EU Vascular Genomics Network
General research aims:
The research groups in this network aim at identifying and characterizing endothelial progenitor cells (EPCs) as well as defining the ideal conditions for their expansion, homing to ischaemic organs and production of growth factors for new vessel formation. In particular, they intend:
- to compare gene expression profiles of EPCs isolated from human blood to those of differentiated human endothelial cells, CD34+ cells from bone marrow, or CD14+ mononuclear cells.
- to characterize EPCs isolated from different sources (human blood, mouse bone marrow and ischaemic organ microcirculation), as well as stable EPC lines.
- to optimise EPC homing by identifying relevant molecules and attractors able to induce their reciprocal interaction.
- to identify growth factor receptors and the corresponding signalling pathways present in EPC.
- to localise EPCs in ischaemic organs and to evaluate their effects on organ function.
These goals are being pursued by the establishment of a database for gene profile analysis of endothelial progenitors cell, development of specific viral vectors and the employment of other major techniques made available by post-genomic and trabscriptional tools.
- to characterize EPCs isolated from different sources (human blood, mouse bone marrow and ischaemic organ microcirculation), as well as stable EPC lines.
- to optimise EPC homing by identifying relevant molecules and attractors able to induce their reciprocal interaction.
- to identify growth factor receptors and the corresponding signalling pathways present in EPC.
- to localise EPCs in ischaemic organs and to evaluate their effects on organ function.
Another goal is the development of animal models for the evaluation of the efficacy of cell-based therapy, to improve neovascularisation in ischaemic areas and to promote post-ischaemic tissue regeneration.
A third important objective is to compare the capacity of different stem/progenitor cell subtypes for potential use as cell therapy. The use of stem/progenitor cells as vehicles for angiogenic or anti-apoptotic genes is certainly a priority. In addition, the effect of EPCs number and activity in several models of ischemia (hypertension, diabetes, aging, atherosclerosis, myocardial infarction) is being investigating. Practical applications at clinical centres of the EVGN aim to:
- characterise circulating endothelial progenitor cells in patients with risk factors for coronary artery disease.
- establish a novel repair index for vascular regeneration, stemming from the simultaneous measurement of markers of ongoing endothelial cell injury and circulating endothelial progenitor cells.
- pursue cell therapy with most effective progenitor cells.
- establish a novel repair index for vascular regeneration, stemming from the simultaneous measurement of markers of ongoing endothelial cell injury and circulating endothelial progenitor cells.
- pursue cell therapy with most effective progenitor cells.
Major results achieved:
Among some of the important results achieved by EVGN in the field of clinical EPCs studies there is one providing evidence that high numbers of circulating Endothelial Progenitor Cells (EPCs) correlate to a reduced cardiovascular risk. These findings have profound therapeutic implications as they confirm that current trials aiming at increasing the number of progenitor cells in the damaged area point to the right direction.
Another recent study revealed a basic mechanism directing the progenitor cells to the right organs during blood vessel growth. The "instructing" growth factor is called VEGF (Vascular Endothelial Growth Factor) and its key role in the adult neovascularization process (growth and correct positioning of new blood vessels when and where needed, also called angiogenesis) was recently demonstrated by EVGN scientists.
A recent human clinical trial (TOPCARE-AMI) succeeded in regenerating damaged heart tissue, and obtaining functional recovery of the cardiac muscle, after progenitor cells - isolated from the bone marrow of AMI patients - were reintroduced in the same donor's organism. More than 200 patients were enrolled in the trial and received the therapeutic cells. With respect with a group of untreated patients, these showed a marked positive effect on the remodeling process of the cardiac tissue and an improvement in the growth process of new blood vessels within the infarct area. This trial was the first one to prove a real potential of the cell therapy in the heart attack treatment.
Research groups involved in the network:
This research group works on the role of apoptosis and inflammation in atherothrombosis. It provided the first evidence that apoptotic microparticles that accumulate within the atherosclerotic plaque are a major determinant of plaque thrombogenicity, and proposed endothelial apoptosis as a trigger of plaque surface erosion and thrombosis. Circulating microparticle levels are markedly enhanced patients with acute coronary syndromes or myocardial infarction, and retain the potential of inducing endothelial dysfunction. The group also studies the role of the inflammatory balance in plaque development and stability.
This research group has developed and optimised conditions of embryonic stem cell (ES) differentiation to endothelial cells. The group has isolated, cultured and immortalized endothelial cells from ES cells and is comparing their functional behaviour with that of ECs obtained from early embryos or adult tissues. It has shown that endothelial cell lines from different sources (bone marrow, embryo or ES) are able to incorporate and transdifferentiate to cardiomyocytes in the ischemic heart.
Within the last years, the clinical use of stem/progenitor cells for vascular and cardiac regeneration is the major current focus of this group and in general of the whole Department. With a strong motivatine towards clinically oriented study, this group took part in the human clinical trial TOPCARE-AMI performed on patients with a recent acute myocardial infarction (AMI).
This research group is addressing endothelial progenitor cell mobilisation, differentiation and homing and their contribution to vascular and cardiac regeneration. A clinically-oriented approach allowed this group to lead part of the clinical experiments in the TOPCARE-AMI study. In this study, progenitor cells proved to be able to regenerate damaged heart tissue also providing functional recovery of cardiac muscle.
This research group is studying the molecular mechanisms supporting the development of vascular system in embryo and in adult life. Evidences that nerves and blood vessels follow similar routes of migration during embryogenesis and parallel in some anatomical districts in adult life suggest that molecular pathways may be shared, and led the group to assess the role of molecules identified in axon guidance and in synapses formation (semaphorins, neuropilins and neurexins) as players in vascular tracking.
This research group focuses its activities on the pleiotropic roles of VEGF in neovascularization and vascular maintenance, especially on the ability of VEGF to mediate vascular adjustments to perturbations in oxygen levels, its role as a vascular survival factor and its new emerging role in orchestrating the recruitment of endothelial progenitor cells for adult neovascularization. The group makes extensive use of genetically engineered mice for critical evaluation of the feasibility of pro-angiogenic therapy.
This research group is characterizing genes involved in adhesion and homing of endothelial progenitor cells (EPCs). This group conducts clinical research focussed on the investigation of the correlation between circulating numbers of EPCs, cardiovascular outcome and endothelial function. Among its objectives there is a clinical study involving 500 patients with coronary artery disease, and the clinical evaluation of the angiogenic potential of circulating EPCs.
