Les cèl·lules progenitores endotelials com a tractament neuroreparador angiovasculogènic en la isquèmia cerebral modulat per la metal·loproteïnasa de matriu 9 (mmp-9)

Student thesis: Doctoral thesis

Abstract

Nowadays acute ischemic brain disease, which has a complex pathophysiology, remains one of the most important causes of death and disability worldwide. Currently the only possible treatment is the thrombolytic therapy with tissue plasminogen activator (rt-PA), that can be administered only in the hyperacute phase of ischemic stroke (<4.5 hours). Therefore, it is necessary to investigate new therapies that could be applicable after the hyperacute phase to increase the number of treated patients. Neurorepair therapies are therapeutic approaches that allow restoring cerebral circulation and promoting neuroregeneration. To achieve these objectives it is necessary to enhance angiogenesis and neurogenesis in the ischemic brain. The aim of this thesis is to study the neuropair potential of endothelial progenitor cells (EPCS) and the role of MMP-9 in its modulation. Using a model of permanent cerebral ischemia in mice, we studied the therapeutic potential of EPCs and their secreted factors. The results show an increase of angiogenesis in animals receiving the aforementioned treatments, demonstrating for the first time the therapeutic potential of growth factors secreted by EPCs in a model of cerebral ischemia and providing a tool for autologous pro-angiogenic cell-free therapies. Since it is known that matrix metalloproteinases (MMPs) are required for the extracellular remodeling that occurs during angiogenesis and neurogenesis, this thesis explores the role of MMP-9 as a key molecule in the regulation of pro-angiogenic therapies after cerebral ischemia. In addition, the role of ischemia in the activation and mobilization of the EPCs has also been studied. The results of this thesis show that cerebral ischemia stimulates the release of EPCs to circulation. Furthermore we have also demonstrated that MMP-9 deficiency causes a decrease in the number of circulating EPCs in control animals, which is reversed after the ischemic insult. In vitro tubulogenesis studies showed an increased angiogenic capacity in cells obtained from ischemic animals compared with non-ischemic as well as a decrease of these abilities in MMP-9 deficient animals. The pharmacological inhibition of MMPs, specifically MMP-9 in human EPCs showed the same results, confirming the role of this metalloproteinase in the in vitro angio-vasculogenic abilities of EPCs. Finally, we have developed a model of transient cerebral ischemia in mice by occlusion of the distal middle cerebral artery by compression. This model, with a well-defined cortical infarct and the presence of tissue reperfusion, has a greater homology with human disease and allows us to continue the neurorepair studies in the presence of reperfusion.
Date of Award4 Apr 2014
Original languageCatalan
SupervisorAnna Rosell Novel (Director) & Joan Montaner Villalonga (Director)

Keywords

  • EPC
  • Angiogenisi
  • Stoke

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