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Etude des effets des rayonnements ionisants sur la niche hématopoïétique et traitement du syndrome aigu d'irradiation par thérapie génique chez le macaque irradié à forte dose

Abstract : The hematopoietic stem cell niche represents a complex radiosensitive compartment whose protection is required for recovery from radiation-induced myelosuppression. We initially studied RI effects on endothelial and mesenchymal progenitors by an evaluating radiosensitivity and cell death. Then, we have proposed a new gene therapy strategy based on local and short term secretion of Sonic hedgehog morphogene to favour vascular niche repair and to stimulate residual hematopoietic stem and progenitor cells. We investigated the hematopoietic response of 8-Gy gamma irradiated monkeys to a single intra-osseous injection of xenogeneic multipotent mesenchymal stem cells transduced with a Shh pIRES2 plasmid. Thrombocytopenia and neutropenia duration were significantly reduced in grafted animals and clonogenics normalized from day 42. Areas under the curve of PLTs and ANCs between day 0 and day 30 were significantly higher in treated animals than in controls. Grafting MatrigelTM colonized or not with ASC in immunocompromized mice demonstrated a notable pro-angiogenic activity for Shh-ASC. Long term follow up (180-300 days) confirmed a durable recovery in the four grafted monkeys. Globally this study suggests that grafting Shh-multipotent stem cells may represent a new strategy to cure radiation-induced niche damage.
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Submitted on : Wednesday, October 12, 2011 - 10:27:20 AM
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Philippe Garrigou. Etude des effets des rayonnements ionisants sur la niche hématopoïétique et traitement du syndrome aigu d'irradiation par thérapie génique chez le macaque irradié à forte dose. Médecine humaine et pathologie. Université de Grenoble, 2011. Français. ⟨NNT : 2011GRENS016⟩. ⟨tel-00631339⟩

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