INTERFERON ALPHA MEDIATED REMODELING OF THE BONE MARROW STEM CELL VASCULAR NICHE
(Abstract release date: 05/19/16)
EHA Library. Prendergast Á. 06/10/16; 135176; S143
Dr. Áine M Prendergast
Contributions
Contributions
Abstract
Abstract: S143
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Room H5
Background
Bone marrow endothelial cells (ECs) are a major part of the bone marrow (BM) vascular niche, regulating hematopoietic stem cell (HSC) function and fate. Furthermore, ECs significantly influence the response of an organism to infection, the primary response to which involves synthesis of immune-modulatory cytokines, such as interferon alpha (IFNα). In contrast to the anti-proliferative effect of IFNα on HSCs in vitro, we, and others, have shown that IFNα induces cell cycle entry of HSCs in vivo. Here we have investigated the result of acute IFNα treatment on the BM vascular niche in vivo.
Aims
To investigate the stimulatory effects of acute IFNα treatment on the BM stem cell vascular niche and its role in the chemotherapeutic response.
Methods
To characterize the response of the BM vascular niche to IFNα, wild-type mice were treated with recombinant IFNα or pI:C and were sacrificed 4h or 24h later. BM ECs were subsequently assessed for key inflammatory and EC-stimulatory markers by FACS. IFNα-mediated increased BM vascularity was quantified by in vivo labelling using Alexa 633. BM vessel integrity was assessed using the Evans blue assay. VEGF signalling was antagonized using the Anti-VEGF treatment, Avastin. Mice were co-treated with 5-FU and pI:C to evaluate the effect of IFNα-signalling of chemotherapeutic treatment.
Results
IFNα treatment induced a rapid stimulation of BM ECs in vivo, resulting in increased bone marrow (BM) vascularity and vascular leakage. IFNα-mediated activation of ECs involved the expression of key inflammatory and EC-stimulatory markers. Abrogation of BM EC activation in vivo, using the Anti-VEGF treatment, Avastin, linked VEGF signalling, mediated by BM cell types including HSCs, to IFNα-mediated activation of ECs. Finally, following a period of recovery, IFNα-signalling led to a rapid recovery of 5-FU-mediated cell activation and BM homeostasis.
Conclusion
Our data shows that IFNα stimulation in vivo leads to remodelling of the BM stem cell vascular niche, mediated by VEGF. These data increase our current understanding of the effect of IFNα and anti-VEGF treatment on HSCs and the stem cell niche in vivo. IFNα-mediated recovery from 5-FU treatment has obvious implications for therapy, and thus this effect may influence the clinical application of IFNα.
Session topic: Stem cells and the microenvironment
Keyword(s): Endothelial cell, Hematopoietic microenvironment, Inflammation, Stem cell niche
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Room H5
Background
Bone marrow endothelial cells (ECs) are a major part of the bone marrow (BM) vascular niche, regulating hematopoietic stem cell (HSC) function and fate. Furthermore, ECs significantly influence the response of an organism to infection, the primary response to which involves synthesis of immune-modulatory cytokines, such as interferon alpha (IFNα). In contrast to the anti-proliferative effect of IFNα on HSCs in vitro, we, and others, have shown that IFNα induces cell cycle entry of HSCs in vivo. Here we have investigated the result of acute IFNα treatment on the BM vascular niche in vivo.
Aims
To investigate the stimulatory effects of acute IFNα treatment on the BM stem cell vascular niche and its role in the chemotherapeutic response.
Methods
To characterize the response of the BM vascular niche to IFNα, wild-type mice were treated with recombinant IFNα or pI:C and were sacrificed 4h or 24h later. BM ECs were subsequently assessed for key inflammatory and EC-stimulatory markers by FACS. IFNα-mediated increased BM vascularity was quantified by in vivo labelling using Alexa 633. BM vessel integrity was assessed using the Evans blue assay. VEGF signalling was antagonized using the Anti-VEGF treatment, Avastin. Mice were co-treated with 5-FU and pI:C to evaluate the effect of IFNα-signalling of chemotherapeutic treatment.
Results
IFNα treatment induced a rapid stimulation of BM ECs in vivo, resulting in increased bone marrow (BM) vascularity and vascular leakage. IFNα-mediated activation of ECs involved the expression of key inflammatory and EC-stimulatory markers. Abrogation of BM EC activation in vivo, using the Anti-VEGF treatment, Avastin, linked VEGF signalling, mediated by BM cell types including HSCs, to IFNα-mediated activation of ECs. Finally, following a period of recovery, IFNα-signalling led to a rapid recovery of 5-FU-mediated cell activation and BM homeostasis.
Conclusion
Our data shows that IFNα stimulation in vivo leads to remodelling of the BM stem cell vascular niche, mediated by VEGF. These data increase our current understanding of the effect of IFNα and anti-VEGF treatment on HSCs and the stem cell niche in vivo. IFNα-mediated recovery from 5-FU treatment has obvious implications for therapy, and thus this effect may influence the clinical application of IFNα.
Session topic: Stem cells and the microenvironment
Keyword(s): Endothelial cell, Hematopoietic microenvironment, Inflammation, Stem cell niche
Abstract: S143
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Room H5
Background
Bone marrow endothelial cells (ECs) are a major part of the bone marrow (BM) vascular niche, regulating hematopoietic stem cell (HSC) function and fate. Furthermore, ECs significantly influence the response of an organism to infection, the primary response to which involves synthesis of immune-modulatory cytokines, such as interferon alpha (IFNα). In contrast to the anti-proliferative effect of IFNα on HSCs in vitro, we, and others, have shown that IFNα induces cell cycle entry of HSCs in vivo. Here we have investigated the result of acute IFNα treatment on the BM vascular niche in vivo.
Aims
To investigate the stimulatory effects of acute IFNα treatment on the BM stem cell vascular niche and its role in the chemotherapeutic response.
Methods
To characterize the response of the BM vascular niche to IFNα, wild-type mice were treated with recombinant IFNα or pI:C and were sacrificed 4h or 24h later. BM ECs were subsequently assessed for key inflammatory and EC-stimulatory markers by FACS. IFNα-mediated increased BM vascularity was quantified by in vivo labelling using Alexa 633. BM vessel integrity was assessed using the Evans blue assay. VEGF signalling was antagonized using the Anti-VEGF treatment, Avastin. Mice were co-treated with 5-FU and pI:C to evaluate the effect of IFNα-signalling of chemotherapeutic treatment.
Results
IFNα treatment induced a rapid stimulation of BM ECs in vivo, resulting in increased bone marrow (BM) vascularity and vascular leakage. IFNα-mediated activation of ECs involved the expression of key inflammatory and EC-stimulatory markers. Abrogation of BM EC activation in vivo, using the Anti-VEGF treatment, Avastin, linked VEGF signalling, mediated by BM cell types including HSCs, to IFNα-mediated activation of ECs. Finally, following a period of recovery, IFNα-signalling led to a rapid recovery of 5-FU-mediated cell activation and BM homeostasis.
Conclusion
Our data shows that IFNα stimulation in vivo leads to remodelling of the BM stem cell vascular niche, mediated by VEGF. These data increase our current understanding of the effect of IFNα and anti-VEGF treatment on HSCs and the stem cell niche in vivo. IFNα-mediated recovery from 5-FU treatment has obvious implications for therapy, and thus this effect may influence the clinical application of IFNα.
Session topic: Stem cells and the microenvironment
Keyword(s): Endothelial cell, Hematopoietic microenvironment, Inflammation, Stem cell niche
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Room H5
Background
Bone marrow endothelial cells (ECs) are a major part of the bone marrow (BM) vascular niche, regulating hematopoietic stem cell (HSC) function and fate. Furthermore, ECs significantly influence the response of an organism to infection, the primary response to which involves synthesis of immune-modulatory cytokines, such as interferon alpha (IFNα). In contrast to the anti-proliferative effect of IFNα on HSCs in vitro, we, and others, have shown that IFNα induces cell cycle entry of HSCs in vivo. Here we have investigated the result of acute IFNα treatment on the BM vascular niche in vivo.
Aims
To investigate the stimulatory effects of acute IFNα treatment on the BM stem cell vascular niche and its role in the chemotherapeutic response.
Methods
To characterize the response of the BM vascular niche to IFNα, wild-type mice were treated with recombinant IFNα or pI:C and were sacrificed 4h or 24h later. BM ECs were subsequently assessed for key inflammatory and EC-stimulatory markers by FACS. IFNα-mediated increased BM vascularity was quantified by in vivo labelling using Alexa 633. BM vessel integrity was assessed using the Evans blue assay. VEGF signalling was antagonized using the Anti-VEGF treatment, Avastin. Mice were co-treated with 5-FU and pI:C to evaluate the effect of IFNα-signalling of chemotherapeutic treatment.
Results
IFNα treatment induced a rapid stimulation of BM ECs in vivo, resulting in increased bone marrow (BM) vascularity and vascular leakage. IFNα-mediated activation of ECs involved the expression of key inflammatory and EC-stimulatory markers. Abrogation of BM EC activation in vivo, using the Anti-VEGF treatment, Avastin, linked VEGF signalling, mediated by BM cell types including HSCs, to IFNα-mediated activation of ECs. Finally, following a period of recovery, IFNα-signalling led to a rapid recovery of 5-FU-mediated cell activation and BM homeostasis.
Conclusion
Our data shows that IFNα stimulation in vivo leads to remodelling of the BM stem cell vascular niche, mediated by VEGF. These data increase our current understanding of the effect of IFNα and anti-VEGF treatment on HSCs and the stem cell niche in vivo. IFNα-mediated recovery from 5-FU treatment has obvious implications for therapy, and thus this effect may influence the clinical application of IFNα.
Session topic: Stem cells and the microenvironment
Keyword(s): Endothelial cell, Hematopoietic microenvironment, Inflammation, Stem cell niche
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