DISREGULATED MEGAKARYOCYTE MIGRATION AND MATURATION IS POSSIBLY DUE TO IMPAIRED BONE MARROW SYMPATHETIC NERVETHROUGH NESTIN+ MESENCHYMAL STEM CELL IN CHRONIC IMMUNE THROMBOCYTOPENIA
(Abstract release date: 05/19/16)
EHA Library. Su Y. 06/11/16; 135272; S516
Prof. Yan Su
Contributions
Contributions
Abstract
Abstract: S516
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H4
Background
Impaired megakaryocyte maturation and reduced platelet production is a most important mechanism responsible for immune thrombocytopenia (ITP).Megakaryocyte (MK) maturation in the bone marrow microenvironment (BMME) is accompanied by increased expression of CXCR4 andits migration from the endosteal niche to the vascularniche, where MKs intrude proplatelets into the bone marrow (BM)sinus to release platelets.Thrombopoietin(TPO) is the major physiological regulator of the proliferation and differentiation of MKs,whereas MK migration is regulated by sympathetic nerves and the chemokine CXCL12, which is mainly produced by nestin+ mesenchymal stem cells (MSCs) in the BM.There is no information regarding MK migration or BMME in ITP.
Aims
We sought to investigate the migration and maturation status of MKsin chronic ITP, to measure the sympathetic nervous response, which regulates the migration and maturation of MKs, and to assess the variationin nestin+ MSCs, which produce the potent chemokine CXCL12 under the regulation and protection of sympathetic nerves.
Methods
BM samples were obtained from chronic ITP patients and healthy haematopoietic stem cell donors.The distribution of MKs, sympathetic nerve fibres, Schwann cells and nestin+ MSCs in BMME was analysed by immunohistochemistry and/or immunofluorescence, and quantitative analyses were conducted using confocal microscopy. BM nestin+ MSCs were sorted by flowcytometry. The quantity and apoptosis of nestin+ MSCs and the surface markers CXCR4 and β3-adrenergic receptor (adrb3)on nestin+ MSCs and CXCL12+ nestin+ MSCs were further analysed by flowcytometry.The expression levels of CXCL12 and adrb3 in nestin+ MSCs wereanalysed by real-time quantitative PCR.
Results
The percentage of CD41+ MKs adjacent to the CD34+ BM sinus and CXCR4+CD41+MKs in the BM were both strikingly reduced in chronic ITP patients compared with normal controls.The concentration of CXCL12 was also significantly lower in the BM of ITP patients,and the percentage of CD41+ MKs in the vascular niche and of CXCR4+CD41+MKs correlated with the concentration of BMCXCL12. The percentage of nestin+ MSCs among CD45-CD31-CD235a- stromal cellsin normal controls was 3.8 times higher than that in chronic ITP patients.Consistently, the percentage of live nestin+ MSCs in normal controls was also significantly increased, whereas apoptosis of nestin+ MSCs in ITP patients was significantly increased compared with normal controls. The proportion of CXCL12+nestin+ MSCs in normal controls was much higher than that in ITP patients, which was correlated with the concentration of CXCL12 in the BM.Sympathetic nerve fibres and Schwann cells adjacent todistinctive nestin+ MSCs and vasculature weremarkedlyreduced in the BMof ITP patients, andthe neurotransmitternorepinephrine and adrb3 in nestin+ MSCs were both significantly reduced in ITP patients.
Conclusion
This isthe first report to describe BMME and megakaryocyte migration in chronic ITP. Our research suggests that reduced activity of BM sympathetic nervesis associated with impaired MK migration and maturation, resulting in reduced plateletproduction. With reducedBM sympathetic nerves innervation, nestin+ MSCs arefunctionally compromised and reduced due to increased apoptosis, enhancing the dysregulatedmigration and maturation of MKsvia diminished CXCL12 signalling through CXCR4 on MKs. Protection of sympathetic nerves that prevent MSCapoptosis may provide a potentially powerful strategy to promotethrombopoiesis.
Session topic: Platelet disorders 1
Keyword(s): Megakaryocyte, Mesenchymal stem cell
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H4
Background
Impaired megakaryocyte maturation and reduced platelet production is a most important mechanism responsible for immune thrombocytopenia (ITP).Megakaryocyte (MK) maturation in the bone marrow microenvironment (BMME) is accompanied by increased expression of CXCR4 andits migration from the endosteal niche to the vascularniche, where MKs intrude proplatelets into the bone marrow (BM)sinus to release platelets.Thrombopoietin(TPO) is the major physiological regulator of the proliferation and differentiation of MKs,whereas MK migration is regulated by sympathetic nerves and the chemokine CXCL12, which is mainly produced by nestin+ mesenchymal stem cells (MSCs) in the BM.There is no information regarding MK migration or BMME in ITP.
Aims
We sought to investigate the migration and maturation status of MKsin chronic ITP, to measure the sympathetic nervous response, which regulates the migration and maturation of MKs, and to assess the variationin nestin+ MSCs, which produce the potent chemokine CXCL12 under the regulation and protection of sympathetic nerves.
Methods
BM samples were obtained from chronic ITP patients and healthy haematopoietic stem cell donors.The distribution of MKs, sympathetic nerve fibres, Schwann cells and nestin+ MSCs in BMME was analysed by immunohistochemistry and/or immunofluorescence, and quantitative analyses were conducted using confocal microscopy. BM nestin+ MSCs were sorted by flowcytometry. The quantity and apoptosis of nestin+ MSCs and the surface markers CXCR4 and β3-adrenergic receptor (adrb3)on nestin+ MSCs and CXCL12+ nestin+ MSCs were further analysed by flowcytometry.The expression levels of CXCL12 and adrb3 in nestin+ MSCs wereanalysed by real-time quantitative PCR.
Results
The percentage of CD41+ MKs adjacent to the CD34+ BM sinus and CXCR4+CD41+MKs in the BM were both strikingly reduced in chronic ITP patients compared with normal controls.The concentration of CXCL12 was also significantly lower in the BM of ITP patients,and the percentage of CD41+ MKs in the vascular niche and of CXCR4+CD41+MKs correlated with the concentration of BMCXCL12. The percentage of nestin+ MSCs among CD45-CD31-CD235a- stromal cellsin normal controls was 3.8 times higher than that in chronic ITP patients.Consistently, the percentage of live nestin+ MSCs in normal controls was also significantly increased, whereas apoptosis of nestin+ MSCs in ITP patients was significantly increased compared with normal controls. The proportion of CXCL12+nestin+ MSCs in normal controls was much higher than that in ITP patients, which was correlated with the concentration of CXCL12 in the BM.Sympathetic nerve fibres and Schwann cells adjacent todistinctive nestin+ MSCs and vasculature weremarkedlyreduced in the BMof ITP patients, andthe neurotransmitternorepinephrine and adrb3 in nestin+ MSCs were both significantly reduced in ITP patients.
Conclusion
This isthe first report to describe BMME and megakaryocyte migration in chronic ITP. Our research suggests that reduced activity of BM sympathetic nervesis associated with impaired MK migration and maturation, resulting in reduced plateletproduction. With reducedBM sympathetic nerves innervation, nestin+ MSCs arefunctionally compromised and reduced due to increased apoptosis, enhancing the dysregulatedmigration and maturation of MKsvia diminished CXCL12 signalling through CXCR4 on MKs. Protection of sympathetic nerves that prevent MSCapoptosis may provide a potentially powerful strategy to promotethrombopoiesis.
Session topic: Platelet disorders 1
Keyword(s): Megakaryocyte, Mesenchymal stem cell
Abstract: S516
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H4
Background
Impaired megakaryocyte maturation and reduced platelet production is a most important mechanism responsible for immune thrombocytopenia (ITP).Megakaryocyte (MK) maturation in the bone marrow microenvironment (BMME) is accompanied by increased expression of CXCR4 andits migration from the endosteal niche to the vascularniche, where MKs intrude proplatelets into the bone marrow (BM)sinus to release platelets.Thrombopoietin(TPO) is the major physiological regulator of the proliferation and differentiation of MKs,whereas MK migration is regulated by sympathetic nerves and the chemokine CXCL12, which is mainly produced by nestin+ mesenchymal stem cells (MSCs) in the BM.There is no information regarding MK migration or BMME in ITP.
Aims
We sought to investigate the migration and maturation status of MKsin chronic ITP, to measure the sympathetic nervous response, which regulates the migration and maturation of MKs, and to assess the variationin nestin+ MSCs, which produce the potent chemokine CXCL12 under the regulation and protection of sympathetic nerves.
Methods
BM samples were obtained from chronic ITP patients and healthy haematopoietic stem cell donors.The distribution of MKs, sympathetic nerve fibres, Schwann cells and nestin+ MSCs in BMME was analysed by immunohistochemistry and/or immunofluorescence, and quantitative analyses were conducted using confocal microscopy. BM nestin+ MSCs were sorted by flowcytometry. The quantity and apoptosis of nestin+ MSCs and the surface markers CXCR4 and β3-adrenergic receptor (adrb3)on nestin+ MSCs and CXCL12+ nestin+ MSCs were further analysed by flowcytometry.The expression levels of CXCL12 and adrb3 in nestin+ MSCs wereanalysed by real-time quantitative PCR.
Results
The percentage of CD41+ MKs adjacent to the CD34+ BM sinus and CXCR4+CD41+MKs in the BM were both strikingly reduced in chronic ITP patients compared with normal controls.The concentration of CXCL12 was also significantly lower in the BM of ITP patients,and the percentage of CD41+ MKs in the vascular niche and of CXCR4+CD41+MKs correlated with the concentration of BMCXCL12. The percentage of nestin+ MSCs among CD45-CD31-CD235a- stromal cellsin normal controls was 3.8 times higher than that in chronic ITP patients.Consistently, the percentage of live nestin+ MSCs in normal controls was also significantly increased, whereas apoptosis of nestin+ MSCs in ITP patients was significantly increased compared with normal controls. The proportion of CXCL12+nestin+ MSCs in normal controls was much higher than that in ITP patients, which was correlated with the concentration of CXCL12 in the BM.Sympathetic nerve fibres and Schwann cells adjacent todistinctive nestin+ MSCs and vasculature weremarkedlyreduced in the BMof ITP patients, andthe neurotransmitternorepinephrine and adrb3 in nestin+ MSCs were both significantly reduced in ITP patients.
Conclusion
This isthe first report to describe BMME and megakaryocyte migration in chronic ITP. Our research suggests that reduced activity of BM sympathetic nervesis associated with impaired MK migration and maturation, resulting in reduced plateletproduction. With reducedBM sympathetic nerves innervation, nestin+ MSCs arefunctionally compromised and reduced due to increased apoptosis, enhancing the dysregulatedmigration and maturation of MKsvia diminished CXCL12 signalling through CXCR4 on MKs. Protection of sympathetic nerves that prevent MSCapoptosis may provide a potentially powerful strategy to promotethrombopoiesis.
Session topic: Platelet disorders 1
Keyword(s): Megakaryocyte, Mesenchymal stem cell
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H4
Background
Impaired megakaryocyte maturation and reduced platelet production is a most important mechanism responsible for immune thrombocytopenia (ITP).Megakaryocyte (MK) maturation in the bone marrow microenvironment (BMME) is accompanied by increased expression of CXCR4 andits migration from the endosteal niche to the vascularniche, where MKs intrude proplatelets into the bone marrow (BM)sinus to release platelets.Thrombopoietin(TPO) is the major physiological regulator of the proliferation and differentiation of MKs,whereas MK migration is regulated by sympathetic nerves and the chemokine CXCL12, which is mainly produced by nestin+ mesenchymal stem cells (MSCs) in the BM.There is no information regarding MK migration or BMME in ITP.
Aims
We sought to investigate the migration and maturation status of MKsin chronic ITP, to measure the sympathetic nervous response, which regulates the migration and maturation of MKs, and to assess the variationin nestin+ MSCs, which produce the potent chemokine CXCL12 under the regulation and protection of sympathetic nerves.
Methods
BM samples were obtained from chronic ITP patients and healthy haematopoietic stem cell donors.The distribution of MKs, sympathetic nerve fibres, Schwann cells and nestin+ MSCs in BMME was analysed by immunohistochemistry and/or immunofluorescence, and quantitative analyses were conducted using confocal microscopy. BM nestin+ MSCs were sorted by flowcytometry. The quantity and apoptosis of nestin+ MSCs and the surface markers CXCR4 and β3-adrenergic receptor (adrb3)on nestin+ MSCs and CXCL12+ nestin+ MSCs were further analysed by flowcytometry.The expression levels of CXCL12 and adrb3 in nestin+ MSCs wereanalysed by real-time quantitative PCR.
Results
The percentage of CD41+ MKs adjacent to the CD34+ BM sinus and CXCR4+CD41+MKs in the BM were both strikingly reduced in chronic ITP patients compared with normal controls.The concentration of CXCL12 was also significantly lower in the BM of ITP patients,and the percentage of CD41+ MKs in the vascular niche and of CXCR4+CD41+MKs correlated with the concentration of BMCXCL12. The percentage of nestin+ MSCs among CD45-CD31-CD235a- stromal cellsin normal controls was 3.8 times higher than that in chronic ITP patients.Consistently, the percentage of live nestin+ MSCs in normal controls was also significantly increased, whereas apoptosis of nestin+ MSCs in ITP patients was significantly increased compared with normal controls. The proportion of CXCL12+nestin+ MSCs in normal controls was much higher than that in ITP patients, which was correlated with the concentration of CXCL12 in the BM.Sympathetic nerve fibres and Schwann cells adjacent todistinctive nestin+ MSCs and vasculature weremarkedlyreduced in the BMof ITP patients, andthe neurotransmitternorepinephrine and adrb3 in nestin+ MSCs were both significantly reduced in ITP patients.
Conclusion
This isthe first report to describe BMME and megakaryocyte migration in chronic ITP. Our research suggests that reduced activity of BM sympathetic nervesis associated with impaired MK migration and maturation, resulting in reduced plateletproduction. With reducedBM sympathetic nerves innervation, nestin+ MSCs arefunctionally compromised and reduced due to increased apoptosis, enhancing the dysregulatedmigration and maturation of MKsvia diminished CXCL12 signalling through CXCR4 on MKs. Protection of sympathetic nerves that prevent MSCapoptosis may provide a potentially powerful strategy to promotethrombopoiesis.
Session topic: Platelet disorders 1
Keyword(s): Megakaryocyte, Mesenchymal stem cell
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