Cellules souches et revascularisation post-ischémique : mobilisation, recrutement et perspectives thérapeutiques

Abstract : Following ischemia, many molecular and cellular mechanisms compete to promote post-ischemic revascularization to minimize tissue damage. Bone marrow-derived progenitor and inflammatory cells are especially recruited into the ischemic tissue where they activate and participate in vascular and tissue regeneration. Their pro-angiogenic and pro-vasculogenic capacity also generate great interest in the development of new therapeutic strategies. The objective of this thesis has been to improve our understanding of the mechanisms governing the mobilization and recruitment of bone marrow-derived progenitor cells and to highlight the effectiveness of a treatment based on the use of stem cells to promote post-ischemic reperfusion. In a first work we have demonstrated that catecholamines (dopamine -DA- and norepinephrine -NE-) of the sympathetic nervous system regulate the mobilization of bone marrow-derived progenitor cells via eNOS-dependent signaling. We have shown that DA and NE increase the number of bone marrow-derived cells recruited into the ischemic tissue and stimulate their differentiation into endothelial or inflammatory phenotype cells, which promots post-ischemic revascularization.The recruitment of bone marrow cells also depends on chemokines, and particularly CXCL12 which is known to attract cells expressing CXCR4. The second work of this thesis has shown that the chemoattractant capacity of CXCL12 is also regulated by its ability to bind to heparan sulfate (HS), and thus, to adhere to the extracellular matrix. Indeed, strong interactions between CXCL12 and HS induce an increase in post-ischemic vascular regeneration correlated with better recruitment of bone marrow-derived cells in the injured tissue.Once recruited into the ischemic tissue, stem cells, because of their remarkable capacity of self-renewal, proliferation, differentiation and paracrine activity are excellent activators of post-ischemic revascularization. The third study of this thesis highlights the effectiveness of pluripotent human embryonic stem cells to treat critical limb ischaemia. We also found that their therapeutic potential depends on the miR-21.These studies have demonstrated that the regulation of the mobilization and recruitment of stem cells control the post-ischemic revascularization and highlight the effectiveness of a treatment based on the use of stem cells to promote post-ischemic revascularization.
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Adèle Richart. Cellules souches et revascularisation post-ischémique : mobilisation, recrutement et perspectives thérapeutiques. Médecine humaine et pathologie. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05S014⟩. ⟨tel-00919394⟩

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