BCL3 and vascular endothelial growth factor (VEGF) expression. These effects enhance ECFC-mediated neovasculogenesis in ischemic diseases
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Fig8: Schematic representation of proposed mechanisms by which hypoxia increases clonogenic and proliferative potential, and enhances hypo-ECFC-mediated neovasculogenesis. Hypoxic preconditioning increases the clonogenic and proliferative potential of endothelial colony-forming cells (ECFCs) via the STAT3 pathway and augments the survival of ECFCs via STAT3-mediated BCL3 and vascular endothelial growth factor (VEGF) expression. These effects enhance ECFC-mediated neovasculogenesis in ischemic diseases

Mentions: To our knowledge, this study shows for the first time that hypo-ECFCs enhance the recovery of cells from vascular injury by modulating the STAT3/BCL3 axis via VEGF expression (Fig. 8). The therapeutic efficiency of ECFCs can thus be controlled by modifying the culture conditions or activation of the STAT3/BCL3 pathway, providing insights into the bioactivity circuit needed for ECFC therapy that will improve efficiency in clinical applications.Fig. 8


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

Lee SH, Lee JH, Han YS, Ryu JM, Yoon YM, Han HJ - Stem Cell Res Ther (2015)

Schematic representation of proposed mechanisms by which hypoxia increases clonogenic and proliferative potential, and enhances hypo-ECFC-mediated neovasculogenesis. Hypoxic preconditioning increases the clonogenic and proliferative potential of endothelial colony-forming cells (ECFCs) via the STAT3 pathway and augments the survival of ECFCs via STAT3-mediated BCL3 and vascular endothelial growth factor (VEGF) expression. These effects enhance ECFC-mediated neovasculogenesis in ischemic diseases
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522108&req=5

Fig8: Schematic representation of proposed mechanisms by which hypoxia increases clonogenic and proliferative potential, and enhances hypo-ECFC-mediated neovasculogenesis. Hypoxic preconditioning increases the clonogenic and proliferative potential of endothelial colony-forming cells (ECFCs) via the STAT3 pathway and augments the survival of ECFCs via STAT3-mediated BCL3 and vascular endothelial growth factor (VEGF) expression. These effects enhance ECFC-mediated neovasculogenesis in ischemic diseases
Mentions: To our knowledge, this study shows for the first time that hypo-ECFCs enhance the recovery of cells from vascular injury by modulating the STAT3/BCL3 axis via VEGF expression (Fig. 8). The therapeutic efficiency of ECFCs can thus be controlled by modifying the culture conditions or activation of the STAT3/BCL3 pathway, providing insights into the bioactivity circuit needed for ECFC therapy that will improve efficiency in clinical applications.Fig. 8

Bottom Line: 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.Hypoxia preconditioning facilitates functional bioactivities of ECFCs by mediating regulation of the STAT3-BCL3 axis.

View Article: PubMed Central - PubMed

Affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 140-743, Republic of Korea. ykckss1114@nate.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus