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Phenotyping the Biologic Diversity of Endothelial Cells

Final Activity Report Summary - ENDOTHELIOPATHY (Phenotyping the biologic diversity of endothelial cells)

In patients with diabetes, old age or cardiovascular diseases (CVD), small blood vessels decay and disappear. Tissues therefore lose their supply with oxygen and nutrients. This situation is referred to as ischaemia and underlies many life threatening conditions. Our main research goal was to develop strategies to counteract the development of ischaemia in diabetic and CVD patients.

We discovered that during diabetes, small vessels were also lost in the bone marrow (BM). This was of particular importance as the BM is a reservoir of stem and progenitor cells, able to reconstitute cells of various kinds throughout the body and therefore serving as a 'backup' for lost and damaged cells. The microvasculature, i.e. the network of small blood vessels in the BM, mediates and controls the release of stem and progenitor cells into the blood, from where they can then reach other parts of the body and initiate healing. We found that, during diabetes, areas of the bone marrow, normally serving as a depot of stem and progenitor cells, termed 'niches', disappeared together with the microvessels. This might explain the reduction in the number of therapeutically efficient progenitor cells in the blood, as was reported before. By treating diabetic mice with a vitamin, benfotiamine, we were able to halt the loss of microvessels in the BM and stabilise progenitor cell niches.

Following this progress we aimed to test the effectiveness of benfotiamine, which was already clinically used for other purposes, in patients with diabetes in order to preserve their bone marrow microvasculature and stem cell niches. Some of the cells released into the blood from the BM could promote the growth of new small blood vessels into ischaemic tissues and thus restore the blood supply. Those cells were termed circulating pro-angiogenic cells (CPC). We discovered that the recruitment of CPC from the blood into ischaemic tissues was mediated by a substance named bradykinin. CPC of mice which lacked the receptor for bradykinin were unable to reach the ischaemic tissue and promote new blood vessel growth. We also found that CPC of CVD patients migrated less towards bradykinin in comparison to healthy CPC. This might in part explain previous findings that cells in the blood of patients with CVD were less able to support the stability and regrowth of blood vessels.

We therefore isolated from the blood of CVD patients cells which were able to migrate towards bradykinin and discarded the cells which were not able to do so. We found that the migrating cells could stimulate the organisation of endothelial cells in an experimental model that mimicked the growth of new blood vessels. Cells that did not migrate were not able to support endothelial cells in this way. Although the overall number of cells capable to migrate was lower in the blood of patients suffering from acute myocardial infarction, migrating cells could still be obtained. Importantly, the therapeutic capacity of migrating cells from CVD patients was comparable to healthy cells during in vitro experiments. Consequently, we estimated that the patient's own migrating cells could in the future be used to stimulate the regrowth of small vessels after myocardial infarction.

In a third project we explored another source of autologous pro-angiogenic cells. The saphenous vein, often transplanted into the heart during bypass graft surgery, contains cells that can support the formation of new blood vessels and stabilise them. As the blood or BM of CVD patients often harbour only a low number of therapeutically useful CPC, cells from the saphenous vein could be isolated in the future to support the healing heart after the bypass surgery. This is even more relevant as usually considerable pieces of the vessel remain as a leftover after the surgery and could therefore be available without additional risk to the patient. By the time of the project completion we were investigating mechanisms of their function and aimed to develop methods to derive those cells for later clinical use in autologous cell therapy.