Neurovascular Lesions
Team
Brigitte Onteniente: Research Director DR2 (INSERM)
Michel Cailleret : Research Engineer (INSERM)
Michel Cailleret : Research Engineer (INSERM)
Valérie Itier : Professor (University Paris 12)
Jerôme Polentes: Associate scientist (CECS)
Marion Brénot : Qualified research technician (CECS)
Olivier Chose : Associate scientist (CECS)
Marion Brénot : Qualified research technician (CECS)
Olivier Chose : Associate scientist (CECS)
Ischemic stroke is a leading cause of death and long-term disability, and accounts for a large proportion of the health care costs of industrialized countries. Although stroke is mainly of polygenic origin, a large number of single-gene disorders such as hypercoagulable states, nonatherosclerotic vasculopathies and cardiac, hematologic, or connective disorders have been described as well-known causes of stroke. In addition, a number of monogenic stroke disorders exist that are related to small and large arterial abnormalities leading to stenosis, occlusion, and dissection of blood vessels. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), CARecessiveASIL, hereditary endotheliopathies, Fabry disease, pseudoxanthoma elasticum, type 1 neurofibromatosis, familial MoyaMoya disease, type IV Ehlers-Danlos syndrome, and the Marfan syndrome. Despite substantial research into cytoprotection, and a remarkable number of positive results from laboratories, no efficient agent has been shown conclusively to be clinically effective in acute neurovascular lesions to date.
Our studies aim at defining new therapeutic strategies to decrease the clinical consequences of cerebrovascular lesions. Approaches include stem cell therapy and protein therapy with an original anti-ischemic fusion protein.
Determining the potential and optimal conditions of embryonic stem cell therapy in stroke
The use of stem cells with multipotent properties has become a challenging research field for most clinical areas. It is of particular importance in disciplines that desperately lack treatment options, such as stroke. Given their expected capacity to self-renew and differentiate efficiently into the desired cell type, clonal populations of stem cells (SC) promise to produce beneficial effects in a number of diseases.Several studies indicate that SC transplantation has a therapeutic potential in stroke, with sources of SC that include embryonic, foetal and adult SC, and lines derived from teratoma. However, much crucial information is still laking before SC transplantation becomes a clinical reality. For produce the "ideal" graft need to be better defined; changes in their properties induced by transplantation into lesioned brain structures are poorly understood, as is the full extent of functional improvement at long-term post-stroke delays.
Totally preclinically-oriented, our work relies on the development of imaging and behavioural techniques for experimental research that allow a direct comparison with data obtained in clinical settings. Our main objectives are to:
• Identify the transplant (type of cell line, stage of differentiation, number of cells), and transplantation procedures (location of the transplant, post-stroke delay), which provide the best long-term functional recovery.
• Establish a correlation between structural, imaging, and functional parameters, to define links between non-invasive imaging and histological assessments of brain damage.
• Quantify the potential of SC therapy in non-human primates transplanted according to the optimal procedures determined in rodents.
• Identify the transplant (type of cell line, stage of differentiation, number of cells), and transplantation procedures (location of the transplant, post-stroke delay), which provide the best long-term functional recovery.
• Establish a correlation between structural, imaging, and functional parameters, to define links between non-invasive imaging and histological assessments of brain damage.
• Quantify the potential of SC therapy in non-human primates transplanted according to the optimal procedures determined in rodents.
Characterizing host-graft interactions that are crucial for the survival, differentiation and integration of transplanted progenitors
The ischemic brain is the site of extensive remodeling in the chronic phase, with secretion of a number of factors that are known to influence the proliferation and differentiation of neural progenitors, i.e. cytokines, chemokines and neurotrophic factors. The impact of such reactions on SC is still unknown. As a counterpart, grafted cells release a number of factors that can help the self-repair mechanisms of the host brain. This part of the project aims more specifically at characterizing the interactions between grafted ES-derived progenitors and their ischemic host brain. It is our assumption that the molecular dialogue that host tissues and grafted cells establish contains key factors that can be used to improve the integration of grafted cells, minimize adverse effects and increase the functional benefit of SC therapy in stroke. This part of the project is performed in the frame of the regional IngeCELL program (Medicen Paris Region, http://www.medicen.org/).
Determining the potential of protein therapy with an anti-ischemic fusion protein
Protein therapy is routinely used for a number of recombinant proteins, including interferons, growth hormone, erythropoïetin or insulin. The complex panel of actions of biological proteins explains the great efficacy of drugs that cannot be reproduced by small chemicals.
With this concept in mind, we have designed and produced a fusion protein, now named TAT-XT, which links the HIV1-TAT protein transduction domain to two domains of the X chromosome-linked inhibitor of apoptosis (XIAP, Guegan et al., 2006). XIAP is an ideally pleiotropic molecule that combines inhibition of several caspases and death pathways with activation of pathways responsible for post-ischemic survival and remodeling. Coupling with TAT confers the protein the ability to cross any cell membrane and the blood-brain barrier.
The proof of concept has been obtained in two models of stroke (rat and mice, permanent and transient MCAO) and in a model of cardiac ischemia.
We now focus on the actions of TAT-XT on the origin of the brain damage, i.e. the endothelial compartment. Reinforcing the resistance of arterial walls to ischemia might decrease the occurrence of ischemic lesions. This part of the work is performed in collaboration with Regis Bordet (Lab Pharmacology, University of Lille).
With this concept in mind, we have designed and produced a fusion protein, now named TAT-XT, which links the HIV1-TAT protein transduction domain to two domains of the X chromosome-linked inhibitor of apoptosis (XIAP, Guegan et al., 2006). XIAP is an ideally pleiotropic molecule that combines inhibition of several caspases and death pathways with activation of pathways responsible for post-ischemic survival and remodeling. Coupling with TAT confers the protein the ability to cross any cell membrane and the blood-brain barrier.
The proof of concept has been obtained in two models of stroke (rat and mice, permanent and transient MCAO) and in a model of cardiac ischemia.
We now focus on the actions of TAT-XT on the origin of the brain damage, i.e. the endothelial compartment. Reinforcing the resistance of arterial walls to ischemia might decrease the occurrence of ischemic lesions. This part of the work is performed in collaboration with Regis Bordet (Lab Pharmacology, University of Lille).
