Final Report Summary - VASC-GEN (Endoglin-Mediated Vascular Regeneration to Promote Heart Repair)
Cardiovascular disease is the number one cause of death worldwide. According to statistics (British Heart Foundation, 2014), there were over 175,000 episodes of acute myocardial infarction (MI) in the United Kingdom in 2012. MI, also known as a heart attack, is most commonly due to the obstruction of coronary vessels by blood clots forming over a ruptured plaque. The loss of the local vascular supply initially leads to loss of cardiomyocyte function and subsequently to irreversible cardiomyocyte necrosis, scarring and reduced cardiac function. Although the overall mortality of MI has been decreasing over the past decades – due to improvement in acute therapy – heart failure prevalence is rising as those who have survived acute heart condition eventually develop heart failure in the future. There is a major and urgent need to further improve the clinical treatments for MI patients to reduce cardiomyocyte cell death and preserve heart function. This key advance in therapy depends on improving the vascular supply to the infarcted region as rapidly as possible.
It has been recently found that a heterogeneous cardiac stem cell population cultured from heart tissue biopsies and known as the cardiosphere derived cells (CDCs) are able to significantly rescue heart function in pre-clinical MI models. Research is ongoing to investigate the pro-angiogenic roles of CDCs in heart repair, with the aim of using these cells in early intervention therapies. These CDCs promote heart repair by releasing factors that enhance various repair processes including new vessel formation (angiogenesis) and this ability is reduced when the endoglin gene is lacking. The EU funded Intra-European Fellowship VASC-GEN is focused on the comparison of the CDC’s secretome with and without endoglin in order to identify the key combinations of pro-angiogenic factors in the secretome.
In this report we summarize the research activity performed by Dr. Simon Tual-Chalot (STC, the fellow) during the Marie-Curie IEF at the Institute of Genetic Medicine, Newcastle University under the supervision of Pr. Helen Arthur.
During this project, STC compared the secretome of endoglin-positive and endoglin deleted CDCs in vitro. This required being proficient in CDCs culture. He then showed the secretome of CDCs promoted angiogenesis, and that this process was endoglin-dependent. He also determined which part of the pro-angiogenic process was affected.
After several proteomics approaches, STC compared the secretome of CDCs with and without endoglin and explored the microvesicles contribution of the pro-angiogenic effect of the CDCs. After being proficient in the mouse myocardial infarction as well as in using mouse cardiac MRI to analyse heart function, the fellow examined the influence of CDCs with and without endoglin on cardiac repair after myocardial infarct.
STC achieved many significant results related to the main objectives of the VASC-GEN project. First of all, STC confirmed the requirement for endoglin in the paracrine process of CDC-mediated angiogenesis. The fellow then established that endoglin expression in CDCs leads to paracrine effects that enhance endothelial cell proliferation without affecting cell metabolic activity and found that the endoglin expression in the secretome of CDCs positively affects angiogenesis by enhancing endothelial cell migration in vitro. In addition, the fellow identified 10 angiogenesis related proteins, including several associated with the TGFbeta signalling pathway, that are downregulated in the secretome of the CDCs without endoglin compared to the secretome of CDCs with endoglin. Using mass spectrometry analysis of the whole secretome, STC found that proteins from the SMAD binding family, from the Platelet Derived Growth Factor binding family as well as extracellular matrix proteins are dysregulated in the secretome of CDCs without endoglin. The fellow then established that the pro-angiogenic effect of CDCs is not generated by the microvesicles and therefore must reside in the microvesicle- independent secretome. Using a mouse model of myocardial infarction, the fellow did not confirm any beneficial effect of CDCs on the cardiac function, but did show that CDCs had reduced paracrine pro-angiogenic effects in the absence of endoglin in vivo that promoted the formation of new, functional (perfused) and mature (muscularised) vessels.
So far, only a few studies have explored the mechanisms of cardiac regeneration following administration of CDCs. The goal of our project was to determine which proteins secreted from CDCs can promote heart repair.
With this work, we have highlighted that the positive-endoglin-CDCs have an enriched pro-angiogenic secretome, and we have characterised their pro-angiogenic properties. These finding will be submitted for publication in the near future to a high-ranking international scientific journal (we aim for Circulation, IF: 14.94). An additional manuscript identifying early predictors of progressive adverse remodelling in a mouse model of myocardial infarction will be submitted to the American Journal of Physiology Heart Circ Physiol
(IF 4) in August 2015.
In the long term, identification of the pro-angiogenic factors in the CDC secretome will lead us to the use of nanobeads able to generate controlled release of the essential pro-angiogenic proteins as an optimal therapy for ischaemic disease.
Scientist in charge:
Pr. Helen Arthur
Institute of Genetic Medicine
International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ
Tel: +44 (0) 191 241 8648
E-mail: helen.arthur@ncl.ac.uk
Internet site: http://www.ncl.ac.uk/igm/staff/profile/helen.arthur(se abrirá en una nueva ventana)
Marie-Curie Fellow:
Dr. Simon Tual-Chalot
Institute of Genetic Medicine
International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ
Tel: +44 (0) 191 241 8690
E-mail: simon.tual-chalot@ncl.ac.uk
Internet site: http://www.ncl.ac.uk/igm/staff/profile/simon.tual-chalot(se abrirá en una nueva ventana)
It has been recently found that a heterogeneous cardiac stem cell population cultured from heart tissue biopsies and known as the cardiosphere derived cells (CDCs) are able to significantly rescue heart function in pre-clinical MI models. Research is ongoing to investigate the pro-angiogenic roles of CDCs in heart repair, with the aim of using these cells in early intervention therapies. These CDCs promote heart repair by releasing factors that enhance various repair processes including new vessel formation (angiogenesis) and this ability is reduced when the endoglin gene is lacking. The EU funded Intra-European Fellowship VASC-GEN is focused on the comparison of the CDC’s secretome with and without endoglin in order to identify the key combinations of pro-angiogenic factors in the secretome.
In this report we summarize the research activity performed by Dr. Simon Tual-Chalot (STC, the fellow) during the Marie-Curie IEF at the Institute of Genetic Medicine, Newcastle University under the supervision of Pr. Helen Arthur.
During this project, STC compared the secretome of endoglin-positive and endoglin deleted CDCs in vitro. This required being proficient in CDCs culture. He then showed the secretome of CDCs promoted angiogenesis, and that this process was endoglin-dependent. He also determined which part of the pro-angiogenic process was affected.
After several proteomics approaches, STC compared the secretome of CDCs with and without endoglin and explored the microvesicles contribution of the pro-angiogenic effect of the CDCs. After being proficient in the mouse myocardial infarction as well as in using mouse cardiac MRI to analyse heart function, the fellow examined the influence of CDCs with and without endoglin on cardiac repair after myocardial infarct.
STC achieved many significant results related to the main objectives of the VASC-GEN project. First of all, STC confirmed the requirement for endoglin in the paracrine process of CDC-mediated angiogenesis. The fellow then established that endoglin expression in CDCs leads to paracrine effects that enhance endothelial cell proliferation without affecting cell metabolic activity and found that the endoglin expression in the secretome of CDCs positively affects angiogenesis by enhancing endothelial cell migration in vitro. In addition, the fellow identified 10 angiogenesis related proteins, including several associated with the TGFbeta signalling pathway, that are downregulated in the secretome of the CDCs without endoglin compared to the secretome of CDCs with endoglin. Using mass spectrometry analysis of the whole secretome, STC found that proteins from the SMAD binding family, from the Platelet Derived Growth Factor binding family as well as extracellular matrix proteins are dysregulated in the secretome of CDCs without endoglin. The fellow then established that the pro-angiogenic effect of CDCs is not generated by the microvesicles and therefore must reside in the microvesicle- independent secretome. Using a mouse model of myocardial infarction, the fellow did not confirm any beneficial effect of CDCs on the cardiac function, but did show that CDCs had reduced paracrine pro-angiogenic effects in the absence of endoglin in vivo that promoted the formation of new, functional (perfused) and mature (muscularised) vessels.
So far, only a few studies have explored the mechanisms of cardiac regeneration following administration of CDCs. The goal of our project was to determine which proteins secreted from CDCs can promote heart repair.
With this work, we have highlighted that the positive-endoglin-CDCs have an enriched pro-angiogenic secretome, and we have characterised their pro-angiogenic properties. These finding will be submitted for publication in the near future to a high-ranking international scientific journal (we aim for Circulation, IF: 14.94). An additional manuscript identifying early predictors of progressive adverse remodelling in a mouse model of myocardial infarction will be submitted to the American Journal of Physiology Heart Circ Physiol
(IF 4) in August 2015.
In the long term, identification of the pro-angiogenic factors in the CDC secretome will lead us to the use of nanobeads able to generate controlled release of the essential pro-angiogenic proteins as an optimal therapy for ischaemic disease.
Scientist in charge:
Pr. Helen Arthur
Institute of Genetic Medicine
International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ
Tel: +44 (0) 191 241 8648
E-mail: helen.arthur@ncl.ac.uk
Internet site: http://www.ncl.ac.uk/igm/staff/profile/helen.arthur(se abrirá en una nueva ventana)
Marie-Curie Fellow:
Dr. Simon Tual-Chalot
Institute of Genetic Medicine
International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ
Tel: +44 (0) 191 241 8690
E-mail: simon.tual-chalot@ncl.ac.uk
Internet site: http://www.ncl.ac.uk/igm/staff/profile/simon.tual-chalot(se abrirá en una nueva ventana)